AIMS Volume 2

Protocols in
Neonatology
Core Protocols
Third Edition

Ramesh Agarwal
Ashok Deorari
Vinod K Paul
M Jeeva Sankar
Anu Sachdeva

CISPR Dedicated to Education

CBS Publishers & Distributors Pvt Ltd
 Contents

Contributors vii
Preface to the Third edition
Preface to the First Edition

Section 8: Metabolic, Hematological, Immunological, Genetics

and Endocrine Disorders
27. Hypocalcemia 293
28. Hypog ycemia 301
29. Polycythemia 313
30. Approach to Bleeding Neonate 322
Section 9: Genitourinary Tract
31. Acute Kidney Injury
32. Management of Antenatally Diagnosed Hydronephrosis 348
33. Posterior Urethral Valve 350
Section 10: Miscellaneous
34. Follow-up of High-risk Neonates 357
35. Retinopathy of Prematurity 380
36. Hearing Screening 395
37. Umbilical Cord Blood Banking 402
Section 11: Diagnostic Modalities and Procedures
38. Neonatal Chest X-ray 409
39. Arterial Blood Gases: Interpretation 419
40. Blood Culture and CSF Examination 427
41. Umbilical Cord Blood Sampling 434
42. Central Vascular Access 437
ххії AlIMS Protocols in Neonatology

Section 12: Therapeutic Modalities

43. Oxygen Saturation Policy in the NICU 451
44. Surfactant Replacement Therapy in Neonates 454
45. Fluid and Electrolyte Management 463
46. Continuous Positive Airway Pressure 471
47. Heated Humidified High Flow Nasal Cannula Therapy 479
48. Nasal Intermittent Positive Pressure Ventilation 483
49. Parenteral Nutrition 489
50. Peritoneal Dialysis 504
51. Blood Component Therapy 510
52. Kangaroo Mother Care 522
53. Pain Assessment and Management 531
54. Donor Human Milk 545
55. Developmentally Supportive Care 549

Annexures
1. Drug Dosages 557
2. Medication Use in G6PD Deficiency 575
3. Drug Dose Modification in Acute Kidney Injury 576
4. Immunization Schedule 579
Index i-iv
 Section

Metabolic, Hematological,
8
Immunological, Genetics and
Endocrine Disorders

27. Hypocalcemia
28. Hypoglycemia
29. Polycythemia
30. Approach to Bleeding Neonate
 CHAPTER

27
Hypocalcemia

Hears tonized caium is essential to lany biologi proceses

including coagulation, neuromuscular functioning, integrity of cell
membrane, and many cellular enzymatic reactions.

CALCIUM HOMEOSTASIS DURING THE FETAL AND NEONATAL PERIOD

Calcium (Ca) is actively transferred from mother to fetus during

the last trimester, as demonstrated by a significantly higher level of
total Ca concentration in cord blood compared to maternal serum.'
Serum Ca (SCa) in the fetus is 10 -11 mg/ dl at term that maintains a
gradient of maternal-to-fetal calcium of 1:1.4. Parathyroid hormone
(PTH) and calcitonin (CT) do not cross the placental barrier. PTH-
related peptide (PTHrP) is the primary regulator of the positive
Ca balance across the placenta. Though vitamin D is critical for
mineral ion homeostasis and bone development during adult life,
fetal mineral ion homeostasis is mostly independent of it.
After birth, the SCa levels in neonates depend on PTH secretion,
dietary calcium intake, renal calcium reabsorption, and skeletal
calcium and vitamin D status. Hence, after delivery, SCa levels
start decreasing-the rate and extent of decrease are inversely
proportional to the gestation —and reach a nadir of 7.5-8.5
mg/di in healthy term neonates by day 2 of life. This postnatal
drop in SCa may be related to decreased PTH level, end-organ
unresponsiveness to PTH, abnormalities of vitamin D metabolism,
hyperphosphatemia, hypomagnesemia, and hypercalcitonemia,
which occur by 12-24 hours of age. PTH levels increase gradually
in the first 48 hours of life, and normal levels of SCa are achieved by
the 3rd to 4th day of life.* Efficacy of the intestinal absorption and
the renal handling of Ca mature by 2-4 weeks. This transition phase
is responsible for the increased risk of early-onset hypocalcemia in
high-risk neonates.
291
292 AlIMS Protocols in Neonatology

DISTRIBUTION OF CALCIUM IN THE BODY

Body Ca exists in two major compartments: skeleton (99%) and
extracellular fluid (1%). Ca in the extracellular fluid is present
in three forms —bound to albumin (40%), bound to anions like
phosphorus, citrate, sulfate, and lactate (10%), and as free ionized
form (50%). Ionized serum calcium (iSCa) is crucial for many
biochemical processes, including blood coagulation, neuromuscular
excitability, cell membrane integrity and function, and cellular
enzymatic and secretory activity.
Measurement of the total serum Ca (tSCa) concentration alone
can be misleading because the relationship between tSCa and iSCa
is not always linear. The correlation between the two is poor when
the serum albumin concentration is low and, to a lesser degree,
with disturbances in acid-base status, which occur frequently in
premature or sick infants. With hypoalbuminemia, tSCa is low, while
iSCa is normal. Falsely low iSCa may be recorded in alkalosis and
with heparin contamination of blood samples. The tSCa falls by
about 0.8 mg/ dI (0.2 mmol/L) for every 1.0 g/ dl fall in the plasma
albumin concentration.
Therefore, the estimation of tSCa is a poor substitute for measuring the
iSCa.
DEFINITION

Hypocalcemia is defined by different tSCa and iSCa cutoffs in

preterm and term infants (Table 27.1). 6
Hypocalcemia is usually classified into two categories based
on the age of onset. Early-onset hypocalcemia presents within
the first 72-96 hours and usually requires short-term calcium
supplementation. In contrast, late-onset hypocalcemia usually
presents after 96 hours and requires long-term therapy.

Table 27.1: Definition of hypocalcemia

Gestation Total serum calcium lonic serum calcium
Preterm <7 mg/dl (1.75 mmol/L) <4 mg/dl (1 mmol/L)
Term <8 mg/dl (2 mmol/L) <4.8 mg/dl (1.2 mmol/L)
SCa is usually reported in different units viz. mg/dl, mEq/l, and mmol/l. The relationship
among these units is related to the following equations:
mmol/L = [mg/dl x 10] ÷ molecular wt; mEq/L = mmol/L × valency
Since the molecular weight of Ca is 40, and the valence is +2, 1 mg/dl is equivalent to 0.25
mmol/L and 0.5 mEq/L. Thus, values in mg/dl may be converted to molar units (mmol/L)
by dividing it by 4.
 Hypocalcemia 293
EARLY-ONSET NEONATAL HYPOCALCEMIA (ENH)
This condition is relatively common and seen within the first
3-4 days of life in the following clinical settings (Table 27.2).
There is no universal recommendation regarding routine
screening of at-risk infants for ENH. However, it may be considered
in the following categories of infants:
a. Preterm infants born before 32 weeks of gestation.
b. Infants of diabetic mothers.
c. Infants born after severe perinatal asphyxia (defined as an Apgar
score <4 at 1 minute of age)
Schedule for screening: at 24 and 48 hours of age.

Clinical Presentation
Asymptomatic: ENH is usually asymptomatic (unlike the late onset
hypocalcemia) and is incidentally detected.
Symptomatic: The symptoms may be neuromuscular irritability -
myoclonic jerks, jitteriness, exaggerated startle, and seizures. They
may represent cardiac involvement like tachycardia, heart failure,
prolonged QT interval, and decreased contractibility. More often,
they are nonspecific and unrelated to the severity of hypocalcemia.
Apnea, cyanosis, tachypnea, vomiting, and laryngospasm are other
symptoms.
Diagnosis
Laboratory: by measuring total or ionized serum calcium. Ionized
calcium is the preferred mode for the diagnosis of hypocalcemia.
ECG: QoTc >0.22 seconds or QTc >0.45 seconds
QT interval in seconds
Qlc = JR - R interval in seconds
Table 27.2: Causes of early-onset hypocalcemia
Prematurity
Preeclampsia
Infants of diabetic mother
Perinatal stress/asphyxia
Maternal intake of anticonvulsants (phenobarbitone, phenytoin sodium)
Maternal hyperparathyroidism
latrogenic (alkalosis, use of blood products, diuretics, phototherapy, lipid
infusions, etc.)
294 AlIMS Protocols in Neonatology

QT interval in seconds
Colc = JR - R interval in seconds
(QT interval is measured from the origin of the q wave to the
end of the T wave on ECG; QoT is measured from the origin of the
q wave to the origin of the T wave).
A diagnosis of hypocalcemia based only on ECG criteria is likely
to yield a high false-positive rate. Although these parameters
have a reasonable correlation with hypocalcemia in LBW infants
(sensitivity of 77% and specificity of 94.4%), 7 neonates suspected
to have hypocalcemia by ECG criteria should have the diagnosis
confirmed by measurement of serum calcium levels.

Treatment
Asymptomatic hypocalcemia: Infants detected to have hypocalcemia
on screening but are otherwise asymptomatic should receive
80 mg/kg/ day of elemental calcium (8 ml/kg/ day of 10% calcium
gluconate; 1 ml = 9.4 mg of elemental calcium) for 48 hours. This
may be tapered to a 50% dose for another 24 hours and then
discontinued. Neonates tolerating oral feeds may be treated with
oral calcium (IV preparation may be used orally).
Symptomatic hypocalcemia: These infants should receive a bolus
dose of 2 ml/kg/ dose diluted 1:1 with 5% dextrose over 10 minutes
under cardiac monitoring. When there is severe hypocalcemia with
poor cardiac function, calcium chloride 20 mg/kg may be given
through a central line over 10-30 minutes (because calcium chloride,
unlike gluconate salt, does not require metabolism by the liver for
the release of free calcium). This should be followed by continuous
IV infusion of 80 mg/kg/day elemental calcium for 48 hours.
Continuous infusion is preferred to IV bolus doses (1 ml/kg/ dose q
6 hourly). Calcium infusion should be dropped to 50% of the original
dose for the next 24 hours and then discontinued. Normal calcium
values should be documented at 48 hours (i.e. before weaning the
infusion). The infusion may be replaced with oral calcium therapy
on the last day.

Precautions and Side Effects

Bradycardia and arrhythmia are known side effects of bolus IV
calcium administration. Hence, bolus doses of calcium should be
diluted 1:1 with 5% dextrose and given slowly over 10-30 minutes
 Hypocalcemia 295

under cardiac monitoring. Continuous infusion is preferred to

IV bolus. An umbilical venous catheter (UVC) may be used to
administer calcium after ensuring that the tip is positioned in
the inferior vena cava. Hepatic necrosis may occur if the tip of
the UVC lies in a branch of the portal vein. The umbilical artery
catheter (UAC) should never be used for giving calcium injections.
Accidental injection into the umbilical artery may result in arterial
spasms and intestinal necrosis.
Skin and subcutaneous tissue necrosis may occur due to
extravasation. Hence, IV sites where calcium is infused should be
checked at least two hourly to monitor for extravasation.

Prolonged or Resistant Hypocalcemia

This condition should be considered in the following situations:
• Symptomatic hypocalcemia unresponsive to adequate doses of
calcium therapy.
• Infants needing calcium supplements beyond 72 hours of age.
• Hypocalcemia presenting at the end of the first week.
These infants should be investigated for causes of LNH (see below).

LATE ONSET NEONATAL HYPOCALCEMIA (LNH)

It usually presents at the end of the first week of life. It is usually

symptomatic in the form of neonatal tetany or seizures and is
generally caused by high phosphate intake (iatrogenic). The
common causes are listed in Table 27.3.

Examination
Neonates with LNH should have an examination with particular
emphasis on cataracts, hearing, and any evidence of basal ganglia
involvement (movement disorder) in the follow-up.

Investigations
Investigations listed in Table 27.4 should be considered in LNH or
if the hypocalcemia does not respond to adequate doses of calcium.
The workup is vital to determine the etiology.
Hypoparathyroidism should be strongly suspected if
hypocalcemia is present with hyperphosphatemia and a normal
renal function (See Table 27.5 for interpretation of diagnostic
investigation).
296 AlIMS Protocols in Neonatology

Table 27.3: Causes of late-onset hypocalcemia

1. Increased phosphate load: cow milk, renal insufficiency
2. Hypomagnesemia
3. Vitamin D deficiency
4. Maternal vitamin D deficiency
5. Malabsorption
6. Hepatobiliary disease

7. PTH resistance
8. Transient neonatal pseudo-hypoparathyroidism
9. Hypoparathyroidism
a. Primary: hypoplasia/aplasia (DiGeorge's syndrome, CATCH 22
syndrome), activating mutations of the calcium sensing receptor (CSR)
b. Secondary: maternal hyperparathyroidism, metabolic syndromes
(Kenny-Caffey syndrome, long-chain fatty acyl CoA dehydrogenase
deficiency, Kearns-Sayre syndrome.
10. Autosomal dominant hypocalcemic hypercalciuria
11. latrogenic: Citrated blood products, lipid infusion, bicarbonate therapy,
loop diuretics, glucocorticoids, phosphate therapy, aminoglycosides
(mainly gentamicin), viral gastroenteritis, phototherapy

Table 27.4: Investigations required in infants with persistent/late-onset

hypocalcemia
First line Second line
Serum phosphate Serum magnesium (Mg)
Serum alkaline phosphatase (SAP) Serum parathormone levels (PTH)
Liver function tests 25-hydroxyvitamin D levels (25-OH D)
Renal function tests (RFT) Urine calcium creatinine ratio
X-ray chest/ wrist Maternal calcium, phosphate, and
Arterial pH alkaline phosphatase

Table 27.5: Interpretation of investigations

Disorder causing hypocalcemia Findings
Hypoparathyroidism High: phosphate
Low: SAP, PTH, 25-OH D
Pseudohypoparathyroidism High: SAP, PTH, Phosphate
Low: 25-OH D
Chronic renal failure High: phosphate, SAP, PTH, deranged RFT
Low: 25-OH D, pH (acidotic)
(Contd.)
 Hypocalcemia 297

Table 27.5: Interpretation of investigations (Contd.)

Disorder causing hypocalcemia Findings
Hypomagnesemia High: PTH
Low: phosphate, Mg, 25-OH D
VDDR I High: SAP, PTH
Low: Phosphate, 25-OH D
VDDR II High: SAP, 25-OH D, PTH
Low: Phosphate
VDDR: Vitamin D dependent rickets

Treatment
The initial treatment of LNH is the same as that of ENH. This should
be followed by specific management according to the etiology and
may, in certain conditions, be life-long.
1. Hypomagnesemia: Symptomatic hypocalcemia unresponsive
to adequate doses of IV calcium therapy is usually due to
hypomagnesemia. It may present either as ENH or later as LNH.
The neonate should receive two doses of 0.2 ml / kg of 50% MgSO4
injection 12 hours apart, deep IM, followed by a maintenance dose
of 0.2 ml/kg/day of 50% MgSO4 PO for 3 days.
2. High phosphate load: These infants have hyperphosphatemia
with near-normal calcium levels. This results from feeding animal
milk with a high phosphate load (e.g. cow's milk). Exclusive
breastfeeding should be encouraged, and animal milk should be
discontinued. Phosphate-binding gels must be avoided.
3. Hypoparathyroidism: High phosphate levels in the absence of
high phosphate intake (cow's milk) and normal renal functions
suggest hypoparathyroidism.°
Supplementing calcium may lead to calcium deposition and
tissue damage if the phosphate level is high. Thus, reduction
of the phosphate load must be attempted to keep the calcium
and the phosphate product less than 55.? These neonates should
be supplemented with calcium (50 mg/kg/day in 3 divided
doses) and 1,25(OH)2 vitamin D3 (0.5-1 pg/day). Therapy
may be stopped in hypocalcemia secondary to maternal
hyperparathyroidism after 6 weeks.
4. Vitamin D deficiency states: These infants have hypocalcemia
associated with hypophosphatemia due to an intact parathormone
response in the kidneys. They benefit from 1,25(OH) vitamin D
supplementation in a dose of 30-60 ng/kg/day.
298 AlIMS Protocols in Neonatology

After starting treatment, neonates with LNH must be monitored

for SCa, phosphate, 24-hour urinary calcium, and calcium
creatinine ratio. Try to keep the calcium in the lower range, as
defective distal tubular absorption leads to hypercalciuria and
nephrocalcinosis. 10

PROGNOSIS AND OUTCOME

Most cases of ENH resolve within 48-72 hours without any
significant sequelae. LNH caused by exogenous phosphate load
and magnesium deficiency also responds well to phosphate
restriction and magnesium repletion, respectively. When caused
by hypoparathyroidism, hypocalcemia requires continued therapy
with vitamin D and calcium. The treatment period depends on
the nature of the hypoparathyroidism, which can be transient, last
several weeks to months, or be permanent.

REFERENCES
1. Schauberger CW, Pitkin RM, Maternal-perinatal calcium relationships.
ObstetGynecol 1979;53:74-6.
2. Linarelli LG, Bobik J, Bobik C. Newborn urinary cyclic AMP and developmental
responsiveness to parathyroid harmone. Pediatrics 1972;50:14-23.
3. Hillman, Rajanasathit S, slatopolsky E, haddad JC. Serial measurements
of serum calcium, magnesium, parathyroid hormone, calcitonin, and
25-hydroxy-vitamin D in premature and term infants during the first week
of life. Pediatr Res 1977;11:789-44.
4. Salle BL, Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH. Perinatal
metabolism of vitamin D. Am J Clin Nutr 2000;71(5 suppl):1317S-245.
5. Singh J, Moghal N, Pearce SH, Cheetham T. The investigation of
hypocalcaemia and rickets. Arch Dis Child. May 2003;88(5): 403-7.
6. Oden J, Bourgeois M. Neonatal endocrinology. Indian J Pediatr 2000;67:217-23.
7. Nekvasil R, Stejskal J, Tuma A. Detection of early onset neonatal
hypocalcemia in low birth weight infants by Q-Tc and Q-oTc interval
measurement. Acta Paediatr Acad Sci Hung. 1980;21(4):203-10.
8. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med
2000;343:1863-75.
9. Sharma J, Bajpai A, Kabra M et al. Hypocalcemia - Clinical, biochemical,
radiological Profile and follow-up in a Tertiary hospital in India. Indian
Pediatrics 2002;39:276-82.
10. Rigo J, Curtis MD. Disorders of Calcium, Phosphorus and Magnesium
Metabolism in Richard J Martin, Avory A Fanaroff, Michele C Walsh(eds) .
Neonatal-Perinatal Medicine- Diseases of the fetus and infant. 8th edition;
Elsevier, Philadelphia, 2006: p1508-14.
 CHAPTER|

28
Hypoglycemia

There is no universal definition for hypoglycemia. The "normal"

range of blood glucose is variable. It depends upon factors like birth
weight, gestational age, body stores, feeding status, availability of
alternative energy sources (such as ketones, lactate, and free fatty

ecies amall as the presence an absence of conditions that affect

DEFINITION
There is no concrete evidence to show the causation of adverse long-
term outcomes by a particular level or duration of hypoglycemia.
While studies have shown that persistent hyperinsulinism has a
definite association with adverse neurological outcomes, there are
no concrete data on the long-term adverse effects of asymptomatic
hypoglycemia in at-risk neonates. Hence, an "operational
threshold" has been defined by consensus. It is defined as a plasma
or whole blood glucose concentration at which clinicians should consider
intervention. A blood glucose level (BGL) of less than 40 mg/
di (plasma glucose <45 mg/dl) has been taken as the operation
threshold for intervention. The WHO defines hypoglycemia as a
BGL of less than 45 mg/ dl (2.2 mmol/L).
Blood glucose levels as low as 30 mg/ dl within 1-2 hours of birth
are common in normal newborns. The term "transitional neonatal
hypoglycemia" (TNH) has been used to describe this transient
phenomenon.? TNH occurs in up to 10% of normal newborns and
represents a normal physiological adaptation to postnatal life. The
American Academy of Pediatrics (AAP) has provided guidelines
for screening at-risk newborns and an algorithmic approach to
management if the plasma glucose is lower than 40 mg/ dl in the
first 24 hours.4
We define hypoglycemia as a blood glucose level (BGL) of less than
40 mg/dI (plasma glucose <45 mg/đl) irrespective of age of the infant.

299
300 AlIMS Protocols in Neonatology

SCREENING FOR HYPOGLYCEMIA

Screening for hypoglycemia is recommended in following high-risk
infants (Table 28.1).
In newborns considered to be at high risk of persistent
hypoglycemia disorders (e.g. genetic/ syndromic disorders
or congenital hyperinsulinism), it is advisable to screen for
hypoglycemia and also for the ability to maintain PG >70 mg/dl
if one feed is missed (i.e. ability to tolerate fasting for 6-8 hours)
before discharge. 6
Schedule for Screening
There is a paucity of literature on the optimal timing and intervals
of glucose monitoring. The lowest blood sugar values are seen
at 2 hours of life. IDMs frequently experience asymptomatic
hypoglycemia very early, viz. 1-2 hours, and rarely beyond 12 hours
(range 0.8-8.5 hours), supporting the need for early screening for
this population. However, preterm and SGA may be at high risk for
up to 36 hours of life.
Some SGA and preterm infants may develop hypoglycemia when
feeding is not established. Based on these assumptions and current

Table 28.1: Indication of routine blood glucose screening

1. Birth weight <2000 g
2. Gestational age ≤35 weeks
3. Small for gestational age infants (SGA)
4. Infant of diabetic mothers (IDM)
5. Large for gestational age (LGA) infants
6. Neonates with Rh-hemolytic disease
7. Neonates born to mothers receiving therapy with terbutaline/propranolol/
labetalol/oral hypoglycemic agents
8. Neonates with morphological features of growth restriction like three or
more loose folds of skin around buttocks and thighs, loss of subcutaneous
fat, a difference between head and chest circumference of >3 cm
9. Any sick neonate, e.g. those with perinatal asphyxia, polycythemia, sepsis,
shock, etc. during the acute phase of illness
10. Family history of a genetic form of hypoglycemia
11. Congenital syndromes (e.g. Beckwith -Wiedemann), abnormal physical
features (e.g. midline facial malformations, microphallus)
12. Neonates on total parenteral nutrition
 Hypoglycemia 301

Table 28.2: Schedule of blood glucose monitoring

Category of infants Time schedule
1. At-risk neonates (Table 28.1) 2, 6, 12, 24, 48, and 72 hours of life (72
hours for S No 3,7, and 8 in Table 28.1)
2. Sick neonates (sepsis, asphyxia, Every 6-8 hours (individualize as needed)
polycythemia, shock during
acute phase of illness)
3. Neonates on parenteral nutrition Initial 72 hours: every 6-8 hours
After 72 hours: once a day
Infants exhibiting signs compatible with hypoglycemia at any time also need to be
investigated

knowledge, Table 28.2 elaborates on the schedule and frequency of

monitoring in different situations.
Parents should be informed that their infant is at-risk for
hypoglycemia and therefore requires blood tests at regular intervals.
This will ensure appropriate parental participation in monitoring
and allay fears if further interventions are needed.
Infants in Whom Screening is Not Required
Screening for hypog ycemia is not recommended in healthy,
breastfed, term appropriate-for-gestational age (AGA) infants.
However, term infants with poor feeding, cold stress, or born to
mothers with inadequate lactation may be considered for screening.
Method of Blood Glucose Level Estimation
Point-of-care (POC) reagent strips (glucose oxidase method):
Though widely used, glucose estimation by this method is
unreliable, especially at levels in which therapeutic intervention is
required, such as BGL <40-50 mg/ dl. They are useful for screening
purposes, but low values must be confirmed by laboratory testing.
However, treatment of hypoglycemia may be initiated based on the
results of the reagent strips.
It is crucial to consider the variations between capillary and
venous, blood and plasma, and immediate and stored samples
(whole blood sugar value is about 15% less than that of plasma
value, and the BGL can fall by 14-18 mg/ dl per hour in samples
that await analysis).? Arterial samples have slightly higher values
than venous or capillary samples.
The newer generation glucose reagent strips generate a current
when glucose reacts with enzymes such as glucose oxidase or
302 AlIMS Protocols in Neonatology

glucose dehydrogenase. The amount of current is proportional to

the amount of glucose in plasma. These second-generation glucose
readers are more accurate than the previous version but still
unreliable in infants with low BGL. A novel approach to measuring
dermal glucose concentration using highly sensitive sensors
based on glucose binding protein (GBP) technology has also been
developed.°
Recently continuous glucose monitoring sensors (CGMS) have
been used in glucose monitoring in newborns.? Monitoring by CGMS
helps detect hypoglycemia that may be missed on routine screening.
However, many of these episodes may be clinically insignificant and
thus may lead to overtreatment. Also, there are practical issues in the
use of CGMS in NICU because the use of CGMS requires inserting
a probe into the subcutaneous tissue, which might increase the risk
of infection. Future studies are needed to determine the safety and
efficacy of CGMS in the neonatal population.
Laboratory diagnosis: This is the gold standard for measuring
blood glucose. Glucose can be measured by either the glucose
oxidase (calorimetric) method or the glucose electrodes (used in
blood gas machines). Blood samples should be analyzed quickly
to avoid erroneously low glucose levels. Therefore, samples must
be transported in tubes containing glycolytic inhibitors such as
fluoride.

SYMPTOMS OF HYPOGLYCEMIA

It is well known that low BGL may not manifest clinically and be
asymptomatic.' There is considerable controversy regarding the
need to treat infants with low BGLs but without any symptoms.!
A smaller proportion of infants with hypoglycemia can be
symptomatic. Symptoms of hypoglycemia include neurogenic
(autonomic) and neuroglycopenic symptoms. Neurogenic
symptoms occur due to sympathetic nervous discharge triggered
by hypoglycemia and include both adrenergic and cholinergic
responses. Neuroglycopenic symptoms result from a deficient
supply of primary fuel (glucose) to the brain. Clinical signs of
hypoglycemia are variable and may include stupor, jitteriness,
tremors, apathy, episodes of cyanosis, convulsions, intermittent
apneic spells or tachypnea, weak and high-pitched cry, lethargy,
and difficulty in feeding. Episodes of sweating, sudden pallor,
hypothermia, and cardiac arrest have also been reported in neonates.
 Hypoglycemia 303

DIAGNOSIS
• Asymptomatic hypoglycemia is said to be present when BGL is
less than 40 mg/ di (to be confirmed by laboratory estimation),
but the infant does not manifest any clinical features.
• Symptomatic hypoglycemia should be diagnosed if
hypoglycemia (BGL is <40 mg/dl) coexists with clinical
symptoms. Neonates generally manifest nonspecific signs that
result from a variety of illnesses. Therefore, careful evaluation
should be done to look for all possible causes, especially those
attributed to hypoglycemia.
If clinical signs attributable to hypoglycemia persist despite
intravenous glucose, then other causes of persistent/ resistant
hypoglycemia should be explored.

MANAGEMENT
Asymptomatic Hypoglycemia
Figure 28.1 summarizes the management of an infant with
asymptomatic hypoglycemia.
Direct breastfeeding is the best option for a trial of oral feeding. If
the infant cannot suck, expressed breast milk may be given. Breast
milk promotes ketogenesis (ketones are important alternative
sources for the brain, along with other sources such as pyruvate, free
fatty acids, glycerol, and amino acids). If breast milk is not available,
then formula feeds may be given.
Recently buccal dextrose gel has been used to prevent and treat
asymptomatic hypoglycemia. Commercially available dextrose gel
(200 mg/kg) is applied to the dried buccal mucosa, and the infant is
encouraged to feed. Blood glucose is rechecked 30 minutes after gel
administration. It has been found to reduce the number of episodes
of hypoglycemia, recurrence rates, and need for admission to NICU
and to improve exclusive breastfeeding rates at discharge in at-risk
late preterm and term neonates.12
A few randomized clinical trials in SGA 13 and large-for-gestational
agel infants found that the sugar or sucrose-fortified milk (5 g sugar
per 100 ml milk) raises blood glucose and prevents hypoglycemia.
Hematoloaical, Immunoloaical. Genetics and Endocrine Disorders

Such supplementation may be tried in asymptomatic neonates with

blood sugar levels between 20 and 40 mg/ di. However, this practice
can compromise breastfeeding rates, so one should be prudent in
exercising this option. • Metabolic.
304 AlIMS Protocols in Neonatology

Symptomatic Hypoglycemia
All symptomatic infants should be treated with IV fluids. A2 ml/kg
bolus of 10% dextrose (200 mg/kg) should be given for symptomatic
hypoglycemia (including seizures). The bolus should be followed
by continuous glucose infusion at 6-8 mg/kg/min. BGL should be
checked after 30 min and then every 6 hours until blood sugar is >50
mg/dl (Fig. 28.1). If BGL stays below 50 mg/ d1 despite bolus and
glucose infusion, glucose infusion rate (GIR) should be increased
in steps of 2 mg/kg/min every 15-30 min until a maximum of
12 mg/kg/min.
Hypoglycemia
Blood glucose <40 mg/dl

Asymptomatic Symptomatic
including seizures

Bolus of 2 ml/kg
20-40 mg/dl <20 mg/dl 10% glucose

Trial of oral feeds TV glucose infusion @ 6 mg/kg/min

Monitor hourly till euglycemic
and then 6 hourly
Monitor the blood
sugar after 1 hour

Blood sugar >50 mg/dL Blood sugar <50 mg/dl

>40 mg/dl <40 mg/dl

Stable for 24 hours on Increase glucose
IV uids; 2 values of by 2 mg/kg/min till
fl
Frequent feeds blood sugar >50 mg/dl euglycemia

Monitor blood Weaning by 2 mg/kg/min every Increase till the glucose

sugar 6 hourly 6 hours; Toral feeds; infusion rate is
Monitoring to continue 6 hourly >12 mg/kg/min
Stop after 48 hours
Stop IV uids when Refer to specialist
fl
the rate is 4 mg/kg/min center for further
Before discharge and the infant is stable investigation(s)
ensure that
there is no
feeding dif culty Stop monitoring when Hydrocortisone
fi
Diazoxide (not in SGA)
2 values are more than
50 on full oral feeds Glucagon (not in SGA)
Octreotide
Fig. 28.1: Algorithm for management of neonatal hypoglycemia
 Hypoglycemia 305

After 24 hours of IV glucose therapy, once two or more consecutive

BGLs are >50 mg/ dl, the infusion can be tapered off at 2 mg/kg/
min every 6 hours with BGL monitoring. A concomitant increase in
oral feeds must accompany tapering. Once a rate of 4 mg/kg/min
of glucose infusion and adequate oral intake is achieved, and the
BGLs are consistently above 50 mg/ di, the infusion can be stopped.
It is vital to ensure continuous glucose infusion, preferably
using an infusion pump without interruption. Do not stop glucose
infusion abruptly, as severe rebound hypoglycemia may occur.
Avoid using more than 12.5% dextrose infusion through a peripheral
vein due to the risk of thrombophlebitis.
Practical tip
If there is persistent hypoglycemia, check the intravenous line for patency. Also,
recheck the intravenous fluid preparation and infusion rate.

Recurrent/resistant Hypoglycemia
This condition should be considered when the infant fails to maintain
normal BGL despite a GIR of 12 mg/kg/ min or when stabilization
is not achieved by 7 days of therapy. High levels of glucose
infusion may be needed in these infants to achieve euglycemia.
Hyperinsulinism must be excluded because it is the most common
cause of persistent hypoglycemia. Hyperinsulinemic hypoglycemia
can be congenital (due to mutations affecting the regulation of
insulin secretion from the pancreas) or acquired (neonates with
maternal diabetes, birth asphyxia, polycythemia, Rh incompatibility,
and severe intrauterine growth restriction, Beckwith-Wiedemann
syndrome, etc.). Diagnosis of hyperinsulinism is based on critical
sample assay, and the criteria are given below in Table 28.3.
Typical critical sample assay should include (i) glucose, (ii) insulin,
(iii) cortisol, and (iv) beta-hydroxybutyrate and free fatty acids.
Other important causes of resistant hypoglycemia are listed in
Table 28.4.
Besides increasing GIR, a few drugs may also be tried for resistant
hypoglycemia. Before administration of drugs, take the samples to
investigate the cause (Table 28.5).
The drugs that are used are listed in Table 28.6.
Do not use diazoxide or glucagon in small-for-gestational age infants.
Other management options in resistant hypoglycemia are:

Mike sinlim ta, ere of apan sually given oraliton • Metabolic. Hematoloaical. Immunoloaical. Genetics and Endocrine Disorders
 Hypoglycemia 307

Table 28.5: Investigations to be done in resistant hypoglycemia*

Blood Urine
• Serum insulin levels, C-peptide, IGFBP3, thyroid • Urine ketones
hormones • Urine reducing
• Serum cortisol levels substances
• Growth hormone levels • Urine GCMS
Serum ammonia
• Serum lactate levels, free fatty acids, blood BOHB
Galactose 1 phosphate uridyl transferase levels
• Tandem Mass spectroscopy (TMS)
Genetic testing for mutations like SUR1 and KiR6.?
Samples should be taken at the time of hypoglycemia

Table 28.6: Treatment options in resistant hypoglycemia

Drug Dose Route Mode of action Side effects
Hydrocortisone 10 mg/kg/PO/IV Reduces Hyperglycemia,
day BD peripheral hypertension
glucose
utilization
Increases
gluconeogenesis
Increases
glucagon effect
Diazoxide* 5-15 mg/ PO K channel Fluid retention,
kg/day agonist hypertrichosis,
TDS cardiac failure
Octreotide 5-35 mcg/ S/C Somatostatin Cholelithiasis,
kg/day analogue transient
TDS/QID inhibits insulin growth
secretion impairment,
tachyphylaxis
Glucagon* 0.2 mg/kg S/Cor IM Glycogenolysis,Nausea,
increased vomiting, skin
gluconeogenesis rash, rebound
hypoglycemia
*Do not use diazoxide or glucagon in small-for-gestational age infants.

Some of the practically helpful formulae in the management of

hypoglycemia are given in Table 28.7. The concentration of 10%
308 AlIMS Protocols in Neonatology

Table 28.7: Useful formulae

body weight
1. GIR mg/kg/min)=% of dextrose (in kg) xx6rate (ml/hour(6(D
being infused x weight)
x rate)

144× % of dextrose
2. Infusion rate (mg/kg/min) = V rate (mL/kg/day)
3. Infusion rate (mg/kg/min) = Fluid rate (ml/kg/day) × 0.007 x % of dextrose
infused

Table 28.8: Achieving appropriate glucose infusion rate at different daily

uid intakes
fl
Daily uid volume Glucose infusion rate (GIR)
fl
(ml/kg/day) 6 mg/kg/min 8 mg/kg/min 10 mg/kg/min
D10 D25 D10 D25 D10 D25
60 42 18 24 36 5 55
75 68 7 49 26 30 45
90 90 - 74 16 55 35
105 85* - 99 6 80 25
120 100* 120 97 18
*Add 20 ml/kg of normal saline to provide 3 mEq/kg of sodium.

dextrose and 25% dextrose to achieve appropriate glucose infusion

rate (GIR) at different daily fluid intakes are given in Table 28.8.

FOLLOW-UP AND OUTCOME

The outcome of neonatal hypoglycemia is determined by factors
like duration, degree of hypoglycemia, rates of cerebral blood flow
and cerebral utilization of glucose, and comorbidities. Particular
attention should be paid to the neurodevelopmental outcome,
overall IQ, reading ability, arithmetic proficiency, and motor
performance. The infants must be assessed at one month corrected
age for vision. At 3, 6, 9, 12, and 18 months of corrected age, they
need to be followed up for growth, neurodevelopment, vision, and
hearing loss. Vision can be assessed with the Teller acuity cards,
while hearing is assessed by brainstem-evoked auditory responses.
Neurodevelopment must be evaluated by the clinical psychologist
using DASII/similar scales. MRI at 4-6 weeks provides a good
estimate of hypoglycemic injury and should be considered in the
follow-up of such infants.18
 Hypoglycemia 309

Hypoglycemia and neurodevelopment outcome—what is the evidence?

• A systemic review involving 18 studies concluded that there is no good
correlation between hypoglycemia and neurodevelopment outcome, and
further well-designed, high-quality studies are needed. '9
• Patterns of cerebral injury and neurodevelopmental outcomes were studied
in 35 neonates with symptomatic hypoglycemia without evidence of HIE,
and it was seen that 94% had white matter abnormalities; on follow-up at
18 months of age, 65% had impairment in development.20
• The recently published 'Children with Hypoglycemia and their Later
Development (CHYLD) study that prospectively evaluated the long-term
effects of neonatal hypoglycemia in 477 at-risk late preterm and term
neonates reported that hypoglycemia was not associated with increased
risk of combined neurosensory impairment at 4.5 years but was associated
with a dose-dependent increased risk of poor executive function and visual
motor function; severe, recurrent and undetected episodes of hypoglycemia
increased this risk.21

REFERENCES

1. Adamkin DH, Polin R. Neonatal hypoglycemia: is 60 the new 40? The

questions remain the same. J Perinatol. 2016;36:10-2.
2. Adamkin DH. Neonatal hypoglycemia. Semin Fetal Neonatal Med.
2017;22:36-41.
3. Stanley CA, Rozance PJ, Thornton PS, De Leon DD, Harris D, Haymond
MW, et al. Re-Evaluating "Transitional Neonatal Hypoglycemia": Mechanism
and Implications for Management. J Pediatr. 2015;166:1520-5.el.
4. Committee on Fetus and Newborn. Postnatal Glucose Homeostasis in Late-
Preterm and Term Infants. PEDIATRICS. 2011;127:575-9.
5. Kalhan S, Parimi P. Gluconeogenesis in the fetus and neonate. Semin
Perinatol. 2000;24:94-106.
6. Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K,
et al. Recommendations from the Pediatric Endocrine Society for Evaluation
and Management of Persistent Hypoglycemia in Neonates, Infants, and
Children. J Pediatr. 2015;167:238-45.
7. Cowett RM, Damico LB. Capillary (heel stick) versus venous blood sampling
for determination of glucose concentration in neonate. Biol Neonate. 1992.
62-6.
8. Woo HC, Tolosa L, El-Metwally D, Viscardi RM. Glucose monitoring in
neonates: need for accurate and non-invasive methods. Arch Dis Child Fetal
Neonatal Ed. 2014;99:F153-7.
9. Rozance PJ, Hay WW Jr. New approaches to management of neonatal
hypoglycemia. Matern Health Neonatol Perinatol. 2016 May 10;2:3.
10. Lucas A, Morley R. Outcome of neonatal hypoglycemia. Br Med J.
1999;318:194.
310 AlIMS Protocols in Neonatology

11. Filan PM, Inder TE, Cameron F), et at. Neonatal hypoglycemia and occipital
cerebral injury. J Pediatr. 2006;552-5.
12. Edwards T, Liu G, Battin M, Harris DL, Hegarty JE, Weston PJ, Harding JE.
Oral dextrose gel for the treatment of hypoglycaemia in newborn infants.
Cochrane Database Syst Rev. 2022 Mar 18;3:CD011027.
13. Singhal PK, Singh M, Paul VK. Prevention of hypoglycemia: A controlled
evaluation of sugar fortified milk feeding in small- for- date infants. Indian
Pediatr. 1992;29(11):1365-9.
14. Singhal PK, Singh M, Paul VK. A controlled study of sugar fortified milk
feeding in prevention of neonatal hypoglycemia. Indian J Med Res.
1991;94:342-5.
15. Thompson-Branch A, Havranek T. Neonatal Hypoglycemia. Pediatr Rev.
2017 Apr;38(4):147-57.
16. Güemes M, Hussain K. Hyperinsulinemic Hypoglycemia. Pediatr Clin North
Am. 2015;62:1017-36.
17. Eichenwald EC, Hansen AR, Martin C, Stark AR, editors. Cloherty and Stark's
manual of neonatal care. Eighth edition. Philadelphia: Wolters Kluwer; 2017.
18. Duvanel CB, Fawer CL, Cotting J. Long term effects of neonatal hypoglycemia
on brain growth and psychomotor development in small-for-gestational age
preterm infants. J Pediatr. 1999;134(4):492-8.
19. Boluyt N, Kempen A van, Offringa M. Neurodevelopment After Neonatal
Hypoglycemia: A Systematic Review and Design of an Optimal Future Study.
Pediatrics. 2006 Jun 1;117(6):2231-43.
20. Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral
injury and neurodevelopmental outcomes after symptomatic neonatal
hypoglycemia. Pediatrics. 2008;122:65-74.
21. McKinlay CJD, Alsweiler JM, Anstice NS, Burakevych N, Chakraborty A,
Chase JG, et al. Association of Neonatal Glycemia With Neurodevelopmental
Outcomes at 4.5 Years. JAMA Pediatrics. 2017;171:972.
 CHAPTER|

29
Polycythemia

Polycythemia-increased hematocrit-is associated with

hyperviscosity of blood. As the blood viscosity increases, there is
an impairment of tissue oxygenation and perfusion and a tendency
to form microthrombi. Significant damage may occur if these events
occur in the cerebral cortex, kidneys, and adrenal glands. Hence,
polycythemia requires urgent diagnosis and prompt management.
The viscosity of blood is directly proportional to hematocrit and
plasma viscosity and inversely proportional to the deformability of
red blood cells. Symptoms of hypoperfusion correlate better with
viscosity as compared to hematocrit. Viscosity is, however, difficult
to measure at the bedside. Hyperviscosity is therefore suspected
in the presence of an abnormally high hematocrit with or without
suggestive symptoms.
The relationship between viscosity and hematocrit is almost
linear, up to a hematocrit of 65% and exponential thereafter. 1,2 The
polycythemia-hyperviscosity syndrome is thus usually confined
to infants with hematocrits of more than 65%; it is very rare with
hematocrits of <60%.

DEFINITION
Polycythemia is diagnosed in the presence of a venous hematocrit
of more than 65% or a venous hemoglobin concentration of more
than 22 g/ di. Hyperviscosity is defined as a viscosity greater than
14.6 centipoise at a shear rate of 11.5 per second.?

INCIDENCE
The incidence of polycythemia varies from 1.5 to 4% of all live
births.4,5 The incidence was 0.7% of live births in the last 7 years
in our unit. Incidence is higher in small-for-gestational age (SGA)
and large-for-gestational age (LGA) infants. About 15% of term
311
312 AlIMS Protocols in Neonatology

SGA infants develop polycythemia compared to 2% of term AGA

infants.
Neonates born at high altitudes also have a higher incidence of
polycythemia.' Maternal smoking is an important risk factor for
polycythemia.? Term neonates born to mothers engaged in smoking
during pregnancy are 2.5 times more likely to require a partial
exchange transfusion for polycythemia than the counterparts of
non-smoker mothers.? Infants born by cesarean section have lower
hematocrit values than those delivered vaginally.' Infants subjected
to delayed cord clamping also carry a higher risk of asymptomatic
polycy themia?

PHYSIOLOGICAL CHANGES IN POSTNATAL LIFE

Significant changes occur in the hematocrit from birth through the

first 24-48 hours of life. The hematocrit peaks at around 2 hours of
age, and values up to 71% may be normal at this age. 10-" It gradually
declines to 68% by 6 hours and usually stabilizes by 12-24 hours.
The initial rise in hematocrit is related to a transudation of fluid out
of the intravascular space.

ETIOLOGY OF POLYCYTHEMIA (TABLE 29.1)12

Table 29.1: Risk factors of polycythemia

Increased erythropoiesis Secondary to transfusions
1. Intrauterine hypoxia 1. Delayed cord clamping
a. Placental insufficiency • Intentional
b. Small-for-gestational-age infant • Unassisted delivery
c. Post-maturity 2. Maternal-to-fetal transfusion
d. Gestational hypertension 3. Twin-twin transfusion
e. Drugs (e.g. propranolol)
f. Severe maternal heart disease
g. Maternal smoking
2. Maternal diabetes
3. Neonatal hyperthyroidism or
hypothyroidism
4. Congenital adrenal hyperplasia
5. Chromosome abnormalities
a. Trisomy 13
b. Trisomy 18
c. Trisomy 21 (Down syndrome)
6. Beckwith-Wiedemann syndrome
 Polycythemia 313
CLINICAL FEATURES

Polycythemia can result in a wide range of symptoms involving

several organ systems (Table 29.2). About 50% of neonates with
polycythemia develop one or more symptoms. However, most
of these symptoms are nonspecific, and may be related to the
underlying conditions rather than due to polycythemia per se.

SCREENING FOR POLYCYTHEMIA

Screening for polycythemia should be done in certain high-risk
groups (Table 29.3).
Table 29.2: Clinical features ascribed to polycythemia and hyperviscosity
Central nervous system
Early: Hypotonia and sleepiness, irritability, jitteriness, seizures and infarcts.
Late: motor deficits, lower achievement and IQ scores.
Metabolism
Hypoglycemia
Jaundice
Hypocalcemia
Heart and lungs
Tachycardia, tachypnea, respiratory distress
Cyanosis, plethora
Chest X-ray: cardiomegaly, pulmonary plethora
Echocardiography: increased pulmonary resistance, decreased cardiac output
Gastrointestinal tract
Poor suck, vomiting
Feed intolerance abdominal distension
Necrotizing enterocolitis
Kidneys
Oliguria
Transient hypertension
Renal vein thrombosis
Hematology
Mild thrombocytopenia
Thrombosis (rare)
Miscellaneous
Peripheral gangrene
Priapism
Testicular infarction
314 AlIMS Protocols in Neonatology

Table 29.3: Screening for polycythemia

Eligible candidates
a. Small-for-gestational age (SGA)
b. Infants of diabetic mothers (IDM)
c. Large-for-gestational age (LGA)
d. Mono-chorionic twins, especially the larger twin.
e. Infants with morphological features of intrauterine growth restriction
such as three or more loose folds of skin around the buttock and thighs,
loss of subcutaneous fat, a difference of head circumference and chest
circumference of >3 cm.
Schedule
2 hours of life; if high, repeat at 6, 12, 24, and 48 hours
Method
Centrifuge venous blood in heparinized capillaries for 3-5 min @ 10000 to
15000 гр.

Any infant with clinical features suggestive of polycythemia should be

investigated for the same.
Blood samples for hematocrit can be obtained by either heel-
prick (capillary hematocrit) or venipuncture (venous hematocrit).
Capillary hematocrit measurements are, however, unreliable and
highly subject to variations in blood flow. They are significantly
higher than venous hematocrits. This difference is even more
apparent in infants receiving a large placental transfusion. 13
Practice tip
Capillary samples may be used for screening, but all high values should be
confirmed by a venous sample for the diagnosis of polycythemia.

METHODS OF HEMATOCRIT DETERMINATION

Two methods are available:
1. Automated hematology analyzer: This calculates the hematocrit
from a direct measurement of mean cell volume and hemoglobin.
2. Microcentrifuge: Blood is collected in heparinized micro-
capillaries (110 mm length and 1-2 mm internal diameter) and
centrifuged at 10,000-15,000 rotations per minute (rpm) for
3-5 minutes. Plasma separates and the packed cell volume is
measured to give the hematocrit.

hemationated and yere es lugar values od. Mosted te

reported data on polycythemia is on centrifuged hematocrits.
 Polycythemia 315

MANAGEMENT
Before the diagnosis of polycythemia is considered, it is mandatory
to exclude dehydration. If the birth weight is known, reweighing
the baby and looking for excessive weight loss (>10-15%) would
help diagnose dehydration. Dehydration, if present, should be
corrected by increasing fluid /feed intake. The hematocrit should
be measured again after the correction of dehydration. Once a
diagnosis of polycythemia is made, associated metabolic problems,
including hypoglycemia, should be excluded.
Management of polycythemia is dependent upon two factors
(Fig. 29.1):
1. Presence of symptoms suggestive of polycythemia and
2. Absolute value of hematocrit.

a. Symptomatic Polycythemia

exchange transtein PED. PET involves removing some porthe

blood volume and replacing it with normal saline to decrease the
hematocrit to a target hematocrit of 55%. Following PET, symptoms
like jitteriness may persist for 1-2 days despite lowering the
hematocrit to physiological ranges.
The volume of blood to be exchanged is given by the formula in
Table 29.4.

Venous hematocrit: 65% or more

Exclude dehydration
(Check weight loss)

Symptomatic Asymptomatic

Hematocrit: Hematocrit: Hematocrit:

75% or more 70-74% 65-69%

Partial exchange Consider Monitor for

transfusion (PET) hydration symptoms
Fig. 29.1: Management algorithm of polycythemia
316 AlIMS Protocols in Neonatology

Table 29.4: Volume to be exchanged in PET

Volume to be exchanged

= Blood volume* × (observed hematocrit - desired hematocrit)

Observed hematocrit
For example, for a 35 weeks gestation newborn weighing 2 kg (assumed blood
volume 90 ml/kg) and observed hematocrit of 75% and desired hematocrit of
55%, the amount of blood to be exchanged would be:
= 2x90 x 75-55
75
= 48 ml of blood to be exchanged with normal saline to bring
hematocrit from 75-55%
Rule of thumb: Volume of blood to be exchanged is usually 20 ml/kg
* Refer Rawlings chart'5 for estimating the blood volume; as a rough guide, it is 80-90 ml/kg
in term babies and 90-100 ml/kg in preterm babies.

PET: peripheral vs. umbilical route: PET may be carried out via the
peripheral or the central route. In the former, blood is withdrawn from
the peripheral arterial line and replaced with saline simultaneously
via a peripheral venous line. In the central route, blood is withdrawn
from the umbilical venous catheter, while saline is replaced by a
peripheral vein. Alternatively, the umbilical venous catheter may be
used in the central route to withdraw blood and replace saline (pull-
and-push technique similar to double volume exchange transfusion
for severe jaundice), or the blood is withdrawn from the umbilical
arterial line and saline replaced from the umbilical venous line.
One prospective study found increased infection rates without
increased risk of NEC following partial exchange using the umbilical
vein. 16 Though there is no concrete evidence against using the
umbilical vein for partial exchange, the peripheral venous route
seems to be a safer option.
PET: choice of exchange fluid: Crystalloids such as normal saline
(NS) are preferred over colloids because they are less expensive
and are easily available. Crystalloids produce a nearly comparable
reduction in hematocrit as colloids'7,18 and do not have the risk of
transfusion-associated infections. Moreover, adult plasma has been
shown to increase blood viscosity when mixed with fetal erythrocytes.
Evidence: Choice of exchange fluid for PET
A systematic review determined efficacy of crystalloid versus colloid solutions
to identify the best fluid for PET: 17
(Contd.)
 Polycythemia 317
(Contd.)
Evidence: Choice of exchange uid for PET

fl
• Clinically unimportant difference in hematocrit favoring colloids than
crystalloids:
- at 2-6 hours: 2.3% (95% Cl 1.3-3.3%)
- at 24 hours: 1.7% (95% CI 0.8-2.7%)
• This difference was more significant when NS was compared to plasma but
absent when compared with 5% albumin.
• No side effects of using colloids were found.
We use only normal saline for partial exchange transfusion.
b. Asymptomatic Polycythemia
The line of management in infants with asymptomatic polycythemia
depends upon their hematocrit values.
i. Hematocrit 75% or more: These infants are usually managed
with PET.
ii. Hematocrit between 70 and 74%: Conservative management
with hydration is tried in these infants. An extra fluid/ feeds
of 20 ml/kg may be added to the daily fluid requirements.
The additional fluid may be ensured by either enteral
(supervised feeding) or parenteral route (IV fluids). Rationale
for this therapy is that additional fluids result in hemodilution
thereby reducing the blood viscosity.
ili. Hematocrit between 65 and 69%: These infants only need
monitoring for symptoms of polycythemia and reestimation
of hematocrit. Further management depends upon the
repeat hematocrit values. The RCT on fluid supplementation
(20-25 ml/kg over 6-8 hours) vs. no fluid supplementation
in 55 late preterm and term neonates with asymptomatic
polycythemia (hematocrit: 65-70%) found no significant
difference in the need for partial exchange transfusion
between the two groups.19
Evidence for Management of Polycythemia
Evidence: Partial exchange transfusion for polycythemia
A Cochrane review 2010)20 on this issue showed:
• No effect on neonatal mortality (one study; RR 5.23; 95% Cl 0.66 41.3).
• No difference in developmental delay (4 low quality studies; RR 1.45, 95%
Cl 0.83-2.54).
• Increased risk of NEC in infants receiving PET (2 studies; RR 11.18, 95%
Cl 1.49, 83.64).
• No differences in short-term complications including hypoglycemia (two
studies) and thrombocytopenia (one study). • Metabolic. Hematoloaical, Immunoloaical, Genetics and Endocrine Disorders
 318 AlMS Protocols in Neonatology

PET reverses the physiological abnormalities associated with

polycythemia-hyperviscocity syndrome. It improves capillary
perfusion, cerebral blood ow, and cardiac function. However, there

fl
is little data to suggest that PET improves long-term outcomes in
patients with polycythemia. The Cochrane review (2010) concluded
that there are no proven clinically significant short or long-term
benefits of PET in polycythemic infants who are clinically well or
who have minor symptoms related to hyperviscosity. Also, PET
may increase the risk of NEC. 20
However, the studies included in the review were of low quality;
also, most surviving infants were not assessed for developmental
outcomes, and therefore, the true risks and benefits of PET are
unclear. The study by Iris et al. showed that restrictive management
of polycythemia does not increase short-term complications.21
Giten the uncertainty regarding the long-term outcomes, it is preferable
to restrict PET in symptomatic infants with a hematocrit of >65% and in
asymptomatic neonates with a hematocrit of >75%.

REFERENCES
1. Mackintosh TF, Walkar CH. Blood viscosity in the newborn. Arch Dis Child
1973;48:547-53.
?. Pribbs RH. Neonatal Polveythemia. In: Rudolph ABled): Pediatrics, 16* ec
New York: Appleton Century Crotts, 1997, pp 179.
3. Ramamurthy RS. Brans WY. Neonatal Polycythemia I. Criteria tor dragnose
and treatment. Pediatrics 1981:68: 168-74.
4. Wirth FH, Coldberg KE, Lubchenco LO: Neonatal hyperviscucity !
incidence. Pediatrics 1979;63:833-6.
5. Stevens K, Wirth FH. Incidence of neonatal hyperviscosity at sea levei
Pediatrics 1980:97:118.
6 Bada HS, Korones SB, Pourcyrous M, et al. Asymptomatic syndrome co
polve therac to pen iscocity: effect of partial exchange transfusion. J Peckatr
1992:120.379-85
7. Amorason FO. Pauly TH. Hutchison A4. Maternal smoking andi pursan
exchange ransuson for secratal polycythemia. Am / Perinatol 2002.14

349-34.
§. Labetzes R. Ben-Shachar 5. Mimouni FB. et al. Mode of deliven and neonvas
cematocrit. Am | Pericatol 2000:17:163-5.

9. Huhan Ex. Hasan ES. Late us early clamping ol the umbilical curd in tuls-
fero soundle sustemate review and meta-analysis et controlled mazis

АМА 207:297:1241-52
19 Sochat M. Meriob P. Resper S21. Neonatal Polverthema. I. Earis diagraun
zed nudesce abiding to trse of sampling. Pedatrics 1484,3.7-10.
50c hon 6
 Polycythemia 319

11. Shohat M, Reisner SH, Mimouni F, et al. Neonatal polycythemia II. De nition

fi
related to time of sampling. Pediatrics 1984;73:11-3.
12. Oski FA, Naiman IL: Hematologic problems in the newborn, ed 3,
Philadelphia, 1982, WB Saunders.
13. Oh W. Neonatal polycythemia and hyperviscosity. Pediatr Clin North Am
1986;33:523-32.
14. Goldberg K, Wirth FH, Hathaway WE, et al. Neonatal hyperviscocity II.
Effect of partial exchange transfusion. Pediatrics 1982;69:419-25.
15. Rawlings JS, Pettett G, Wiswell TE, et al. Estimated blood volumes in
polycythemic neonates as a function of birth weight. J Pediatr 1982;101: 594-9.
16. Rodriguez-Balderrama 1, Rodriguez-Juarez DA, Cisneros-Garcia N, et al.
Comparison of 2 methods of partial exchange transfusion in newborns with
polycythemia: peripheral-peripheral and central-peripheral]. Bol Med Hosp
Infant Mex 1993;50:633-8.
17. de Waal KA, Baerts W, Ofiringa M. Systematic review of the optimal fluid
for dilutional exchange transfusion in neonatal polycythaemia. Arch Dis
Child Fetal Neonatal Ed 2006;91:F7-10.
18. Deorari AK, Paul VK, Shreshta L, Singh M. Symptomatic neonatal
polycythemia: Comparison of partial exchange transfusion with saline versus
plasma. Indian Pediatr 1995; 32:1167-71.
19. Sundaram M1, Dutta S, Narang A. Fluid Supplementation versus No Fluid
Supplementation in Late Preterm and Term Neonates with Asymptomatic
Polycythemia.Indian Pediatr. 2016 Nov 15;53(11):983-6.
20. Ozek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent
neurodevelopmental disability in infants with polycythemia. Cochrane
Database Syst Rev 2010 Jan 20;(1):CD005089.
21. Morag 1, Strauss T, Lubin D, Schushan-Eisen 1, Kenet G, Kuint J. Restrictive
management of neonatal Polycythemia. Am J Perinatol 2011;28:677-82.

etabolic, Hematological, Immunological, Genetics and Endocrine Disorders

 30
Approach to Bleeding Neonate

Compared to older children and adults, neonates have quantitative

and qualitative differences in components of the hemostatic
system: the platelets tend to be hyporeactive, levels of coagulation
factors (vitamin K dependent factors II, VII, IX, X) are decreased,
and contact factors (XI, XII) are reduced to about 50% of typical
adult values, translating to prolonged prothrombin time (PT)
and activated partial thromboplastin time (aPTT). However, the
increased bleeding risk is counteracted by factors that promote
hemostasis (high levels of vWF, elevated hematocrit, and reduced
levels of natural anticoagulants). The overall hemostatic system in
healthy neonates is thus well-balanced; however, systemic diseases
can tilt this balance and result in bleeding.!

ETIOLOGY OF BLEEDING

Bleeding can be due to a defect in any of the steps in the hemostatic

pathway (Fig. 30.1.23

CLINICAL FEATURES

Neonate with bleeding diathesis can present with significant

bleeding (intraventricular hemorrhage, pulmonary hemorrhage.
lower gastrointestinal hemorrhage) or minor bleeding events
(petechiae, mucosal bleeds, cephalhematoma, blood-tinged
endotracheal tube secretions in mechanically ventilated infants.
and oozing from the umbilical stump or sites of blood draws, etc.)
Platelet disorders usually present with petechiae, small mucosal
bleeds, and ecchymosis. Immune thrombocytopenia, particularly
NAIT, can have a varied presentation ranging from mild to moderate
bleeding resolving within a week to severe intracranial hemorrhage
(ICH) leading to death or neurodevelopmental sequelae. Untreated
cases can present with ICH in 10-20% of patients and sequelae in
20% of survivors.

320
 Approach to Bieeding Neorate 321

Bleeding neonate

Defects Defects in Combined Vessel wall

in platelets coagulation defects defects

Drugs DIC Hemangioma

Quantitative Qualitative (indomethacin. ECMO Vascular
defect defect (rare) antihistaminic) Hepatic malformation
Bernard-Soulier dysfunction Trauma
syndrome (sepsis,
Glanzmann shock)
Early onset Late onset thrombasthenia
(<72 hours) (>72 hours)

Perinatal Late-onset Inherited defectsAcquired

asphyxia sepsis Hemophilia defects
Perinatal/ NÉC VWD VKDB
IU infection IU infection Dys brinogenemia Drugs
fi
Autoimmune Amegakaryocytic (transplacental
(ITP, SLE. thrombocytopenia exposure-
HIV) (TAR, FA) phenytoin.
Alloimmune warfarin,
(NAIT) salicylates)
IUGR Liver disease
DIC
Fig. 30.1: Algorithmic approach to etiology of bleeding
DIC: Disseminated intravascular coagulation; NAIT: Neonatal alloimmune thrombocy-
topenia; NEC: Necrotizing enterocolitis; ITP: Immune thrombocytopenia; SLE: Systemic
lupus erythematosus; VKDB: Vitamin K de ciency bleeding; ECMO: Extracorporeal
fi
membrane oxygenation; SDH: Subdural hemorrhage; TAR: Thrombocytopenia absent radii;
IU: Intrauterine; IUCR: Intrauterine growth retardation; HIV: Human immunode ciency
fi
virus; FA: Fanconi anemia; WD: von Willebrand disease

Coagulation disorders are often acquired, though inherited

coagulation disorders like hemophilia A, B, and vWD can
manifest in the neonatal period. Hemophilia in the neonatal
period presents with iatrogenic bleeding (oozing/ hematoma
following venipuncture, IM injections) or spontaneous hemorrhage
(intracranial/extracranial hemorrhage). Rarely, severe deficiencies
of fibrinogen and factors VII, X, and XIII present in the neonatal
period with soft tissue bleeds and umbilical stump bleeding (80%
cases of factor XIII deficiency).
Fresh bleeding from the GI tract in an otherwise well neonate
may be fetal or maternal in origin. The alkali denaturation test,
commonly known as the Apt-Downey test or Apt test, may be done
to differentiate fetal from maternal blood (Table 30.1). • Metabolic, Hematological, Immunological, Genetics and Endocrine Disorders
322 AlIMS Protocols in Neonatology

Table 30.1: Steps of APT test

1. Mix one part of the bloody stool or vomitus with five parts of sterile water
2. Centrifuge it for 2 minutes and separate the clear pink supernatant
(hemolysate).
3. Add 1 ml of 0.25 N (1%) sodium hydroxide to 4 ml of hemolysate.
4. Hemoglobin A (HbA) changes from pink to yellow-brown (maternal blood,
while hemoglobin F (HbF) stays pink (fetal blood).

INVESTIGATIONS

Any neonate with a bleeding disorder should undergo baseline

investigations, including complete blood count (CBC) with platelet
count (PC), PT, and aPTT (Table 30.2). Further workup is decided
based on history, clinical presentation, and results of baseline
investigations. Viscoelastic tests such as thromboelastography /
rotational thromboelastometry (TEG/ROTEM) are being
evaluated in neonates as they rapidly assess whole blood
hemostasis using small volumes of blood.* Test results should
always be interpreted based on age and analyzer- and reagent-
specific reference values.

Table 30.2: Investigations in a neonate with suspected bleeding disorder

Level 1 Blood count
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Fibrinogen/D-dimer (in sick neonates)
Level 2 Peripheral smear (differential diagnosis of thrombocytopenia)
Human platelet antigen analysis (suspect NAIT)
Single clotting factor assay depending on PT/aPTT constellation
Mixing study (useful in presence of factor inhibitors)
Level 3 Platelet function analysis (Platelet aggregometry)

Practical tips
• Lise venous blood samples for diagnosing coagulation disorders: avoid
capillary samples.
• Use 3.2% trisodium citrate (light blue capped tubes) as the anticoagulation
agent for taking samples; avoid the heparinized source.
• Underrilling 1<90% and overfilling (>110%) of collection tube result in
prolongation/ shortening of clotting time, respectively.
• The sample should be capped and transported at room temperature within
1 hour; avoid refrigeration or transportation in ice.
 Approach: to Bleeding Neorate
323
• Platelet count: Platelet count <150 × 10°/I. denotes
thrombocytopenia. The mean platelet count is 2200 x 100/L
in most preterm infants, but the 5th centile may be as low as
104 x 10º/L for those ≤32 weeks gestation and 123 ≤10°/L. for
late preterm and term neonates. Nevertheless, a platelet count
of <100 x 100/L. warrants evaluation.

When to suspect NAIT in neonatal thrombocytopenia?

Diagnosis: All criteria necessary
• Fetal or neonatal thrombocytopenia.
• Identification of a paternal, fetal, or neonatal platelet antigen that the mother
lacks.
• Identification of maternal antibodies to that antigen.
Human platelet antigen (HPA) analysis" is useful in suspected NAIT wherein
the presence of antiplatelet antibodies directed against HPA (most commonly
HPA 1a (80%), HPA 5b (10-15%)| is tested. If negative for common antigens,
cross-react the mother's sera with the father's platelets for rare HPA antigens.
'Human platelet antigen genotyping done at the National Institute of Immunohematology,
Mumbai.

• Peripheral smear: Useful in the differential diagnosis of

thrombocytopenia. 1 platelet/ oil immersion field in a peripheral
smear corresponds to a count of 10000-15000/mm. Look
for platelet size (giant platelets indicate hyper utilization) or
fragmented RBCs (>10% of schistocytes suggest DIC) in the
peripheral smear.
• Coagulation pathway: Tests assessing the coagulation pathway
should begin with PT and aPTT (Table 30.3). Subsequent tests
are ordered based on clinical presentation. Vitamin K deficiency
bleeding (VKDB) is characterized by prolonged PT and aPTT (the
latter may be normal in early vitamin K deficiency). Mild vitamin
K deficiency is characterized by elevated 'Proteins induced by
vitamin K absence' (PIVKA) levels. Factor XII deficiency is a
distinct entity that causes isolated aPTT prolongation with no
clinical bleeding. Reference ranges for coagulation tests are
available for term and preterm neonates (Table 30.4).
• Fibrinogen levels: Decreased in sepsis, hypoxia, liver disease,
and consumptive states.
• D-dimer assay: Increased in sepsis, DIC, liver disease, and
thromboembolism.
An algorithmic approach to a bleeding neonate is given in
Fig. 30.2. • Metabolic, Hematological, Immunological, Genetics and Endocrine Disorders
 AlIMS Protocols in Neonatology
324

Table 30.3: Interpretation of coagulation tests

Prolonged PT (Assesses Prolonged aPTT Prolonged PT and aPTT

factors V, VII, X, and (Assesses factors
fibrinogen) VIII, IX, XI, V, and X)

Factor VII de ciency Factor de ciency Disseminated intravascular

fi
fi
Vitamin K de ciency (VIII, IX, XI) coagulation (DIC)
fi
(mild) Severe VWD Liver disease
Warfarin therapy Dys brinogenemia Vitamin K de ciency

fi
fi
Heparin (severe)
contamination A brinogenemia

fi
Dys brinogenemia

fi
Table 30.4: Neonatal reference ranges for common coagulation tests measured
on day of life 1°

PT (s) aPTT (s) Fibrinogen (mg/di))

<27 weeks® 14.4-36.7 40.5-158.5 70-480
28-34 weeks" 13.9-20.6 30-57 87-470
30-36 weeks® 10.6-16.2
27.5-79.4 150-373
Full Term* 10.1-15.9 31.3-54.5 167-399
*Reference ranges reflect 2.5th-97.5th percentiles.
"Reference ranges reflect 5th-95th percentiles.
*Reference ranges calculated from mean +SD (2SD below and above the mean)

MANAGEMENT

I. If De nite Etiology is Not Known

fi
Consider giving the following:
1. Vitamin K: 1 mg IV/IM, if not received at birth or status
unknown. Infants on prolonged antibiotic therapy (≥2 weeks)
may be given vitamin K IM/IV 0.5 mg weekly.
2. Fresh frozen plasma (FFP): 15-20 ml/kg for significant or active
bleeding; repeat q 8-12 hours, if needed. However, specific factor
deficiencies must be treated with factor concentrates whenever
available (refer to the Chapter 51: Blood Component Therapy).
3. Platelets: Neonates, particularly high-risk neonates, have a
favorable outcome when a lower platelet count threshold is used
for transfusion (Table 30.5).
4. Whole blood/packed red blood cell (PRBC): Usually given in
severe blood loss. Ensure to take pretransfusion samples for
diagnostic testing before transfusion; if not done, wait for 2 weeks
 Approach to Bleeding Neonate 325

É DIC

Sepsis RVT
NEC

- I

SevereVKDB
"Sick baby PC - N PT aPTT- I
Liverdisease

- N

Physical examination
Sick looking/well looking Hepatosplenomegaly
Type of bleeding (localised/generalised) Sex of baby PC - N PT aPTT- N

Alteredvascularintegrity hypoxia,acidosis)
(prematurity,

Bleeding neonate

- L- N
Baseline investigations

PCPT aPTT- N
Immune cytopenia

thrombo-

VKDB

"Well' baby

PC - N PT aPTT- I
Factordeficiencies
(VIII, Severe
IX,XI) VWD

Platelet count (PC), prothrombin time (PT), activated partial thromboplastin time (aPTT)

History Family h/o bleeding

ITP): drugs (aspirin, anticonvulsant)
Maternal illness (infection, HELLP, SLE,
H/o birth asphyxia, trauma

aPTT. N
Factor VI
de ciency
fi
-N

PC -N aPTT. N
defects
Qualitativeplatelet
Local causes(trauma)

• Metabolic, Hematological, Immunological, Genetics and Endocrine Disorders

326 AIMS Protocols in Neonatology

Tatuss, Sugested thresholds of platelet count for neonatal platete.

Platelet count Condition
<25,000 /mm' Neonates with no bleeding (including neonates with NAIT
if no bleeding and no family history of ICH)

<50,000 /mm' • Neonates with bleeding

• Current coagulopathy
• Before surgery
• NAIT if previously affected sibling with ICH

<1,00,000 /mm' Major bleeding, e.g. signi cant VH

fi
Major surgery
NAIT with ICH

NAIT: Neonatal alloimmune thrombocytopenia; ICH: Intracranial hemorrhage:

IVH: Intraventricular hemorrhage

in case of PRBC / platelet transfusion and 4 weeks in case of whole

blood transfusion.
5. Clotting factor concentrates: Concentrates are available for
factors VIII, IX, VII, and XIII.

Il. If a Speci c Etiology is Known

fi
A. Immune thrombocytopenia?s

1. NAIT
a. Antenatal management: IVIG (1-2 g/kg/week) with or
without steroids (prednisolone 0.5-1.0mg/kg/day) in
pregnant women with a history of serologically confirmed
fetal or alloimmune thrombocytopenia and previous fetus or
newborn with intracranial hemorrhage."
b. Postnatal management (Table 30.6)
i. Do cord platelet count
ii. Do USG Cranium to rule out ICH
2. Autoimmune thrombocytopenia
a. Perform platelet count (PC) on day one or from cord blood:
i. If PC is normal, repeat on day three; if normal, no furthes
evaluation.
üi. If PC is between 100 and 150 x 10º/L, repeat between days
3 and 5 of life.
ili. If PC <100 × 10º/L, repeat PC daily; more frequently if
clinical bleeding or PC <50 × 10°/L.
 Approach to Bleeding Neonate 327

Table 30.6: Postnatal management of NAIT

Platelet count Treatment Dose
‹25,000 /mm' in asymptomatic Random donor 10 ml/kg
neonates with no family history platelets' (RDP)
of ICH
‹50,000/mm ' in preterm neonates
or neonates with a family history of
intracranial bleed
<1,00,000 /mm' in neonates with
ICH
<50,000 /mm' in asymptomatic Intravenous 1 g/kg/d for 2 days
neonates immediately following immunoglobulin OR 400 mg/kg/
platelet therapy (IVIG) day for 5 days
Thrombocytopenia refractory to Methylprednisolone 1 mg/kg BD for
both platelets and IVIG 3-5 days
*Antigen negative platelets (preferred, if available). Blood banks should be immediately
noti ed in cases of suspected NAIT
fi
b. Perform cranial ultrasound to rule out intracranial bleeding
in neonates with PC <50 × 100/L.
c. Management
i. PC <30 x 10°/L: RDP + IVIG (1 g/kg/ day × 2 days)
ii. PC of 30-50 x 109/L: IVIG alone
Unlike NAIT, donor-pooled platelets are usually destroyed by
the ubiquitous circulating antibodies in autoimmune etiology,
making platelet transfusion less efficacious. RDPs serve as a
temporary measure, while IVIG remains the treatment of choice
and rapidly raises platelet count.
B. Vitamin K deficiency bleed (VKDB)
The different types of VKDB, possible causes, their clinical
presentation, and management are given below in Table 30.7.
C. Hemophilia
Factor replacement therapy is the treatment of choice for

beautiesas Burp lache these poshould be monstered

complications associated with factor replacement therapy is the
formation of neutralizing antibodies (inhibitors). Both plasma-
derived and recombinant factor concentrates carry this risk,
although the risk may be lower with 3rd generation plasma-
derived factor concentrates. Also, cranial ultrasound should • Metabolic, Hematological, Immunological, Genetics and Endocrine Disorders
 AlIMS Protocols in Neonatology
328

Table 30.7: Vitamin K de ciency syndromes

fi
Type Time of onset Cause Site of bleed Treatment
Early First 24 hours Maternal Cephalhematoma, Consider FFP
after birth medications umbilical stump, for clinical
(anticonvulsants,intracranial bleed
antibiotics, Vitamin K
antitubercular usually not
drugs) effective
Classic 1-7 days Lack of Gastrointestinal, Parenteral
after birth prophylactic mucocutaneous, vitamin K
vitamin K; post- Consider FFP
Poor feeding circumcision,
for clinical
(breastfed) umbilical stump; bleed
rarely intracranial
Late 1-8 weeks Fat Gastrointestinal, Parenteral
after birth malabsorption mucocutaneous, vitamin K
(biliary atresia, intracranial Consider FFP
alpha-1- for clinical
antitrypsin bleed
de ciency), Recombinant
fi
poor feeding, factor VIla
liver and (for mild
gastrointestinal cases)
disorders

be undertaken before discharge in all neonates with severe or

moderate hemophilia.
Consider one of the following:
a. FFP/cryoprecipitate: In case of severe bleeds.
b. Factor VIII concentrate in Hemophilia A: 1 IU/kg raises
factor levels by 2%.
c. Factor IX concentrate in Hemophilia B: 1 IU/kg raises factor
levels by 1%.

REFERENCES

1. Reel-Vilk 5. The conundrum of neonatal coagulopathy. Hematol Am Soc

Hematol Educ Program 2012;2012:450-4.
2. Ruins 1, Mutray NA. Neonatal thrombocytopenia: causes and management.
Arch Dis Child-Fetal Neonatal Ed 2003;88:359-64.
3. Amnis Vournas S. The bleeding neonate. In: Hematology Meeting Reports
(strely Haematologica Reports) Internet]. 2009 cited 2017 May 51.
Available from: http://www.pagepress.org/journals/index.php/hir/article/
 Approach to Bleeding Neonate 329

4. Eberl W. Diagnostic Challenges in Newborns and Infants with Coagulation

Disorders. Hamostaseologie. 2020;40:84-7.
5. Davenport P, Sola-Visner M. Hemostatic Challenges in Neonates. Front
Pediatr. 2021 Mar 2;9:627715.
6. New HV, Berryman J, Bolton-Maggs PHB, Cantwell C, Chalmers EA, Davies
T, et al. Guidelines on transfusion for fetuses, neonates and older children.
Br | Haematol 2016;175:784-828.
7. Batton E, Leibel SL. Immune-Mediated Neonatal Thrombocytopenia.
Neoreviews. 2022 Jul 1;23:462-71.
8. Eichenwald EC, Hansen AR, Martin C, Stark AR, editors. Cloherty and Stark's
manual of neonatal care. Eighth edition. Philadelphia: Wolters Kluwer; 2017.

9. Chalmers E, Williams M, Brennand I, Liesner R, Collins P, Richards M, el

al. Guideline on the management of haemophilia in the fetus and neonate.
Br | Haematol 2011;154:208-15.
 Section

9
Genitourinary Tract

31. Acute Kidney Injury

32. Management of Antenatally Diagnosed
Hydronephrosis
33. Posterior Urethral Valve
 CHAPTER E

31
Acute Kidney Injury

Acute kidney injury (AKI), common morbidity among sick neonates,

is an independent risk factor for mortality. ' The old term acute renal
failure has now been replaced with 'acute kidney injury (AKI) to
emphasize the importance of early recognition and intervention at
the time of injury rather than waiting until complete organ failure.
AKI is defined as an abrupt (within 7 days) reduction in kidney
function: an increase of serum creatinine either more than or equal
to 0.3 mg/dl (26.4 pmol/L) or more than equal to 50% (1.5-fold)
from the baseline, or oliguria of <1 ml/kg per hour over 24 hours.?

INCIDENCE
A large multicentre study (AWAKEN) reported an AKI incidence
in 29.9% of neonates. The incidence of AKI varies from 1 to 56%,
depending on the study population.? Among the neonates with AKI,
more than 65% are within seven days of life.
At-risk Population
• Sick and small neonates, especially extremely low birth weight
neonates.
• Perinatal asphyxia.
• Neonates with other concurrent morbidities (malformations,
intraventricular hemorrhage, and necrotizing enterocolitis).
• PDA (hemodynamically significant).
• Congenital cardiac defects (post-surgery).
• Bronchopulmonary dysplasia.
• Nephrotoxic medications (aminoglycosides, ACE inhibitors).

Staging
In 2013, the Working Group on the Kidney Diseases: Improving
Global Outcomes (KDIGO) clinical practice guidelines published
a classification for AKI that applied to the pediatric population.
333
334 AlIMS Protocols in Neonatology

Table 31.1: Classi cation of Neonatal AKI?

fi
Stage Change in serum creatinine (S Cr) Urine output over
24 hours
0 No change or rise <0.3 mg/dl within 48 hours >1 ml/kg/hour
Rise in serum creatinine by 0.3 mg/dl within 51 ml/kghour
48 hours or 21.5-1.9 times rise in serum
creatinine from the lowest previous value within
seven days

2 22-2.9 times increase in serum creatinine from 50.5 ml/kg/hour

the lowest previous value

3 23 times rise in serum creatinine from the lowest 50.3 ml/kg/hour

previous value or 22.5 mg/dl or the initiation
of dialvsis
Futilling either serum creatinine based or urine output-based criteria classi es the neonate

fi
in that particular stage. The lowest previous value of serum creatinine should be considered
as the baseline, preferably on day 3 of live or later.

Later, the KDIGO definition was modified for defining neonatal

AKI (Table 31.1).?

Practical tip
• Even an increase in serum creatinine by 0.3 mg/dl is sufficient to suspect AKI.
• SCr of 2.5 mg dl represents glomerular filtration rate of less than 10 ml
min/1.73 m'.

HISTORY

a. Prenatal history:
• Maternal drug intake like ACE inhibitors (enalapril) or NSAIDs
(indomethacin).
• Maternal uncontrolled diabetes (associated with genitourinary
malformations).
• Oligohydramnios (fetal oliguria due to bilateral congenital
renal disease, bilateral/lower urinary tract obstruction, or
maternal drugs).
b. Family history of polycystic kidney disease, renal tubular
disorders, and congenital nephrotic syndrome.
c. Birth and postnatal history: Perinatal asphyxia, respiratory
distress, sepsis, and shock may predispose the kidneys to
anoxic injury culminating in acute tubular necrosis or oliguria
in asphyxia.
 Acute Kidney tguy 335

d. Micturition history: About 7% of neonates do not void in the

first 24 hours; hence no passage of urine beyond 24 hours has to
be evaluated. The most common cause of delayed micturition
is inadequate perfusion of the kidneys. However, intrinsic renal
disorders and urinary tract obstruction must be ruled out.
Examination
Assess for:
a. Hydration status (edema/dehydration).
b. Signs of dehydration: Tachycardia, sunken fontanel, sunken eyes,
or dry mucous membrane.
c. Signs of hypervolemia: Edema over dependent areas like labia,
scrotum, and posterior scalp.
d. Hemodynamic stability: Heart rate, blood pressure, and
respiratory rate.
e. Dysmorphism (abnormal ears, preauricular pits, ambiguous
genitalia, hypospadias, abdominal wall defects, aniridia, or Potter
facies).
f. Urine stream and / or dribbling.
g. Any abdominal mass: Suprapubic mass could indicate a palpable
bladder, post void residual bladder suggests a posterior urethral
valve (PUV), or assess for palpable kidneys.
h. Input and output of fluids and electrolytes.
Fluid overload percentage is calculated in critically ill infants

Fluid overload (%) = Input (.) - Output (L) × 100

Premorbid weight (kg)
Markers of AKI: At present, serum creatinine and urine output
remain the best available markers of AKI. Newer biomarkers
like serum cystatin C and urine neutrophil gelatinase-associated
lipocalin are still under evaluation.
Serum creatinine: The limitations of serum creatinine in identifying
AKI in neonates are:
• Serum creatinine levels during the first 48 hours of life reflect
maternal creatinine levels.
• It declines at varying rates depending on the gestational age. In
preterm infants, it can initially be higher than maternal levels
peaking at roughly four days due to reabsorption in the renal
tubules and decreased total body fluid, followed by a gradual
decline to normal levels by 3-4 weeks.
336 AlIMS Protocols in Neonatology

• It rises late and may remain normal during the first 24-48 hours
after renal injury and until about 25-50% of renal function
is lost
• It does not indicate the nature and timing of the renal injury

Urine output: Oliguria is defined as a urine output of less than

1 ml/kg/hour after the first day of life in term and preterm neonates.
However, urine output has the following limitations:
• Not all AKI is associated with oliguria. AKI in neonates can be

• Some term neonates may void for the first time at around 24 hours
of life.
• Oliguria can also occur in the syndrome of inappropriate ADH
(SIADH) secretion without AKI.
• VLBW infants without AKI may have an oliguric phase that
resolves spontaneously in the first few days of life.

Practical tip
Neonatal Al may be nonoliguric and can be missed if serum creatinine is not
monitored in patients at high-risk of AKI.

Newer Techniques

Near-infrared spectroscopy: Near-infrared spectroscopy (NIRS) is

a non-invasive tool to identify inadequate renal tissue oxygenation.

Previous literature has shown a correlation between low renal

tissue oxygenation (RrSO:) in the first 24 hours of age and the later
development of AKI. RrSO, persistently below 50 for 8-12 hours
had a sensitivity of 64% and specificity of 71% with AUC-0.98.5

Novel biomarkers: Urinay NGAL and cystatin C have been

evaluated in preterm neonates and found to have a sensitivity of 9e,
and 80°o, respectively; however, higher cost and limited evidence
preclude their use in routine practice.

ETIOLOGY

Based on the site of origin of insult, it can be three types:"

1. Pretenal (75-80%)
 Acute Kidney Injury 337

Although prerenal or post-renal causes can be reversible during

the early phase, persistent insult can progress to intrinsic AK1.
Although widely used, this classification is imprecise due to
overlapping pathophysiological mechanisms? This distinction
has blurred with the increasing recognition of AKI as a continuum
of volume responsiveness through unresponsiveness. Practically,
response to fluid resuscitation has a definite role in reversing renal
damage in the former?

EVALUATION
Laboratory investigations: The affected neonates require evaluation
for the cause and the complications of AKI. Besides serum creatinine
and blood urea, serum electrolytes, arterial blood gas, urine sodium,
and creatinine are generally required
Role of indices: While differentiation of prerenal and intrinsic renal
failure may be based on urinary indices (Table 31.2), their clinical
utility is limited. The urine sample for measuring indices must be
obtained before the fluid and diuretic challenge. Preterm neonates lose
more sodium in the urine due to tubular immaturity. A FENa of
more than 2.5-3.0% is associated with intrinsic AKI. Hence a FENa
of more than 6% can be used to define intrinsic AKI in neonates born
between 29-32 weeks." As the values overlap in newborns with and
without AKI, FENa has limited usefulness in neonates. Likewise, a
renal failure index (RFI) of more than 4 in term and more than 8 in
preterm neonates <32 weeks suggests intrinsic AKI.

Urine complete and microscopy: The presence of granular and

hyaline casts, RBC, protein, and tubular cells suggests an intrinsic
cause. In asphyxia, there is an increase in epithelial cells and
transient microscopic hematuria with leucocytes.

Table 31.2: Renal indices to differentiate prerenal from intrinsic renal failure!
Parameters Prerenal Intrinsic renal
Urinary Na ≤20 mEg/L >50 mEq/1.
Renal failure index* Low <1 High >4
Fractional excretion of sodium (FENA)%$ ≤1 >3
Renal failure index RFI: Urinary Na x Serum creatinine
Urine creatinine

*Fractional excretion of sodium (FENa)%:Urinary Na x serum creatinine × 100

Serum sodium x urine creatinine
338 AlIMS Protocols in Neonatology

Urinary biomarkers: The excretion of low molecular weight proteins

like betar-glycoprotein is a sensitive indicator of tubular damage, as
in asphyxia. The role of urine and serum biomarkers in predicting
AKI in neonates is evolving. Promising biomarkers of AKI include
serum and urine neutrophil gelatinase-associated lipocalin (NGAL),
urine interleukin-18 (IL-18) and kidney injury molecule-1 (KIM-1),
B-2-microglobulin and serum cystatin C.?

Ultrasonography and Doppler: Renal ultrasonography helps

diagnose congenital anomalies like polycystic kidneys, renal
dysplasia, and obstructive uropathy. Renal Doppler studies are
performed when renal vascular lesions are suspected.

Glomerular Filtration Rate (GFR)

GFR is calculated using the Schwartz formula as follows:10
Estimated GFR (eGFR in mL/ min/1.73 m?)
K x Length (cm)
= Serum creatinine (mg /ml)
K = 0.33 in preterm infants aged < 1 year and 0.45 in term
infants aged < 1 year

MANAGEMENT

There are no specific drugs to prevent or treat AKI. Treatment relies

on supportive care, correction of fluid and electrolyte abnormalities,
acid-base homeostasis, treatment of complications, avoidance of
nephrotoxins, and renal replacement therapy whenever required.
A detailed description of drug dose modification in AKl is provided*
(see Annexure 3).

Initial Management: When a baby has not passed urine for

12 hours, examine the baby for the distended bladder by palpating
the abdomen or ultrasound (if available at bedside). Avoid bladder
catheterzation to prevent infection, but it may be necessary for sick
neonates. If required, it has to be done with a 5 Fr lubricated feeding
tube under strict asepsis. Compression of the bladder (suprapubee
pressure) should be avoided, especially in preterm infants, for fear of
ubicoureteric reflex and rarely bladder rupture.°
The common causes of prerenal azotemia are hypovolemia.
systemic hypotension, and hypoxia (in nearly 80% of cases). After
confirming the absence of urine in the bladder, a fluid challenge can
be given." In the absence of obvious signs of fluid overload, a normal
 Acute Kidney Injury
339

Acute kidney injury

• Assess and correct dehydration

• Check for predisposing conditions like hypotension, hypoxia.
and hypovolemia
• Avoid nephrotoxic agents

: Monitor serum a zinger ensure serum Na in norma range)

• Replace insensible losses
• Adequate nutrition

• Assess urinary bladder size by clinical or bedside USG if available

• POCUS for volume status and cardiac contractility
• No evidence of CCF

Normal saline bolus 10 ml/kg over 20 mins with

inj. Furosemide 1 mg/kg as infusion over 20 mins

Urine output <1 ml/kg/hour

Urine output > 1 ml/kg/hour

Intrinsic renal failure Pre-renal failure

Early renal replacemnt

therapy

Fig. 31.1: Management algorithm for neonatal AKI

UOP: Urine output; CCF: Congestive cardiac failure

saline bolus of 10-20 ml/kg can be given over 60 min.? Despite the
uid challenge, if urine output fails to ensue, furosemide in a single
fl
dose of 1 mg/kg can be given (in a non-dehydrated patient) (Fig. 31.1).
The only use of diuretics in patients with incipient or established
fluid overload with AKI does not improve the outcomes as diuretics
by itself cause acute tubular injury and may not be effective when
intrinsic AKI had already set in. Neonates who do not pass urine
after furosemide are unlikely to improve urine output. Due to
the high incidence of progressive AKI in such patients, renal
replacement therapy should be considered.

Fluid Management
Fluids must be restricted to insensible water loss (IWL) plus urinary
(and other) losses. The urinary loss must be replaced volume for
volume. The IWL in a term neonate is approximately 20 ml/kg/day • Genitourinary Tract
340 AlMS Protocols in Neonatology

(400 ml/body surface area. In preterm neonates, this can vary

prescription should be revised based on urine output, weight, and

volume status every eight hours.
In oligo-anuric children, the IWL should be replaced with 5-10%
dextrose. The urine output should be replaced volume by volume
with N/5 saline?
During the polyuric phase, meticulously monitor urine output
serum electrolytes and replace them with appropriate amounts of
sodium, potassium, and water.?

ELECTROLYTE DISTURBANCES

Hyponatremia
Neonates can have hyponatremia in oliguric as well as non-oliguric
renal failure. It is due to dilution secondary to water retention; hence,
it must be corrected with fluid restriction. In most cases, there is no
sodium deficit.
Serum sodium must be monitored 12 hourly. Restricting
fluids will suffice if serum sodium is between 120-135 mEq/L
If hyponatremia is associated with symptoms like seizures, or if
serum sodium is less than 120 mEq/L, it requires prompt correction.
with 3% hypertonic saline over 2 hours, using the formula.

Na required (mEq) = [Na desired - Na actuall × body weight (kg) × 0.5

Hyponatremia unresponsive to the above therapy is an indication

of dialysis. Neonates with nonoliguric AKI may have urinary
sodium losses of up to 10 mEq/kg/day, which must be replaced.
Care should be taken not to increase the serum sodium by more
than 0.5 mEq/L/hour.

Hyperkalemia

Hyperkalemia (K* >6.5 mEq/L') is one of the most dangerous

complications of AKI. It results from reduced glomerular filtration
rate, urinary potassium secretion, acidosis, immature tubular
response to aldosterone, and cellular breakdown.

Practical tip

li hyperkalemia is associated with hypoglycemia, hyponatremia and

nypotension, consider adrenal insufficiency.
 Acute Kidney Injury
341

The rst step in managing hyperkalemia is to stop potassium-

fi
containing uids and the drugs which can accentuate hyperkalemia

fl
(indomethacin, ACE inhibitors, and potassium-sparing diuretics).
ECG will help in diagnosing the cardiac effects of hyperkalemia.
If ECG changes are evident, IV calcium gluconate 10% is given.
This will decrease the myocardial excitability but will not lower the
potassium levels.
This should immediately be followed by methods to decrease
potassium levels. Hyperkalemia in AKI is an indication for starting
peritoneal dialysis; all three medical measures should be instituted
while awaiting initiation of dialysis (Table 31.3).
Practical tips
• Saturate the plastic tubing with insulin solution before infusing to the baby.
• Oral or rectal administration of resins is avoided because it is associated
with the risk of concretions, hypernatremia and fluid overload, especially
in VLBW infants and those with poor peristalsis; adding resins to milk feed
and using decanted supernatant is useful in managing patients with chronic
hyperkalemia.
• Salbutamol aerosol may not be very effective in neonates.

Table 31.3: Management of Hyperkalemia*

Medication Dose Mechanism/ Degree Onset of

of effect action
Calcium 0.5-1 ml/kg over Modi es myocardial 5-10 min
fi
gluconate (10%) 5-10 min excitability, with no
decrease in K levels
Glucose and 0.5 g/kg/h of glucose Intracellular uptake 30 min
insulin and 0.1 U/kg/hour of potassium
infusion of insulin
Salbutamol IV 4 pg/kg over 20 minIntracellular uptake 30-40 min
infusion of potassium
Peritoneal Use a dialysate with Dialysis Minutes
dialysis no K+ concentration
Cation exchange 1 g/kg intrarectally Exchange of K for 1-2 hours,
resin (Na/Ca Na or Ca. 1g/kg may take up
polystyrene reduces K levels by to 6 hours
sulfonate) 0.5-1 g per mEq K*, 1 mEq/kg
decant supernatant,
and discard
residue
*Carries risk of intestinal perforation and hypernatremia.
"Oiten used in chronic than acute hyperkalemia.
342 AlIMS Protocols in Neonatology

Hypocalcemia
Hypocalcemia occurs due to hyperphosphatemia and resistance
to parathyroid hormone. Symptomatic hypocalcemia should
be corrected by infusing 10% calcium gluconate at a dose of
0.5-1 ml/kg over 5-10 min under cardiac monitoring, followed by
maintenance calcium at 8 ml/kg/day added intravenously. Also,
during the oliguric phase, no intake of phosphorous/ magnesium
is to be provided. Calcium carbonate preparations are preferred if
the baby is fit for enteral feeds.

Role of dopamine: The Cochrane meta-analysis of three studies

concluded that dopamine has no role in the management of acute
renal failure due to indomethacin. 12
Dopamine acts via DA, and DA receptors at doses less than
5 pg per kg per min to increase renal blood flow. Preterm infants are
hypersensitive to alpha receptors; hence, low amounts of dopamine
can cause vasoconstriction and raise renal vascular resistance. 5
This may explain the difficulty in using dopamine to improve
renal function. While dopamine, combined with frusemide, causes
natriuresis and diuresis in preterm infants with RDS and oliguria,
current guidelines do not recommend its use in managing patients
with AKI.!

Theophylline: KDIGO guidelines recommend a single dose

of theophylline (5-8 mg/kg) in neonates with severe perinatal
asphyxia for prevention. We do not routinely use theophylline in
neonates with severe asphyxia.

Fenoldopam
It is a selective dopamine-1 receptor agonist causing renai
vasodilatation resulting in increased blood ow and GFR. Therapy
fl
with fenoldopam for preventing or treating neonatal AKI is not
recommended.

Nutrition
The goal is to provide 100 kcal/kg/day as neonates with AKI are
catabolic. Proteins or amino acids can be provided in a dose of
1-2 g/kg/day If enteral feeding is possible, breast milk should be
used as its content of phosphorous and potassium are low; failing
which, low phosphate formula can be given. Caloric density cun te
increased by adding medium-chain triglycerides. A central venous
 Acute Kianey Inury
343
catheter may be needed to infuse hypertonic glucose to prevent
hypoglycemia if the baby is on parenteral nutrition.

Acidosis
Mild metabolic acidosis is common in neonates with AKI. If pl
is <7.2 and bicarbonate < 18 mEq/L, sodium bicarbonate is given
in a dose of 1-2 mEg/kg over 3-4 hours while monitoring for
fluid overload, bypernatremia, intracranial hemorrhage, and
hypocalcemia. Neonates with severe or persistent acidosis in the
presence of AKI require dialysis.

Hypertension
Fluid overload in neonatal AKI can result in hypertension, which can
be controlled with uid restriction and antihypertensive agents. The
fl
development of severe hypertension should raise suspicion for renal
artery or venous thrombosis. Neonates with severe hypertension are
managed with continuous IV infusion of nitroprusside, labetalol,
or nicardipine. Commonly used antihypertensives in newborns are
oral amlodipine (0.1-0.3mg/kg/ dose q 12-24 hourly) and enalapril
(0.1-0.4 mg/kg/day q 6-12 hourly). Other drugs that may be
administered include beta blockers and hydralazine. Cautious use
of ACE inhibitors is required, particularly in premature neonates;
lower doses may lead to renal hypoperfusion and progression of
renal injury.'
Renal Replacement Therapy
The indications of renal replacement therapy (RRT) are:
• Hyperkalemia
• Hyponatremia with volume overload (pulmonary edema, severe
hypertension)
• Metabolic acidosis (pH<7.20 despite medical management)
• Hypocalcemia
• Hyperphosphatemia refractory to therapy
• Inability to provide adequate nutrition due to fluid restriction.
While anuria, along with the above, is an absolute indication for
initiating renal replacement therapy (RRT), dialysis should begin
early to prevent catastrophic metabolic complications and the risk
of mortality associated with more than 15-20% fluid overload.
The two purposes of RRT are ultrafiltration (removal of water)
and dialysis (removal of solutes), and it can be provided by acute
 AlIMS Protocols in Neonatology
34$

peritoneal dialysis (PD), intermittent hemodialysis, or continuous

renal replacement (CRRT).

OUTCOME AND FOLLOW-UP

Nan-aliguric AKI has a better prognosis when compared to

oliguric renal failure. Mortality ranges from 25 to 78% in oligo
anuric AKI!" Newborns who have had AKI are predisposed to
developing chronic renal failure in the future. While most studies
are retrospective, prospective studies have also shown decreased
GFR (5-23%), proteinuria (12-17%), hyperfiltration (11-13%), and
hypertension (3-19%) during follow-up. Neonates with AKI (RIFLE
groups injury and failure) had a 4-times higher risk of developing
hypertension or CKD than those without AKI.! Therefore, all
neonates who develop AKI need follow-up, especially since
prematurity and low birth weight are independent predictors for
the development of CKD.!° Adequacy of growth and nutrition,
blood pressure, proteinuria, and renal function status has to be
monitored at least three months after the resolution of AKI and
long-term after that.

REFERENCES
Askenazi Di. Grifin R, McGwin G, et al. Acute kidney injury is independenth

associated with mortality in very low birth weight infants: a matched case-

control analysis. Pediatr Nephrol 2009;24:991-7.

1 Zippitell M. Ambalavanan N, Askenazi DI, et al. Developing a neonatal

acure kidney injury research definition: a report from the NIDDK neonatal
AXI workshop. Pediat Res. 2017;82(4):569-73.

1. Nica A, Bonachea EM, Askenazi DJ. Acute kidney injury in the fetus and
secrate. Seminfetal Neonatal Med. 2017;22(21:90-7.

4 Secon JC, Bochaker L. Sethi SK, et al. incidence and outcomes of neonatal
acute ludrey injury (AWAKEN): a multicentre, multinational, observational

conor mudy. Lancer Child Adolesc Health.2017:1(3):184-94.

2 Harer MW, Adegboro CO, Richard LJ, McAdams 8M. Non-invasive

continuous resul tsue crygenation monitoring to identivy preterm neonate

it cod nor acute kidrey injury Pediatr Nephrol 2021 Jun; 36(6): 1617-25.

hersches R, Lodige 8, Bulla M. Renal insufficiency in the neonatal period

Cho Negena 195% 4054-3.

1 Pugga A. Sirea A, Cedats A Photocois in Pediatric Nephrology, 1st e. CS:
cutlisters and Osaladars For Lit
peritoneal dialysis (PD), intermittent hemodialysis, or continuous
renal replacement (CRRT).

OUTCOME AND FOLLOW-UP

Non-oliguric AKI has a better prognosis when compared to

oliguric renal failure. Mortality ranges from 25 to 78% in oligo
anuric AK1.15 Newborns who have had AKI are predisposed to
developing chronic renal failure in the future. While most studies
are retrospective, prospective studies have also shown decreased
GFR (5-23%), proteinuria (12-17%), hyperfiltration (11-13%), and
hypertension (3-19%) during follow-up. Neonates with AKI (RIFLE
groups injury and failure) had a 4-times higher risk of developing
hypertension or CKD than those without AK1.16 Therefore, all
neonates who develop AKI need follow-up, especially since
prematurity and low birth weight are independent predictors for
the development of CKD.! Adequacy of growth and nutrition,
blood pressure, proteinuria, and renal function status has to be
monitored at least three months after the resolution of AKI and
long-term after that.

REFERENCES

1. Askenazi DJ, Griffin R, McGin G, et al. Acute kidney injury is independently

associated with mortality in very low birth weight infants: a matched case-
control analysis.Pediatr Nephrol 2009;24:991-7.
2. Zappitelli M, Ambalavanan N, Askenazi DJ, et al. Developing a neonatal
acute kidney injury research de nition: a report from the NIDDK neonatal
fi
AKI workshop. Pediatr Res. 2017;82(4):569-73.
3. Nada A, Bonachea EM, Askenazi DJ. Acute kidney injury in the fetus and
neonate.SeminFetal Neonatal Med. 2017;22(2):90-7.
4. Jetton JG, Boohaker LJ, Sethi SK, et al. incidence and outcomes of neonatal
acute kidney injury (AWAKEN): a multicentre, multinational, observational
cohort study. Lancet Child Adolesc Health.2017;1(3):184-94.
5. Harer MW, Adegboro CO, Richard LJ, McAdams RM. Non-invasive
continuous renal tissue oxygenation monitoring to identify preterm neonates
at risk for acute kidney injury.Pediatr Nephrol.2021 Jun; 36(6):1617-25.
6. Hentschel R, Lodige B, Bulla M. Renal insufficiency in the neonatal period.
Clin Nephrol 1996: 46:54-8.

7. Bagga A, Sinha A, Gulati A. Protocols in Pediatric Nephrology, 1st e. CBS

publishers and Distributors Pvt Ltd.
8. Ishizaki Y, etal, evaluation of diagnostic criteria of acute renal failure in
premature infants.ActaPaediatripn 1983,35:311-5.
 Acute Kidney Injury 345

9. Marin T, DeRossett B, Bhatia J. Urinary Biorarkers to Predict Neonatal Acute

Kidney Injury: A Review of the Science.) Perinat Neonatal Nurs. 2018 Jul/
Sep; 3203):266-74.
10. Basalely, A., Liu, D. &Kaskel, F.J. Big equation for small kidneys: a newly
proposed model to estimate neonatal GF R.'ediatr Nephrol 35, 543-6 (2020).
11. Chawla D, Agarwal R, Deorari AK, Paul VK.Fluid and electrolyte managerent
in term and preterm neonates.AlMS-NICU protocols 2008.
12. Friedrich JO, Adhikari N, Herridge MS. Meta-analysis: Low dose dopamine
increases urine output but does not prevent renal dysfunction or death.Ann
Intern Med 2005;142:510-24.
13. Seri I. Effects of low dose dopamine infusion on cardiovascular and renal
functions cerebral blood ow and plasma cathecolamines levels in sick
fl
preterm neonates. Pediatric Res 1993, 34:742-9.
14. Tulassy T, Seri 1, Acute oliguria in preterm infants with hyaline membrane
disease; interaction of dopamine and frusemide. Acta PediatrScand
1986,75:420-4.
15. Chevalier R. Prognostic factors in neonatal acute renal failure.Pediatrics
1984; 74:165-272.
16. Chaturvedi S, Ng KH, Mammen C. The path to chronic kidney disease
following acute kidney injury: a neonatal perspective.Pediatr Nephrol.2017;
32(2):227-41.

ary Tract
CHAPTER

32
Management of Antenatally
Diagnosed Hydronephrosis

LUTO present

MCU' within 48 hours

Grade® III-V VUR

LUTO absent

VUR present

MCƯ' at
4-6 weeks

APD> 10 mm
Grade I-II VUR USG monitoring
UTD' P2-P3 or

SFU grade III/IV or

Normal

Antenatally detected hydronephrosis

APD <10 mm
SFU' grade I/ll
or UTD' P1 with until resolution*

14-6 weeks inenevery 6-12 months

Obstructive pattern with split

Consider pyeloplasty if: renal function of <40%,
detroiting nycroneross

Fig. 32.1: Management of antenatally diagnosed hydronephrosis

at 6-8 weeks

USG
abnormal

Renal dynamic scan (RDS)

Repeat USG at 4-6 weeks Normal

USG monitoring till
resolution* Repeat RDS'

• Non obstructive pattern:

• Persistence or worsening:

Nop reguredk
 Management of Antenatally Diagnosed Hydronephrosis

*Counsel
*Give antibiotic prophylaxis on the day of procedure (amoxicillin 40 mg/kg one hour prior to, and 20 mg/kg aiter parents
6 hours of the procedure). consult pediatrician.
regarding increased risk of urinary tract infections due to VUR; perform urinalysis and urine culture for any fever without focus and SUrinary Tract Dilatation (UTD) classi cation for hydronephrosis: Postnatal (P) staging beyond 48 hr of life, as follows:
fi
or dilatation

Vesicoureteric re ux
APD: Anteroposterior diameter of renal pelvis; LUTO: Lower urinary tract obstruction: MCU: Micturating cystourethrogram; USC: Ultrasound; VUR:
UTD-PO: Normal pelvi-calyceal system and APD <10 mm UTD-P1: Pelvis and central calyces dilated and APD 10 mm to <15 mm UTD-P2: Central and peripheral calyces dilated; abnormal ureter and APD ≥15 mmUTD-P3: Central and peripheral calyces dilated; abnormal ureter or bladder; abnormal renal parenchymal thickness or appearance and APD 215 mm
Grade I: Reflux that involves only the ureter
Grade II: Reflux that involves the ureter, pelvis and the calyces with no dilatation of the and normal calyceal fornices fornices
Grade III: Reflux that involves moderate dilatation and/or tortuosity of the ureter, moderate dilatation of the pelvis and no or slight blunting of the Grade IV: Reflux that involves moderate dilatation of the pelvis and the blunting of the Grade
fornices *Antibiotic
V: Reflux that involves gross dilatation of the and tortuosity of the ureter, pelvis and the calyces prophylaxis: Cephalexin at a dose of 10 mg/kg single daily dose
fl
'Lower urinary tract obstruction (LUTO) is suggested by bilateral hydroureteronephrosis associated with oligohydramnios, bladder wall thickening and/ *Grades of VUR (International reflux study committee)

• Grade I: Urine in pelvis barely splits pelvis

• Grade II: Urine lls intra-renal pelvis ‡ extra-renal pelvis and one or few major calyces dilated• Grade III: SFU grade Il and minor calyces uniformly dilated and normal parenchymal thickness • Grade IV: SFU grade Ill and thin parenchyma
fi
SCiety of tal Urology Se grading for hydroneprosis
CHAPTER

33
Posterior Urethral Valve

Posterior urethral valves (PUV) are the most common cause of lower
urinary tract obstruction (LUTO). The incidence ranges from 1 in
4000-8000 live births.

CLASSIFICATION

PUV has three categories:

a. Type 1 (90-95%) is composed of a ridge, which is continuous
from the verumontanum, that divides into two fork-like leaflets
and gets attached to the anterior urethra.

b. Type 2 is no longer considered a form of PUV but a dissection

artifact, which was reported to extend from the vermontanum
to the internal sphincter and the bladder neck
c. Type 3 (5-10%) is found at various levels of the posterior urethra
that forms a diaphragm with a small opening in the center.

CLINICAL PRESENTATION ,2

a. Antenatal: Severe obstruction can lead to oligohydramnios. The

increased urinary bladder pressure may rupture the renal calyx
resulting in urinary ascites or perinephric urinoma.
b. Postnatal: Neonates with severe PUV can present with
respiratory distress secondary to lung hypoplasia. There can
be signs of severe systemic illness, such as lethargy and poor
feeding. Lung hypoplasia occurs due to oligohydramnios during
the canalicular phase of lung development (16-28 weeks of
gestation). The abdomen may be distended because of urinary
ascites, hydronephrosis, or distended bladder. Vesicoureteric
reflux (VUR) is present in approximately one-third of the patients

DIAGNOSIS

a. Antenatal: Prenatal ultrasonography can identify a third of cases.

The findings include bilateral hydroureteronephrosis, dilated
348
 Posterior Urethral Valve 349

and thickened bladder (normal bladder thickness up to 3 mm),

and the posterior urethra (keyhole sign). Severe cases would
have large bladder diverticula or patent urachus. A thickened
bladder is a better predictor of PUV than the keyhole sign.
b. Postnatal: Ultrasonography shows variable degrees of
hydroureteronephrosis, thick bladder wall, and dilated posterior
urethra. Voiding cystourethrogram (VCUG) shows the hallmark
findings of an enlarged and elongated posterior urethra and

blade neck hyperteople Followed by action, cystoscopy is

Management4,5
a. Antenatal: Vesico-amniotic shunt can reverse the oligohydramnios
but does not change the overall outcome. Fetal cystoscopy and
ablation of the valves have been tried, but it has high complication
rates (Fig. 33.1).
b. Postnatal
1. Drainage of the bladder: Insert a small catheter (without
balloon) or feeding tube to drain the bladder. If it is impossible
to catheterize, place a suprapubic catheter, do a VCUG and leave
the catheter until the neonate is stable enough for valve ablation.
2. Valve ablation: Once the neonate is stable enough with stable
creatinine levels, PUV can be ablated. A check cystoscopy or a
VCUG is performed to confirm the procedure's effectiveness.
If the urethra is too small to pass a fetal cystoscope, consider
suprapubic diversion until valve ablation can be performed
safely.
3. High urinary diversion: Despite adequate bladder drainage,
if there is still progressive dilatation of the upper tract, no
improvement in renal function, or recurrent urinary tract
infections, consider high urinary diversion.
4. Vesicostomy: Cutaneous vesicostomy is an alternative to

growth until ablation of the valves can be carried out.

However, it could decrease the bladder's capacity.
5. Vesicoureteric reflux: Give antibiotic prophylaxis in high-
grade VUR in the initial months. High grade reflux is usually
associated with a poorly functioning kidney.
6. A poorly functioning bladder may respond to early initiation
of oxybutynin. High post-void residue might require clean Canitaurinar, Trant

intermittent catheterization (CIC).

 AIMS Protocols in Neonatology

Improvement in urinary tract dilatation

Recurrent UTI, or dilated improvement in kidney

upper tract with no function

High urinary diversion

Bladder drainage (Suprapubic

catheterization or vesicostory)

-Ureterostory closure and valve ablation

for cystoscopia valve fulguration

Unstable or urethral apening too small

Clinical examination Kidney function tests

Ultrasound and MCU

Neonate with suspected PUV

Improvement in kidney function and no UTI

No improvement in kidney function and urinary tract dilatation

Stable and cystoscope is

negotiable through urethral opening

ent Catheterization, MCD: Micturating cystourethrography. UTI. Urinary tract infections

tract dilatation
Cystoscopic valve ablation

function and urinary

Improvement in kidney
Monitor kidney function, and for bladderdysfunction and UTI; check cystoscopy after 3months anticholinergic agents for overactivebladder; CIC if high post void residue Fig, 33.1. An algorithmic approach for managing a neonate with suspected posterior urethral valves (PUV), A neonate with suspected

sechon y

instability.
PUV is considered 'unstable' in the presence of impaired kidney function, dyselectralytemia, or urosepsis with or without hemodynamic
OC. Clean warmitt
 Posterior Urethral Valve
351
OUTCOMES
Ten-year survival is more than 90% for those diagnosed with PUV
in the rst year of life. The primary determinant of mortality in
fi
the neonatal period is pulmonary hypoplasia. The risk of chronic
kidney disease is nearly 20%, and end-stage kidney disease is 11%.
Infants with PUV post-ablation need lifelong monitoring as bladder
dysfunction and day/night incontinence are significant concerns.
High baseline creatinine in the first year, associated renal dysplasia,
and severe bladder dysfunction are risk factors for end-stage kidney
disease progression.In the first six months of age, male infants with
lower renal parenchymal area in the renal ultrasound are at higher
risk for progression to CKD/ESRD.

REFERENCES
1. Ansari MS, Gulia A, Srivastava A, Kapoor R. Risk factors for progression to
end-stage renal disease in children with posterior urethral valves. J Pediatr
Urol. 2010;6:2614.
2. Bilgutay AN, Roth DR, Gonzales ET Jr, Janzen N, Zhang W, Koh CJ, et al.
Posterior urethral valves: Risk factors for progression to renal failure. J Pediatr
Urol. 2016;12:179.e1-7.
3. Oktar T, Acar O, Sancaktutar A, Sanli O, Te k T, Ziylan O. Endoscopic
fi
treatment of vesicoureteral re ux in children with posterior urethral valves.
fl
Int Urol Nephrol 2012;44:1305-9.
4. Morris RK, Malin GL, Quinlan-Jones E, Middleton LJ, Hemming K, Burke D,
et al. Percutaneous vesicoamniotic shunting versus conservative management
for fetal lower urinary tract obstruction (PLUTO): a randomised trial. Lancet
Lond Eng 2013;382:1496-506.
5. Nassr AA, Shazly S a. M, Abdelmagied AM, Araujo Júnior E, Tonni G, Kilby
MD, et al. Effectiveness of vesicoamniotic shunt in fetuses with congenital
lower urinary tract obstruction: an updated systematic review and meta-
analysis. Ultrasound Obstet Gynecol Off | Int Soc Ultrasound Obstet
Gynecol. 2017;49:696-703.
6. Pulido JE, Furth SL, Zderic SA, Canning DA, Tasian GE. Renal parenchymal
area and risk of ESRD in boys with posterior urethral valves. Clin | Am Soc
Nephrol. 2014;9(3):499-505.
 Section
10
Miscellaneous

34. Follow-up of High-risk Neonates

35. Retinopathy of Prematurity
36. Hearing Screening
37. Umbilical Cord Blood Banking
 CHAPTER

34
Follow-up of
High-risk Neonates

Improving perinatal-neonatal care has led to increased survival

of newborns' at high risk of post-discharge morbidities, including
growth failure, ongoing medical illnesses, neurosensory impairment,
and developmental deficits.
What is the evidence?
A recent systematic review? has reported a high prevalence of long term
neurodevelopmental sequelae after different intrauterine and neonatal insults,:
sepsis 40.0%, meningitis 42.0%, HIE 31.0%, preterm birth 31.0%, jaundice
18.0%, tetanus 26.0%, CMV infection 41.0%.
Most common sequelae: Learning difficulties, cognition or developmental
delay; cerebral palsy; hearing impairment and visual impairment. 3,4

An appropriate and comprehensive follow-up program for high-

risk infants will help detect and manage any morbidity associated
with perinatal events early. It shall ensure intact survival, optimum
growth, and optimal quality of life for these infants.

SETTING-UP-FOLLOW-UP CARE SERVICES

High-risk Clinic: Follow-up of high-risk infants should be done in a

dedicated high-risk clinic (HRC). A detailed description is provided
under "Procedure for follow-up."
High-risk Follow-up Team: High-risk infant follow-up requires a
multidisciplinary approach and an experienced and dedicated team,
including personnel from various specialties. Ideally, the team should
comprise a neonatologist/pediatrician, a clinical psychologist and an
early interventionist, a physiotherapist, an occupational therapist, a
neurophysiologist and speech therapist, a nutritionist, and a medical
social worker. An ophthalmologist and pediatric neurologist should
also be a part of the team, available for ready referral.
The neonatologist /pediatrician is the nodal person of the team
who provides and coordinates for holistic management of the high-
355
 356 AIMS Protocols in Neonatology

risk infant and counsels the family. The responsibilities include

assessing the child on each visit, including growth and nutrition,
managing ongoing morbidities, neurodevelopmental screening, and
coordinating care with different specialists involved in managing
the infant. Clinical psychologist performs formal developmental
evaluation and manages behavioral and other domain-specific
problems, while early interventionists work to enhance and
facilitate the development of milestones in all domains of action;
the physiotherapist is primarily responsible for the assessment and
grading of muscle tone and power and plan appropriate training for
an infant with tone abnormalities, prescription of appliances/ casts
and rehabilitation of infants with impairment/disability and the
occupational therapist works to promote neuro-motor coordination
and perceptual skills, fine motor functions, oro-motor coordination
and training in activities of daily living like feeding, bathing, and
dressing of children with special needs. Nutritionist can provide
detailed complementary feeding advice and serves to manage
infants with failure to thrive and those with special conditions
(e.g. inborn errors of metabolism). The medical social worker is
an essential interface between the follow-up care team and family,
who helps to address parental expectations and social and socio-
economic issues and coordinates for rehabilitation and integration of
infants with impairment/disability. An ophthalmologist is required
for treatment and follow-up of ROP and visual assessment and
management of refractory errors, strabismus, etc. Neurologist aids
in drug therapy and long-term management of neurological illnesses
such as refractory seizures. Other specialists from pediatric genetics,
pediatric surgery, pediatric cardiology, pediatric gastroenterolog:
hematology, etc. may be consulted as and when required.
As outlined above, all setups may not have a complete team of
specialists. It is, therefore, essential that simple tools be available
and the nodal person of the team have working knowledge of all
the domains. Ideally, all the services should be provided under one
roof as far as possible, and appropriate referrals should be sought
as required. The days and timings of the different clinics and the
appointment schedule should be marked on the patient's recurds,
and multiple visits should be avoided.

WHO NEEDS FOLLOW-UP CARE?

A rigorous follow-up of all the neonates discharged from a particular

• Section 10
health facility would neither be practical nor feasible. Therefore
 Follow-up of high-risk Neonates 357

selecting a cohort of neonates at a higher risk of developing adverse

outcomes is essential—'at-risk' or 'high-risk' infants are critical.
Selection of high-risk infants should be based on the gestational
age, birth weight, occurrence and severity of perinatal/neonatal
illnesses, interventions received in the neonatal intensive care unit
(NICU), presence of malformations, etc.
There are no standardized criteria for defining high-risk infants,
even in tertiary care centers. Commonly used criteria have been
outlined here (Table 34.1). These may be modified depending on
the level of neonatal care provided by the unit and the mix of the
neonatal population the unit caters to.
PREREQUISITES FOR FOLLOW-UP

Discharge planning. Discharge planning should ideally begin many

days before discharge. This gives adequate time to the caretakers to
ask questions and practice skills. The following criteria should be
fulfilled before discharging a high-risk infant:
• Hemodynamically stable; able to maintain body temperature in
an open crib.
• On full enteral feeds (either direct breastfeeding or by paladai/
spoon).
Table 34.1: High-risk neonates who need follow-up care in a tertiarly care
setting
1. Birth weight <1500 grams.
2. Gestation <32 weeks.
3. Infants with BW of 1500 g or more OR gestation 32 week or more AND
a. Intrauterine growth <3rd centile.
b. Meningitis.
c. Received mechanical ventilation for 48 hours or more.
d. Hypoxic ischemic encephalopathy stage 2 or higher.
e. Major malformations.
f. Inborn error of metabolism/chromosomal or genetic disorders/
intrauterine infections.
g. Symptomatic hypoglycemia.
h. Symptomatic polycythemia.
i. Retrovirus positive mother.
j. Hyperbilirubinemia requiring exchange transfusion OR Rh
isoimmunization/cholestasis.
k. Abnormal neurological examination at discharge/seizures.
I. Major morbidities such as chronic lung disease, IVH grade III or more
(Papile's classi cation), and periventricular leucomalacia.
fi
358 AlIMS Protocols in Neonatology

• Parents are confident enough to take care of the infant at home.

• Heat it insult days ais sel ow dith weight

infants, weight should be at least 1600 g before considering
discharge.
• Not on any medications (except for vitamins and iron
supplementation). Ideally, preterm infants on theophylline /
caffeine therapy for apnea of prematurity should be off treatment
for at least 5 days to ensure no recurrence.
• Received vaccination as per schedule (based on postnatal age).
These criteria can be individualized to meet the infant and
family's needs.
Counseling before discharge: Counseling is essential in caring for
these high-risk infants at home; regular counseling sessions should
be done before discharge. Parents should be advised regarding the
following:
• Temperature regulation —proper clothing, cap, socks, kangaroo
mother care, etc.
• Feeding-The focus should be on exclusive breastfeeding.
If required, other types and amounts of milk, method of
administration, and nutritional supplementation, if any, should
be advised as per the child's need.
• Prevention of infections —handwashing, avoidance of visitors, etc.
• Follow-up visits—where and when (refer to Table 34.2).
• Danger signs-recognition and where to report if symptoms are
present.
• Vaccination-schedule, next visit, etc.
• Special needs-e.g. subsequent visits for ROP screening, USG/
MRI brain, etc.
If possible, the family should be provided with the telephone
number of the nursery/health care provider, e.g. the on-duty
doctor, in case the family needs to consult for the infant's illness in
an emergency or otherwise.

PROCEDURE FOR FOLLOW-UP

The family must be provided with a structured discharge summary,

including the details of important events during the hospital stay;
investigations and treatment received, and the schedule of follow-
up visits. The venue and follow-up dates should be indicated on
the discharge summary.
 Follow-up of high-risk Neonates 359

High-risk Clinic: A specified site should be earmarked for follow-

up services. The venue, days, and timings of the clinic should be
fixed. Prior appointments should be given, and ad-hoc visits should
be discouraged. Registration procedures at the clinic should be
simplified to avoid any undue delays.
Venue: Dedicated rooms) in the OPD premises should be
designated for high-risk follow-up.
Days and Timing: One or more fixed days and times of the week
should be allocated for the clinic.
Registration: The high-risk infant should be registered at the clinic
on the first visit following hospital discharge. An OPD card for the
same should be made.
Record Maintenance: A separate file for each high-risk infant should
be made on the day of infant registration in the HRC. The HRC
case file should have a uniform format and include the following
information for each infant:
• Demographic and contact details of infants' family.
• Detailed diagnosis at discharge.

• Details of any intermittent morbidities / any critical investigations,

e.g. cranial USG/ MRI brain.
• Reports of hearing and vision (ROP) screening, as applicable.
• Nutritional details.
• Anthropometry (weight, head circumference, and length).
• Developmental screening chart.
• Neurological assessment proforma.
• Immunization details.
• Doctor's evaluation and note.
A copy of the discharge summary should be maintained in all
these files for a ready referral. Essential details and advice should
also be noted in the OPD card.

WHEN TO FOLLOW-UP

The follow-up schedule should be explained to the parents at

discharge and should also be mentioned in the discharge summary
(see below).
For follow-up visits, at-risk infants can be grouped under two
major categories:
 360 AliMS Protocols in Neonatology

Table 34,2: Follow-up schedule for at-risk infants

Very preterm infants (<32 weeks or <1500 g)
• After 3-7 days of discharge to check if the infant has adjusted well in the
home environment.
• Every 2 weeks until a body weight of 3 kg (6, 10 and 14 week immunization
visits to be covered during these visits).
• Al 3, 6, 9,12, 15 and 18 months of corrected age and then every 6 months
until 8 years of age.
• More visits if required.
Infants with other conditions
• Two weeks after discharge
• At 6, 10, 14 weeks of age
• At 6, 9, 12, 15 and 18 months of corrected/postnatal age, as applicable and
then every 6 months until 8 years of age
• More visits if required.

• Very preterm or very low birth weight (VLBW; <1500 g) infants

and
• Infants with other conditions
The follow-up schedule for both these categories has been
summarized in Table 34.2. This schedule represents a minimum
number of visits for high-risk neonates. More frequent visits are
recommended if the infant has ongoing issues or illness. Note that
first contact of the infant with the health providers after discharge is
essential and helps identify adjustment problems at home. Ideally,
this contact should be achieved by the home visit, preferably within
the first week of discharge.
Very low birth weight infants or those born at less than 32 weeks
gestation (or bigger and sick infants) should be followed up for an
eye check-up for retinopathy of prematurity till the postnatal age
of 44 weeks (see chapter 35: ROP protocol).
Some neurological abnormalities identified in the first year of
life are transient or improve, whereas findings in other children
may worsen over time. Standard follow-up for many multicentes
networks is currently at 18-24 months corrected age. By 12 months,
corrected age, the cognitive and language assessment can be done.
By 18-24 months of corrected age, there is an improved prediction
of early school-age performance.'-8 Long-term follow-up is essential
because minor neurological disabilities may not be detected earli
• Section 10
and become apparent only with increasing age.
 Follow-up of high-risk Neonates 361

Practice tip!
Corrected age: Age of the child since the expected date of delivery. The
correction for gestational immaturity at birth should be done until 24 months
age. All anthropometric parameters and developmental milestones are assessed
according to corrected age to compensate for the prematurity. The initiation
of complementary feeds is also according to corrected age.
Postnatal age: Age of the child since birth. Immunization is done according
to postnatal age.

WHAT SHOULD BE DONE AT FOLLOW-UP?

Table 34.3 summarizes the follow-up plan.
1. Assessment of feeding and dietary counseling: Parents should
be asked about the infants' diet and offered dietary counseling
at each visit. Breastfeeding frequency and adequacy should be
assessed. The amount, dilution, and feeding mode should be
noted if supplemental feeding is given. It is a good idea to enquire
about the source of milk as milk supplied by local vendors is
often diluted (dilution has the same impact on the infant whether
done by the family or the vendor!). It is also essential to record
the duration of exclusive breastfeeding. If an infant is not gaining
adequate weight on exclusive breastfeeding, take care of any
illness or maternal problems which may interfere with feeding
and milk output. Supplementation may be considered if poor
weight gain persists despite all measures to improve breast milk
output.
We start complementary feeding at six months of corrected age.
Initially, semisolids should be advised as per the local cultural
practices. Spend adequate time explaining what and how to
give. Giving too little or dilute complementary food, such as
rice-water, dal-water, too much juice, etc. should be discouraged
(Table 34.4)?
Complementary foods (CF) should include a variety and
adequate quantities of food groups (meat, poultry, fish, or eggs, as
well as vitamin A-rich fruits and vegetables) daily. If not possible,
use fortified foods and vitamin-mineral supplements to ensure
adequate nutrient intake. As infants age, complementary foods
should change from semisolid to solid, and the variety of foods
should also increase. By eight months, infants should eat 'finger
foods.' By 12 months of age, most children eat family food.
Micronutrient supplementation: The LBW Feeding protocol may
be referred to for the same. • Miscellaneous
 362 AlIMS Protocols in Neonatology

...8 years

24..

18

15

12 *
All visits All visits
As indicated

All visits and as and when required

As per schedule (based on postnatal age)

Table 34.3: Follow-up plan for high-risk infants

ROP screening
All visits
Age in months

USC/MRI brain " If the previous test abnormal

Growth monitoring Ongoing morbidities Neurological examination Developmental screening Hearing (BERA) Ophthalmic evaluation
Assessment counseling
Assessment of feeding and dietary
Immunization
Formal developmental assessment

• Section 10
 Follow-up of high-risk Neonates
363

Table 34.4: Amount and frequency of complementary foods

LAge. Foods Frequency

6-8 months Thick, soft porridge (khichri/dalia); Breastfeeding plus
add sugar and oil mixed with either 2-3 meals per day
milk or pounded ground nuts.
Mixtures of mashed foods made of
potatoes or millet or rice; mix with
sh or beans or pounded groundnuts;
fi
add green vegetables
9-11 months -Do- Breastfeeding plus 3-4
Give nutritious snacks between meals, meals/day plus one
like eggs, bananas, or bread snack between meals
12-24 months -Do- 3-4 meals/day plus
Family foods, chopped or mashed if two snacks between
necessary meals

2. Growth monitoring: Growth (including weight, head

circumference, and length) should be monitored and plotted on
an appropriate growth chart at each visit. The infant's growth
pattern (slope of the curve) is compared with the standard curve;
any deviation should be noted and appropriate remedial action
taken. We use Fenton's charts (till 50 weeks postmenstrual age;
PMA)' and WHO growth charts after that for growth monitoring
of preterm neonates."
Anthropometry should be taken during follow-up visits. Weight
and head circumference should be monitored at each visit and
length three monthly. These should be marked on the gender-
specific WHO-MGRS growth charts. The Corrected age of the child
should be used while using these charts for preterm infants.

3. Immunization: Parents should be offered the option of additional

vaccines such as hepatitis B, Hemophilus influenza B, and MMR
(where not in the routine immunization schedule) if they can
afford them. Immunization should be ensured according to
chronological age.
4. Ongoing morbidity surveillance and management: Ongoing
morbidity and its management is one of the essential services
a follow-up clinic is meant to provide. These may relate to
prolonged jaundice, recurrent exacerbations of respiratory
distress in a child with chronic lung disease, gastroesophageal
re ux or other feeding dif culties or inadequate weight gain in
fl
fi
364 AlIMS Protocols in Neonatology

a preterm infant, anemia in an infant with Rh immunization,

cardiac failure in an infant with congenital heart disease,
diagnostic evaluation and intermittent illnesses in an infant bom
to HIV positive mother, etc. The details of any such intermittent
morbidity / hospitalization should be systematically recorded in
the high-risk file as well as the OPD card of the infant.
5. Developmental follow-up:12 Early identification of infants who
are at risk of developmental disability allows for appropriate
parent counseling and for planning for the child's future. This
counseling and planning should consider the uncertainty of
standardized developmental screening tests that should be
performed at 3, 6, 9, 18, and 24 months of corrected age. Regular
screening is more helpful than a single screening to identify
problems, especially in later-developing skills such as language.
Screening does not help in making a diagnosis or designing
a treatment plan but helps identify areas where a child's
development differs from same-age norms.
Early identification of developmental problems should lead
to further developmental and medical evaluation, diagnosis,
and treatment, including early developmental intervention.
A pediatrician/ neonatologist must be well-versed in the normal
developmental milestones and be able to use the available
screening tools effectively so that a formal developmental
evaluation is required only for the most deserving cases.
We currently use Trivandrum Developmental Screening Chart
(TDSC) in our clinic. DDST-Il is also used in some places, though
it requires some training before it may be used. Table 34.5 lists
the commonly available and used screening tests in India.
Practice tip!
Waiting until a child misses a major milestone such as walking or talking
may delay the recognition of a problem that deprives the child bene ts of
fi
early intervention.

Additional tools like VSMS, CBCL, and M-CHAT may be

used beyond infancy (beginning at 18 months of age) for social,
emotional, behavioral, and autism evaluation, respectively
(Table 34.6).
A formal developmental assessment is done using DASI,
which is the Indian adaptation of BSID-Il and is considered to be
the gold standard to date in Indian settings. It measures motor and
mental domains using 230 items in children between 0-30 months
 Follow-up of high-risk Neonates 365

Table 34.3; Developmental screening lest commonly avallable in India

Test Domains Age range No. of Psychometric
assessed items properties
Trivandrum Gross motor, 0-2 years 17 Sensitivity
Development Fine motor, 66.7%;
Screening TestVision/hearing, Specificity
(TDSC)!3 and personal/ 78.8%; validated
social/language against DDST
Denver Gross motor, 0-6 years 123 Sensitivity 83%;
DevelopmentalLanguage,
Screening Fine motor—
Test-ll adaptive, and
Specificiy
(DDST -Il) or/ personal-social.
Denver-ll Also, a behavior
rating scale
Baroda Motor and 0-30 months 54 Sensitivity and
Development mental speci city of

fi
Screening Test 65-95%
(BDST)15

Table 34.6: Other tools relevant to developmental evaluation early in life

Test Brief description Age

Screening tools
Modi ed checklist To identify children who may bene t 16-30 months
fi
fi
of autism for from a more thorough developmental
toddlers (M-CHAT) and autism evaluation
Vineland social Indian adaptation by Malins is 0-15 years
maturity scale available
(VSMS)
in she colorin areas soli-sis
general, self-help eating, self-help
dressing, self-direction, occupation,
communication, locomotion, and
socialization
Vineland adaptive It is a revision of the Vineland social Birth-90 years
behavior scale-ll maturity scale (VSMS)
Assesses personal and social adaptive
behavior skills in five domains-
communication, daily living skills,
socialization, motor skills, and
maladaptive behavior (optional)
(Contd.)
 366 AlIMS Protocols in Neonatology

Table 34.6: Other tools relevant to developmental evaluation eady int

(Conta.)
Test Brief description Age
Screening tools
Child Behavior Assesses different domains of 1.6-5 years
Checklist-Languagebehavior like emotionally reactive,
development anxious depressed, somatic
survey complaints, withdrawn, sleep
(CBCL-LDS 1½) problems, altention problems, and
aggressive behavior, along with
language

of age. However, such tools are considered ideal to be periodically

revalidated to account for secular trends. Also, since the arrival
of BSID-IlI, which helps assess neurodevelopment in different
domains (Cognitive, Language-receptive and expressive, fine
and gross motor, socio-emotional, and adaptive behavior) till
42 months of age, it should be adapted and validated for use in
India. Additional diagnostic tools for autism, intelligence, and
specific learning disabilities may also be required as the child
grows up (Table 34.7).

able 34.7: Few diagnostic tools relevant to high-risk infants

Test Brief description Age
Development • An Indian adaptation of Bayley-ll, standardized Birth-
Assessment on the Indian population. 30 months
Scale for • Assesses two domains—Motor and mental.
Indian Infants • Gives the developmental age of a child
(DASII) expressed as the percentile of normal.
• Provides developmental quotients comparing
the developmental and corrected age of the
child.
Childhood • Behavior rating scale. 3-22 years
Autism • Assessment on fifteen items-relationship to
Rating Scale people, imitation, emotional response, use of
(CARS) body and object, adapt to change, visual and
listening response, response to taste-smell-
touch, presence of fear and nervousness,
verbal and non-verbal communication, activity
level, intellectual response, and general
impression.
• Section 10
(Contd.)
 Follow-up of high-risk Neonates
367

Table 34.7: Few diagnostic tools relevant to high-risk infants (Contd.)

Brief description
Test
Age
Wechsler • Test of Intelligence for younger children. Divided
Preschool • Provides verbal 1Q, periormance 1Q, and full- into two
and Primary scale IQ. age bands:
Scale of • Comprises 14 subsets of three types: core, 2 years
Intelligence- supplemental, or optional, which are - receptive 6 months
Third Edition vocabulary, block design, information, object to 3 years
(WPPSI-III) assembly, picture naming, similarities, symbol 11 months
search, vocabulary, word reasoning, coding, and
comprehension, picture completion, matrix 4-7 years
reasoning, and picture concepts.
3 months
• Children in the two years 6 months - 3 years
11 months age band are administered only the
initial ve subtests.
fi
Malins • An Indian adaptation of Wechsler's Intelligence 6-15 years
Intelligence Scale for Children. 11 months
Scale for • Gives verbal and performance 1Q.
Indian • Assess the following items:
Children - Verbal IQ-Information, comprehension,
(MISIC) arithmetic, similarities, vocabulary, digit span.
- Performance 1Q-Picture completion, picture
arrangement, block design, object assembly,
coding, and mazes.
• Based on test scores, the intelligence grades
are provided as extremely Low, borderline, low
average, average, high average, superior and
very superior.
NIMHANS • The battery of tests for evaluating children Two age
Battery for suspected of having learning disabilities bands:
speci c (dyslexia, dysgraphia, dyscalculia). 5-7 years
fi
learning • Consists of 2 levels for assessment of pre- and
disabilities academic skills for 5-7 years (includes evaluation 8-12 years
of attention, auditory and visual discrimination,
visual and auditory memory, speech and
language, visual-motor, and writing and number
skills) and academic skills at level 2 for age 8-12
years (which include attention, reading, spelling,
perceptual-motor, visual-motor integration,
memory, and arithmetic skills).

Also, if feasible, an objective assessment of the home

environment shall be a good adjunct to any developmental
evaluation of such children.
368 AlIMS Protocols in Neonatology

6. Neurologic examination: The main focus of neurological

assessment during the high-risk follow-up visits is usually the
evaluation of muscle tone besides vision and hearing. However,
a complete neurological examination should be performed
if indicated in a particular child. Amiel Tison's neurological
assessment is currently the most widely used neurological
examination tool during early follow-up of infants.
Evaluation of muscle tone is an integral part of the neurological
examination. A waxing and waning pattern of neuromotor
development from 28 weeks of gestation to the end of the first
year of life was reported by Amiel-Tison. From 28 to 40 weeks
gestation, muscle tone and motor function acquisition spread
from the lower extremities towards the head (caudo-cephalic
progression). After full term, the process is reversed so that
relaxation and motor control proceed downwards for the next
12-18 months (cephalocaudal). So, the upper limbs begin to relax
and acquire skills before the lower limbs. The axial tone follows
a similar pattern. Head control appears first, followed by the
ability to sit, stand and walk. Hypertonia or hypotonia should
be examined by measuring the following angles: adductor angle,
popliteal angle, ankle dorsiflexion, and scarf sign; any asymmetry
between the extremities should also be recorded. Any history of
seizures or involuntary movements should also be recorded.
The following angles should be measured to assess tone, as
shown in Table 34.8:
The Hammersmith Neonatal Neurological Examination (HNNE)
is a practical and easy-to-perform neonatal neurological
examination that has 34 items assessing tone, motor patterns,
observation of spontaneous movements, reflexes, visual and
auditory attention, and behavior.16 Each of the 34 items is

Table 34.8: Muscle tone norms (Amiel-Tison)

Age Adductor. Popliteal Dorsiflexion Scarf sign
(mo)_ angle angle angle
0-3 40-80° 80-100° 60-70° The elbow does not cross
the midline
4-6 70-110°
90-120° 60-70° Elbow crosses midline

7-9 110-140° 110-160° 60-70° The elbow goes beyond

the axillary line
10-12 140-160° 150-170° 60-70°
 Follow-up of high-risk Neonates 369

assigned a score ("raw score"). Each row for a particular item is

scored as 1,2,3,4,5 and if an item falls between two columns, it
is given ½ score, e.g. 3.5. Individual optimality score is assigned
for each item based on the raw score and the total optimality
score is calculated by adding individual optimality score. The
maximum possible score is 34. The presence of a suboptimal
score does not mean that a neonate is abnormal. It just means
that the neonate needs to be reassessed. The number of items
falling outside the 90th centile is a better predictor of the severity
of the outcome than global optimality. Preterm infants at term
are more hyperexcitable and have less flexor tone in the limbs
and less extensor tone in the neck in the sitting posture. They
have a wider range in individual optimality scores than term.
They generally have a wide range and lower scores and it may
be difficult to define an optimality cutoff.
Cerebral palsy usually presents with definitely abnormal
neurological examination with upper motor neuron signs with
motor developmental delay. Hypertonia in lower limbs is defined
as when either adductor angle is restricted to less than the age-
specific norms as per Amiel-Tison or if there is scissoring or tight
tendo-Achilles or restriction of ankle dorsiflexion on extension of
knee. Hypertonia in upper limbs is defined as when the scarf sign
does not cross the midline at one year corrected age. Hypertonia
of the neck extensors can be inferred by an increased gap between
the nape of the neck and examination table with the infant lying in
the supine position. Truncal extensor hypertonia is present when
the body tends to go into hyperextension or opisthotonus. Any
tone abnormality requires a detailed evaluation and management
by a trained physiotherapist.
The level of function in cerebral palsy should be categorized
according to the Gross Motor Functional Classification System
(GMFCS). Notably, even in children without cerebral palsy, the
prevalence of motor impairment is 19% for moderate impairment
and 40% for mild-moderate impairment. With advances in
neonatal intensive care, a new era of this no-CP "high-risk
neonates" may be emerging. To identify these issues the first
formal assessment is done at 3 months corrected age. As a single
assessment is not sufficient, longitudinal follow-up is required
up to at least two years.

During follow-up, at the end of 12 months, three major patterns

can be identified: • Miscellanents
370 AlIMS Protocols in Neonatology

a. Normal at all examinations,

b. Tone abnormalities and developmental delay suggests a
definite brain injury, or
c. Abnormal development at 3, 6 months age and improving at
9 months and normal at 12 months age.
This third pattern of transient tone abnormalities has been
described in preterm infants as neurological abnormalities which
present early and disappear by 1 year of age. These infants have
similar 1Q compared to normal children but have significantly
poor scores in cognitive function and are more likely to present
as learning difficulties as they grow older.
7. Hearing evaluation: High-risk infants have a higher incidence
of moderate to profound hearing loss (2.5-5% vs. 1% in normal
infants). Since clinical screening is often unreliable, brainstem
auditory evoked responses (BAER/BERA) should be performed
on these infants before three months of postnatal age.
We do a screening BERA (Automated Auditory Brainstem
Response-AABR) initially in all cases before discharge. 18 Those who
fail on the first screen are re-screened before discharge to minimize
the false positivity rates! Those failing on the second screen are
referred for a diagnostic BERA in the Department of ENT.
• OAEs may be used at both steps in infants without risk factors,
but for infants with risk factors, it is imperative to use an
AABR for the initial screen so that neural hearing loss will
not be missed
• For premature infants (born at <34 weeks of gestation), hearing
screening should ideally be done after they reach 34 weeks
postmenstrual age as it has been shown to decrease false
positive results.
• For readmissions in the first month of life for all infants at high
risk (e.g. hyperbilirubinemia requiring exchange transfusion
or meningitis), a repeat hearing screening is recommended
before discharge.
• Any infant missing the initial screen should be instructed to
return for a screen after six weeks, which may coincide with
the immunization visit (to minimize fallouts).
However, even after a two-stage screening with an OAE pass
followed by an AABR pass, permanent hearing loss has been
significant.
ups.21 20 Therefore, it is essential to continue hearing tollow-
 Follow-up of high-risk Neonates 371

8. Vision assessment: Besides the check-up for retinopathy of

prematurity which should start in the NICU and continue till
40-44 weeks postconceptional age or till the retinal vessels
have matured (refer to Chapter 35: Retinopathy of Prematurity),
the children should have an assessment for eye problems in
the newborn period and then at all subsequent routine health
supervision visits. The eye evaluation during follow-up should
include the following:22

Ocular history: Parents' observations are valuable and should

be sought. Ask questions such as:
a. Is the child able to see well?
b. If the child holds objects close to her eyes while focusing?
c. Do they find the child's eyes straight?
d. Do the eyes seem to cross or seem hazy?
e. Do eyes appear unusual?
Vision assessment: The vision is evaluated by assessing the
capability to fix and follow among children younger than
three years or those not verbal yet. One should determine if
an eye can fix and maintain it on an object and then be able to
follow the object in different positions. If a child fails to do so,
it indicates a significant visual impairment. The assessment
should be performed with both eyes together and each eye
separately. If there is a poor fixation and following binocularly
after the age of 3 months, one should suspect a significant bilateral
eye or brain abnormality. In such cases, a formal assessment is
required. These examinations should only be done if the child is
awake and alert, as disinterest or lack of cooperation may mimic
a poor vision response.
In addition, an external evaluation of the different eye
structures, including lids, conjunctiva, sclera, cornea, and iris,
should be performed, and ocular alignment should be checked.
Strabismus can occur at any age, indicating serious orbital,
intraocular, or intracranial disease. Examine pupils and red reflex
to detect opacities in the visual axis, such as cataracts, corneal
abnormality, or abnormalities in the posterior side of the eye,
including retinal detachment. Examination of both eyes together
permits the detection of potentially amblyopic conditions like
asymmetric refractive errors or strabismus.
Visual acuity should be formally assessed at nine months of
age using the Cardiff or the Teller acuity cards. Rehabilitation
372 AlIMS Protocols in Neonatology

for visual impairment should be early so that the child gets

appropriate stimulation. The child should be provided with
glasses or corrective surgery as appropriate.
9. Role of neuroimaging:23
For very preterm neonates: Routine screening cranial ultrasound
(CUS) is recommended for preterm neonates below 32 weeks
gestation at the postnatal age of 7-14 days and between 36 and
40 weeks PMA. MRI brain detects more abnormalities than CUS;
however, the current evidence does not support its routine use
for neurodevelopmental prognosis.
Term infants with asphyxia: The conventional (T1, T2) and
diffusion weighted (DWI) MRI scans can help in diagnosis
(global hypoxia-ischemia, focal infarction), time of insult,
and the outcome. The conventional MRI performed during
the neonatal period carries a pooled sensitivity of 91% and
specificity of 51% to detect abnormal neurological outcomes at
≥1 year.
Timing of scan: The prognostic utility of MRI has been shown
from days 3-14. Late MRI (days 8-30) has higher sensitivity than
early MRI (days 1 and 7) for prediction of outcome at age one
year.
Term neonates with bilirubin encephalopathy: An MRI should
be considered for infants with bilirubin encephalopathy. It
should be done in the newborn period once the infant is clinically
stable.
Early Enrichment
The evidence concerning the usefulness of early stimulation and
intervention for high-risk neonates is limited to preterm and low
birth-weight infants, mostly from developed countries.24

What is the evidence

The Newborn Individualized Developmental Care and Assessment Program
(NIDCAP) developed to stimulate preterm infants at levels adapted to the
child's degree of neurological maturity shows promising ndings, primarily
fi
on cognitive and motor development, though the scienti c evidence on the
fi
effects is limited. 25
Early intervention programs (beginning in NICU and post hospital discharge)
suggest positive in uence on cognitive and motor development. 24, 25
fl
Early intervention programs from birth to nine years for children with physica!
disabilities result in positive outcomes for both children and families. 26
 Follow-up of high-nsk Neonates 373

A few measures that may help have been outlined below. These
include tactile, kinesthetic, auditory, and visual components:

Firth-2 months Place your infant's head and neck on the crook of your
elbow and forearm while lifting or carrying her.
2-4 months Help your infant to roll by placing her on either side
and calling her name or making a sound with the rattle
from behind encouraging her to turn.
+-6 months Play different types of music for her to listen.
Make her sit in front of the mirror and imitate the sounds
that she makes.
Roll a medium size ball gently in front of her for her
to follow.
Give her small light rattles to hold in each hand.
Encourage her to sit by herself leaning on her arms and
taking their support.
Start an activity that she enjoys and then stop to see if
she moves her body in the same manner to indicate her
desire to continue the play.
6-8 months Give her a spoon to bang on a steel plate, a small drum
to bang her hand on, a rattle to shake, and paper to
crumble and tear (please be there when she is playing
with paper).
Cover your face with a plain cloth, slowly remove it
and say jha or thuki, and hug her. Repeat the activities
a couple of times on yourself and then take her hand
to pull off the cloth. Once she is familiar with the game
cover her face and you pull off the cloth, clap, and
show excitement.
Call the child by one name only and encourage her to
respond by smiling at her if she looks.
Make her sit independently for 5-10 mins by putting
her brightly colored and musical toys in front of her. If
she loses balance, after some time help her to sit again
by holding her by the hips lightly.
Encourage crawling when she is on her tummy by
placing her favorite toy in front of her just a little out
of her reach so that she has to stretch her hands and
push herself forward.
Repeat the sounds of da da, ma ma, ga ga, ba ba that
she makes. Pretend you understand them and answer
back in your mother tongue with different intonations.
Keep talking to her and naming all the family members
who come to her, hold or play with her.
(Contd.) • Miscellaneous
 AlIMS Protocols in Neonatology
374

(Contd
Put two blocks in each hand and encourage her to bang
8-10 months
them together while looking at them. Encourage her to
clap her hands.
Hold her hand and help her to take out toys one by one
from a tub lled with toys. Once she has learned to take

fi
out the toys, hold her hand and encourage her to drop
the toys back into the tub one by one.
When a family member leaves, ask her to wave bye
bye.
Take her in your lap and show her picture books with
single, large, colorful pictures of everyday objects and
animals. You name and point at the pictures.
10-12 months Show her the functions of objects used in daily life,

like glass for drinking, mobile for talking, comb ior

Encourage her to hold furniture and take some steps
around it.
12-15 months Take her hand and help her to point to a loy or any
food item she wants. You say the name of the toy and
encourage her to take out a sound resembling the name.
Hold her lightly from the back and give her the
con dence to take a few steps on her own.
fi
HOW TO ENSURE A GOOD FOLLOW-UP RATE

A good follow-up rate may be ensured through the following:

The importance of follow-up should be routinely emphasized to
the parents during the hospital stay. Elder members of the family,
especially grandmothers should be involved in the process.
The permanent and present addresses of the families should be
maintained, along with phone numbers. It shall be ideal if a person
of follow-up team like the medical social worker can make an early
visit to the infant's home, either at discharge or within 48-72 hours
of discharge.
1. It is highly desirable that a permanent 24 x 7 helpline no. be
provided to the family at discharge to contact in case of any
problem. Regular contact with the parents with inquiry about
the status of the child during follow-up shall be helpful.
2. An easily accessible, less time consuming, and hassle-free
organizational flow of follow-up services, including the provision
of comprehensive assessments under one roof shall encourage
parents to come for regular follow-ups.
 Fellow-up of high-risk Neonates 375

3. A person who serves as care coordinator and handles all

appointments and services shall add to the quality of care
experience of the families coming for follow-up.
Practice tip!
The most important determinant of if the family would come for follow-up is
the availability of comprehensive and reliable clinical services that family can
access easily in a digni ed manner.
fi
REFERENCES
1. National neonatology forum of India, National neonatal perinatal database-
2002-2003.
2. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long term neurodevelopmental
outcomes after intrauterine and neonatal insults: a systematic review. Lancet
2012 Feb 4;379(9814):445-52. Epub 2012 Jan 13.
3. MKC Nair, Chacko DS, Paul MK, Nair L, George B, Kumar GS. Low birth
weight infants- outcome at 13 years. Indian Pediatrics, vol 46 supplement,
jan 2009 571-574.
4. Chaudhari S, Otiv M, Chitale A, Pandit A, Hoge m. Pune low birth weight
study-cognitive abilities and educational performance at twelve years. Indian
Pediatr 2004 Feb;41:121-8.
5. Drillien C. Abnormal neurological signs in the rst year of life in low birth
fi
weight infants: possible prognostic significance. Dev Med Child Neurol
1997;14:575-84.
6. Weisglas-Kuperus N, Baerts W, Smrkovsky M, Sauer PJ. Effects of biological
and social factors on the cognitive development of very low birth weight
children. Pediatrics. 1993; 92:658-65.
7. Dezoete JA, MacArthur BA, Tuck B. Prediction of Bayley and Stanford-Binet
scores with a group of very low birthweight children. Child Care Health
Dev.2003; 29:367-72.
8. Lee H, Barratt MS. Cognitive development of preterm low birth weight
children at 5 to 8 years old. / Dev Behav Pediatr. 1993; 14:242-9.
9. Guiding principles for complementary feeding of the breastfed child. Freely
downloadable from WHO website (http://whqlibdoc.who.int/paho/2003/
a85622.pdi).
10. Fenton TR, Nasser R, Eliasziw M, Kim JH, Bilan D, Sauve R. Validating the
weight gain of preterm infants between the reference growth curve of the
fetus and the term infant. BMC Pediatr. 2013 Jun 11;13:92.
11. De Onis M, Onyago AW, J, Chumlea WC, Martorell R. Measurement
and standardization protocols for anthropometry used in the construction
of a new international growth reference. Food Nutr Bull 2004 Mar;25(1
suppl):s27-36.
12. Council on Children with Disabilities, Section on Developmental Behavioral
Pediatrics, Bright Futures Steering Committee and Medical Home Initiatives • Miscellaneous
376 AIMS Protocols in Neonatology

for Children with Special Needs Project Advisory Committee. Identifying

infants and young children with developmental disorders in the merli l
home: an algorithm for developmental surveillance and screening. Pedians
2006;118:405-20.
13. Nair MK, George B, Philip E, Lekshmi MA, Haran JC, Sathy N. Trivandrum
Developmental Screening Chart. Indian Pediatr 1991 Aug; 28(8):869-72.
14. Glascoe FP, Byrne KE, Ashford LG, Johnson KL, Chang B, Strickland B
Accuracy of the Denver-ll in developmental screening. Pediatrics 1992
Jun;89 (6 Pt 2):1221-5.
15. Phatak AT, Khurana B. Baroda development screening test for infants. Indian
Pediatr 1991 Jan;28(1):31-7.
16. Dubowitz L, Mercuri E, Dubowitz V. An optimality score for the neurologic
examination of the term newborn. | Pediatr. 1998 Sep; 133(3):406-16.
17. Williams J, Lee KJ, Anderson PJ. Prevalence of motor-skill impairment in
preterm children who do not develop cerebral palsy: a systematic review.
Dev Med Child Neurol. 2010 Mar; 52(3):232-7.
18. Clemens CI, Davis SA.Minimizing false-positives in universal newborn
hearing screening: a simple solution. Pediatrics 2001;107:E29.
19. Coenraad S, Toll MS, Hoeve HL, Goedegebure A. Auditory brainstem
response morphology and analysis in very preterm neonatal intensive care
unit infants. Laryngoscope 2011;121:2245-9. doi: 10.1002/lary.22140. Epub
2011 Sep 6.
20. Lin HC, Shu MT, Lee KS, Ho GM, Fu TY, Bruna S, Lin G. Comparison
of hearing screening programs between one step with transient evoked
otoacoustic emissions (TEOAE) and two steps with TEOAE and automated
auditory brainstem response. Laryngoscope 2005 Nov; 115:1957-62.
21. Committee on Practice and Ambulatory Medicine, Section on Ophthalmology.
American Association of Certi ed Orthoptists; American Association
fi
for Pediatric Ophthalmology and Strabismus; American Academy of
Ophthalmology.Eye examination in infants, children, and young adults by
pediatricians. Pediatrics 2003 Apr; 111:902-7.
22. Ment LR, Bada HS, Barnes P, Grant PE, Hirtz D, Papile LA, Pinto-Martin
J, Rivkin M, Slovis TL. Practice parameter: neuroimaging of the neonale:
report of the Quality Standards Subcommittee of the American Academy
of Neurology and the Practice Committee of the Child Neurology Society.
Neurology 2002 Jun 25;58:1726-38.
23. Thayyil S, Chandrasekaran M, Taylor A, Bainbridge A, Cady EB, Chong WK,
Murad 5, Omar RZ, Robertson NJ. Cerebral magnetic resonance biomarkers
in neonatal encephalopathy: a meta-analysis. Pediatrics 2010;125(2):
e382-95.
24. McCormick MC, Brooks-Gunn J, Buka SL, Goldman J, Yu J, Salganik M,
Scott DT, Bennett FC, Kay LL, Bernbaum JC, Bauer CR, Martin C, Woods
ER, Martin A, Casey PH. Early intervention in low birth weight premature
infants: results at 18 years of age for the Infant Health and Development
Program. Pediatrics 2006 Mar; 117:771-80.
 Follow-up of high-nsk lizonates 377
25. Wallin L, Eriksson M. Newborn Individual Development Care and
Assessment Program (NIDCAP): a systematic review of the literature.
Worldviews Evid Based Nurs 2009;6:54-69.
26. Spittle Al, Orton J, Doyle LW, Boyd R. Early developmental intervention
programs post hospital discharge to prevent motor and cognitive
impairments in preterm infants. Cochrane Database Syst Rev 2007 Apr
18;(2):CD005495
[CHAPTER

35
Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of

the retina in preterm infants. Neonates born at less than 32 weeks of
gestation are at risk of developing ROP. However, preterm infants
bor at 32 weeks or later can also develop severe ROP if they have
had a turbulent clinical course or needed prolonged oxygen therapy.
Nearly one-fourth of neonates undergoing screening may show
some degree of ROP, which regresses on its own in the majority. In
a few infants, ROP, if untreated it can progress to the stage of retinal
detachment and blindness. Timely screening and treatment of ROP
can prevent blindness and minimize visual handicaps.

What is the evidence?

Studies from India have reported ROP (any stage) in 20-52% of the screened
neonates.1-10 More recent studies have reported a lower incidence of ROP
(20-32.3%) and severe ROP (17.7%).'-3

ROP CLASSIFICATION

International Classification of ROP (ICROP) 3rd edition is used for

classifying ROP." ICROP-3 describes vascularization of the retina
and characterizes ROP by its position (zone), severity (stage), and
extent (clock hours) (Fig. 35.1 and Table 35.1).
Aggressive ROP (A-ROP): This is a type of ROP with rapidly
developing pathological neovascularization along with a severe
plus disease. The typical feature of A-ROP is the risk of rapid
progression to retinal detachment without sequential progression
through the typical stages of ROP. A-ROP may also show abnormal
retinal vessels posterior to the previous edge of vascularization.
If not detected and managed, A-ROP can progress rapidly to retinal
detachment. Although, typically described to develop in zone 1 or
posterior zone 11 (hence, previously called aggressive-posterior
ROP) and in extremely preterm neonates, this form of ROP has also

378
 Retinopathy of Prematurity 379

Name L JCR noL _ GA at birth !. J Date of screenind !!

Zone III Posterior

Zone Il zone Il Zone Ill
Zone 1l

Zone I Zone I

Clock
Right eye Left eye
hours
6 Ora 6
serrata
_Optic_

disc
- Macula —

Stage 1 Stage 2 Slage 3

Zone' Mature immature Stage 4 Stage 5
retina No RoP

IP
Kignt eye

!
Len eye III
oner most at to on sage to mene ola notch of
if posterior zone Il is involved add (P) to the noting e.g.. zone II (P)

Type 1 ROP: Needs laser ablation

Type 2 ROP: Re-screen after 1-2 weeks

Needs surgical intervention

Follow-up required after 2 weeks

Further ROP screening not required

Next screening on

Fig. 35.1: Classi cation of retinopathy of prematurity

fi
Table 35.1: International Classi cation of Retinopathy of Prematurity
fi
Location Zone I Circle with an optic nerve at its center and a radius
twice the distance from the optic nerve to the macula.
Zone Il The concentric ring-like area from the edge of
zone I to the nasal ora serrata and similar distance
superiorly, inferiorly, and temporally.
Within zone Il, 'posterior' zone ll is de ned as an
fi
area of the size equal to the distance of two-disc
diameters from the margin of zone I.
(Contd.)
380 AliMS Protocois in Neonatolony

Table 33.1: International Clamification of Retinopathy of Prematurity (Gaeld

Remaining crescent-shaped area of retina peripher al

Zone III
to zone Il.
Severity Presence of thin white demarcation line sepateting
Slage 1
vascular from avascular retina
Addition of height and width to the demarcation line
Stage 2
of stage 1, so as the line becomes ridge
Stage 3 Presence of extraretinal fibrovascular proliferation
with abnormal vessels and fibrous tissue extending,
from ridge to vitreous
Stage 4 Partial retinal detachment not involving macula (4A)
and involving macula (4B)
Complete retinal detachment:
Stage 5
Stage 5A: Optic disc is visible by ophthalmoscopy
(open-funnel delachment)
Stage 5B: Optic disc is not visible because of
retrolental brovascular tissue (maybe closed-funnel
fi
detachment)
Stage 5C: Stage 5B plus anterior segment changes like.
marked anterior chamber shallowing, iridocorneo-
lenticular adhesions, corneal pacification (maybe
closed-funnel detachment)
Plus Presence of dilatation and tortuosity of retinal vessels
disease at posterior pole of eye within zone I. Also associated
with pupillary rigidity and vitreous haze.
Pre-plus Presence of abnormal dilatation and tortuosity of
disease retinal vessels insuf cient for plus disease, but more
fi
than normal
Extent Extent of ROP described in 30° clock hours (a total
of twelve clock hours of 30° each)
An incursion by the ROP lesion of 1-2 clock hours
Notch
into a more posterior zone. If a notch is observed
on screening, the zone of the stage is de ned by
fi
the posterior-most edge with a noting indicating the
presence of the notch.

been reported in more anterior zones of the retina and in bigger

neonates, especially in developing countries.

Regression of the ROP identified by thinning and whitening of

 Retinopathy of Prematurity 381

neovascular tissue can be detected within 1-3 days after anti-VEGF

therapy and 7-14 days after laser photocoagulation. Regression
can be accompanied by continuing normal vascularization of the
remaining retina or arrested vascularization, the latter being called
persistent avascular retina (PAR). PAR occurs with greater frequency
and may involve a larger retinal area after anti-VEGF treatment.
When documenting a retinal screening examination, PAR should
be described by its location and extent."
Reactivation: With laser ablation, the peripheral avascular retina,
the source of VEGF in pathogenesis of ROP is obliterated and can
no longer produce VEGE. However, when monotherapy with anti-
VEGF agents is used, the peripheral avascular retina remains viable
and can continue producing VEGF. As a result, the acute stage ROP
can become reactivated after a phase of regression. Reactivation
of ROP can be seen at any site including original site of ROP at
the junction between vascular and avascular retina, at a new edge
of intraretinal vascular growth, elsewhere in the vascularized
retina, or at multiple sites. Reactivation is observed most between
37-60 weeks postmenstrual age. Incidence and time of reactivation
is affected by choice of different anti-VEGF agents used and their
doses." Reactivation should be documented specifying presence
and location of new ROP features with zone and stage using the
modifier reactivated.'"
SCREENING

The aim of the screening program is to detect ROP early, follow it

up closely during its evolution, and treat if it assumes potentially
serious severity level.

Which Infants should be Screened?

Gestational age and / or birth weight are two important parameters
taken into consideration while deciding which babies to screen for
ROP.
The Rastriya Bal Suraksha Karyakaram (RBSK) recommends the
following criteria for screening:
a. Born at less than 34 weeks of gestation, OR
b. If gestation at birth is not known conclusively, birth weight below
2000 g, OR
c. Born at 34-36 weeks of gestation AND having ANY of the
following risk factors:need of respiratory support, oxygen
therapy for more than 6 hours, sepsis, episodes of apnea and need
382 AlIMS Protocols in Neonatology

of blood transfusion, exchange transfusion or unstable clinical

course as determined by pediatrician. In absence of reliable
records, admission in neonatal intensive care unit (NICU) or
special care newborn unit (SCNU) can be taken as a surrogate
risk factor.
In addition to prematurity, the aforementioned risk factors for developing ROP
represent level of sickness. Sickness is therefore an important underlying factor
that makes higher gestation preterm neonates at risk of developing ROP.

AlIMS, New Delhi instituted its ROP screening program in

early 1990s. We observed a change in the epidemiology of ROP
by early 2000s. Though milder ROP could be seen in infants of
32 weeks or more of gestation, ROP requiring treatment occurred
only in infants of less than 32 weeks gestation or sick infants of
32-35 weeks gestation. Overall, there was a significant reduction in
ROP requiring treatment. Also, AROP has occurred very rarely in
our NICU. Accordingly, we changed our screening criteria to reduce
the unnecessary painful ROP screening and to optimize resource
utilization. We believe that happened due to high quality of care
provided at AIIMS NICU. Also, a screening program being in place
helps in early ROP detection.
Our current criteria of ROP screening are as follows:
a. Born at less than 32 weeks of gestation, OR
b. If gestation at birth is not known conclusively, birth weight
below 1500 g, OR
c. Born at 32-35 weeks of gestation AND having ANY of the
following risk factors:need of respiratory support, oxygen
therapy for more than 6 hours, sepsis, episodes of apnea and
need of blood transfusion, exchange transfusion or unstable
clinical course as determined by pediatrician.
When and How often to Screen
First screening examination should be carried out at 32 weeks of
post menstrual age (PMA) or 4 weeks of postnatal age (PNA),
whichever is later.12
In neonates less than 28 weeks of gestation or with birth weight
less than 1200 g if gestation at birth is not confirmed conclusively,
the first examination for ROP should be performed at 2-3 weeks
postnatal age (PNA).
Practice tip
A good rule to remember is to perform rst screening at 4 weeks of PNA.
fi
 Retinopathy of Prematurity 383

What is the evidence?

Progression of ROP follows a distinct timeline as per PMA rather than postnatal
age PNAl of the infant. ROP may not be detected before 30 weeks of PMA or
before 2-3 weeks of PNA.
The median age at detection of stage 1 ROP is 34 weeks. The vascularization
is complete by 40-44 weeks of gestation. The critical phase during screening
is 32-38 weeks when the infant is likely to reach a severe stage of disease that
may require treatment for prevention of blindness.

Follow-up examinations are normally required every 1-2 weeks

depending upon ROP staging and should be recommended by the
examining ophthalmologist.
ROP screening can be terminated once there is complete
vascularization of retina without any ROP, or if the ROP has shown
regression. This normally happens at around 40-44 weeks of PMA.
However, if anti-VEGF agents are used for treatment, screening
examinations need to continue to detect reactivation after regression.
Where to Examine the Baby?
Neonates are best examined in the neonatal unit itself under
supervision of attending pediatrician/ neonatologist. It is not wise
to transport small babies to ophthalmic outpatient or ward for
examination.
How to Dilate the Pupils?
Pupils are dilated with a combination of phenylephrine 2.5% and
tropicamide 0.5% eye drops. The combination can be instilled
2 times at 10 min intervals half hour before screening. Alternatively,
one drop of tropicamide is instilled every 10 minutes up to 2 times
starting half hour before the scheduled time for examination. This
is followed by phenylephrine, just one drop instilled few minutes
before examination. Phenylephrine is available in 10% concentration;
it should be diluted 4 times before use in neonates. Repeated
instillation of phenylephrine is avoided for the fear of hypertension.
Practice tip
If pupils are not dilating despite administration of adequate mydriatic drops,
AROP should be suspected. These infants should be screened on priority and
appropriate and timely action taken.

What does the Examination Entail?

Screening of ROP involves indirect ophthalmoscopy (10) using
28/30 D lens by an experienced ophthalmologist. After instilling
 384 AlIMS Protocols in Neonatology

a topical anesthetic drop like proparacaine, a wire speculum is

inserted to keep the eyelids apart. First the anterior segment of
the eye is examined to look for tunica vasculosa lentis, pupillary
dilation, and lens/media clarity followed by the posterior pole to
look for plus disease followed by sequential examination of all clock
hours of the peripheral retina. A scleral depressor is often used to
indent the eye externally to examine areas of interest, rotate and
stabilize the eye. Use of scleral depressor increases the pain during
screening examination and can be avoided if the examiner is skilled
to complete the screening without it.

How to Record Findings during Screening?

Ophthalmological notes should be made after each ROP examination,
detailing zone, stage and extent in terms of clock hours of any ROP
and the presence of any pre-plus or plus disease. These notes should
include a recommendation for the timing of the next examination
(if any) and be kept with the baby's medical record.

What Precautions are Taken during Examination?

ROP screening examination can have short-term effects on blood
pressure, heart rate and respiratory function in the premature
baby. The examination should be kept as brief as possible and
precaution is taken to ensure that emergency situations can be dealt
with promptly and effectively. ROP screening is a painful procedure
if not done properly. It should be minimized by administrating a
combination of topical anesthetic eye drops (0.5% proparacaine)
30 seconds prior to examination. Some prefer oral 24% sucrose or
25% dextrose in the dose of 0.5 ml/kg for sucking on gauze just
before the insertion of eye speculum. Baby should not be fed one
hour before examination to avoid vomiting and aspiration. Hand
hygiene should be practiced to maintain asepsis.

What is the evidence?

A systematic review and meta-analysis comprising four studies has reported that

tra scot redu propain darindosasistined signian studieductions

Use of Wide-field Digital Camera for Screening: Wide-field digital

cameras capable of retinal imaging have been evaluated as an
alternative to 10 for screening in preterm infants. Retinal images
taken by camera can be stored, transmitted to expert, reviewed,
• Section 10
analyzed and sequentially compared over time and are useful for
 Retinopathy of Prematurity 385

tele-screening purposes in community programs. However, due to

high cost and variable sensitivity, wide-field digital cameras have
not been used widely as replacement for 10.16 Various lower cost
alternatives have now become available. However, efficacy of these
cameras is dependent not only on technical capabilities but also
on the expertise and supervision of healthcare worker obtaining
the retinal image, mechanism in place for timely review of images
and ability to provide treatment when severe ROP is detected. A
program with all these components needs to be validated before
new generation wide-angle cameras are put into use.
What is the evidence?
Studies comparing wide-field retinal imaging with indirect ophthalmoscopy
(0) have reported variable sensitivity but good specificity. 16

TREATMENT
The treatment involves ablation of peripheral normal avascular
retina and thereby abolishing hypoxic drive of retina (mediated by
over-expression of vascular endothelial growth factor; VEGF). This
results in regression of established ROP.

Indication for Peripheral Retinal Ablation: Treatment of ROP is

based on differentiation of following two types of ROP:
Type 1 ROP (needs treatment):
• Zone I, any stage ROP with plus disease
• Zone I, stage 3 ROP without plus disease
• Zone II, stage 2 or 3 ROP with plus disease
(A-ROP in any zone is also an indication of treatment)
Type 2 ROP (needs close follow up):
• Zone I, stage 1 or 2 ROP without plus disease
• Zone II, stage 3 ROP without plus disease
Peripheral retinal ablation should be conducted for all cases with
type 1 ROP and continued serial examinations are advised for type
2 ROP.
What is the evidence?
Classification of ROP into type 1 and 2 is based on results of Early Treatment for
Retinopathy of Prematurity Randomized Trial (ETROP). ' Before ETROP study
laser ablation was performed in neonates with threshold ROP, a classification
based on location and stage of ROP.
ETROP study demonstrated improved visual outcome if laser ablation is performed
in eyes with high-risk' pre-threshold ROP.Type 1 ROP includes threshold ROP
and subset of pre-threshold ROP likely to bene t from early treatment.
fi
• Micrallananic
 386 AlIMS Protocols in Neonatology

Treatment modalities: ROP may be treated by laser treatment

of avascular retina, intravitreal Anti-VEGF drugs or vitreoretinal
surgery in advanced cases.

A. Laser Treatment
Peripheral retinal ablation is conducted by diode/double-frequency
YAG laser.Ideally, laser therapy should be carried out in the NICU
under the supervision of the neonatology team.
What is the evidence?
In a Cochrane systematic review peripheral retinal ablation as compared to
no treatment was associated with improved structural and functional outcome
in treated eyes. ' Due to ablation of peripheral avascular retina, visual elds

fi
were reduced in treated eyes.

Preanesthetic preparation: Oral feeds should be discontinued

3 hours prior to the procedure. Baby should be started on
intravenous fluids and put on cardio-respiratory monitor. Dilatation
of pupil is to be ensured (as described earlier).
Anesthesia/sedation: Topical anesthesia alone provides insufficient
analgesia for ROP treatment and should not be solely relied upon.
Ideally, neonates should be treated under general anesthesia or
analgesia plus sedation in an operation theatre. However, in absence
of such options in resource limited settings, use of intravenous
fentanyl (bolus of 2 pg/kg followed by infusion of 2 pg/kg/hour
titrated to a maximum of 5 pg/kg/hour to reduce pain) can be
considered for providing analgesia during the procedure. Use of
fentanyl is associated with important but transient side effects and
therefore requires continued observation of the infant for at least
24 hours after the procedure., 19

What is the evidence?

In an open label randomized control trial (NOPAIN-ROP) with two intervention
arms, regimens of intravenous fentanyl and intravenous ketamine provided
adequate analgesia in only a minority of infants (16.3% and 4.5%). Even
the revised higher dose regimens of fentanyl and ketamine did not improve
these proportions (23.1% and 7.1%). Though, in general, the drugs were well
tolerated but a minority did experience signi cant side effects that required
fi
(prolonged monitoring (>24 hours).'

Procedure: Both the eyes can be treated in the same sitting unless
• Section 10
contraindicated by instability of the baby. If baby is not able to
 Retinopathy of Prematurity 387

tolerate the procedure, consider abandoning the procedure for the

time being. Vital signs and oxygen saturation should be monitored
very closely.
Monitoring after laser therapy: After laser therapy first examination
should take place 5-7 days after treatment and should be continued
at least weekly for signs of decreasing activity and regression.
Treatment of any skip areas should be performed if there has been
a failure of the ROP to regress.
Postoperative care:
• The baby should be closely monitored. If condition permits, oral
feeds can be started shortly after the procedure.
• Premature babies, especially those with BPD may have increase
or re-appearance of apneic episodes or an increase in oxygen
requirement. Therefore, they should be carefully monitored for
48-72 hours after the procedure.
• Antibiotic drops (such as chloramphenicol) should be instilled
6-8 hourly for 2-3 days.
B. Intravitreal Anti-VEGF Drugs
Anti-VEGF drugslike bevacizumab or ranibizumab when injected
directly into the vitreous chamber, cause regression of abnormal
vessels without destroying the peripheral retina. As VEGF is an
important mediator of lung growth and brain development, and
there is significant systemic absorption of anti VEGF medication
after intravitreal injection, there are concerns regarding toxicity of
such therapy.
Intravitreal anti-VEGF drugs may be used for treatment of
type 1 ROP involving zone I and zone II posterior ROP. Proper
aseptic injection techniques are important to prevent iatrogenic
complications like cataract and endophthalmitis. Currently there
is insufficient evidence for use of anti-VEGF drugs other than
bevacizumab and ranibizumab.

What is the evidence?

A systematic review suggests that there is no signi cant difference in incidence
fi
of complete or partial retinal detachment (RR: 1.04; 95%CI: 0.21-5.13) between
bevacizumab and laser therapy. There was increased risk of recurrence of ROP
with bevacizumab therapy (RR: 5.36, 95% CI: 1.22-23.50). On subgroup
analysis, the risk of recurrence of ROP needing retreatment was increased in
patients with zone 2 ROP while decreased in zone 1 ROP.20

(Contd.)
 AliMS Protocols in Neohatology
388

1(0001)
In a three-arm, parallel group, superiority trial (RAINBOW study, bilate
intravitreal dose of ranibizumab 0-2 mg, ranibizumab 0-1 mg, and laser therap,
were compared. The primary outcome of treatment success (defined by survival
without active ROP, unfavorable structural outcome, or need for treaters
switch up to 24 weeks after starting investigational treatment) occumed in

80%, 75% and 66% infants,

neurodevelopmental outcomerespectively.Data
is lacking." on long-term effect including

Long-term follow-up retinal examinations including the retinal

periphery are needed till at least 60-65 weeks postmenstrual age
(PMA) after the use of anti-VEGF drugs as there is a definite risk
of reactivation needing a second injection or laser ablation. Other
complications include retinal detachment, persistent avascular
retina, macular anomalies, retinal vascular changes, vitreous
hemorrhage and glaucoma. Due to lack of evidence about long-term
effects including neurological outcomes, parents must be informed
about the benefit and risks, and a written informed consent must
be obtained for use of anti-VEGF drugs, including off-label use.

C. Vitreoretinal Surgery
Vitreoretinal surgery is done for advanced cases of ROP with retinal
detachment in Stage 4-5. The outcomes of early surgery in stage 4
ROP are good, but prognosis in end stage 5 ROP is poor.

PREVENTION

Antenatal
Antenatal steroids: Use of antenatal steroids is a well-known
approach to prevent respiratory distress and intraventricular
hemorrhage, two important risk factors of ROP. Though antenatal
steroids have not reduced occurrence of ROP, perhaps because it
saves smaller babies who are at higher risk of developing ROP, but,
as it reduces sickness level in preterm infants, it is likely to reduce
severe ROP.
Postnatal: Most important risk factor for ROP is prematurity. It is
difficult to prevent prematurity but there are other modifiable risk
factors which require high quality neonatal care.
Delivery Room Interventions
• Delayed cord clamping: Reduces need of blood transfusion and
hence reduces a potential risk factor for ROP.
 Retinopatty of Prematurity 389
• Temperature regulation: Maintaining normothermia reduces
the risk of severe ROP
• Gentle respiratory management: Avoiding injury to lungs and
maintaining preductal saturation in target range for preterm
infants reduces the risk of ROP.
Interventions in neonatal unit: Summarized as POINTS? of care:
Pain control
Oxygen management
Infection control
Nutrition
Temperature control
Supportive care
Pain control: Unnecessary painful procedures should be avoided as
pain makes babies unstable and can increase oxygen requirement
as well as increase the respiratory distress. Use of swaddling and
oral sucrose solution or breastmilk during painful procedures helps
to reduce pain.
Judicious oxygen therapy: Oxygen is a drug, and it should be
used judiciously. Each neonatal unit should have a written policy
regarding when and how to use oxygen and target saturations.
If a preterm neonate <32 weeks' gestation needs resuscitation
at birth, inhaled oxygen concentration (FiO) should be titrated to
prevent hyperoxia and achieve gradual increase in oxygen saturation
(70% at 3 minutes and 80% at 5 minutes after birth).2 During acute
care of a sick preterm neonate, ROP is more likely to develop if partial
pressure of oxygen in arterial blood is more than 80 mm Hg.

Oxygen levels in blood should be continuously monitored using pulse oximetry

keeping a saturation target of 91-95%. It is important that a work culture is
inculcated wherein physicians and nurses respond to monitor alarms.
What is the evidence?
A large scale RCT (SUPPORT trial) indicated that maintaining low saturations
(85% to 89%) compared to high saturations (91-95%) death preterm infants
<28 week did not reduce composite outcome of in or severe ROP but it resulted
in lower severe ROP and higher death rates.?*

Therefore it is recommended that saturations in preterm

neonates be maintained between 91 and 95%. Saturations should be
monitored in preterm infants receiving oxygen therapy to prevent
hyperoxia or hypoxia.
390 AlIMS Protocols in Neonatology

Infection control: Infection control bundles like hand washing, steps

of hand hygiene, maintaining sterility during invasive procedures,
measures to maintain skin integrity and antibiotic stewardship are
often beneficial.
Nutrition: Good nutrition including early and exclusive breastmilk
feeding to premature infants has proven short term as well as long
term benefits, including lowering the rates of ROP. Poor postnatal
weight gain is an important risk factor for significant ROP.
Other: Judicious use of blood transfusions: Transfusion of
packed RBCs is another risk factor of ROP. Adult RBCs are rich in
2,3 DPG and adult Hb binds less firmly to oxygen, thus releasing
more oxygen to the retinal tissue. Refer to the Chapter 51: Blood
Component Therapy.
Other interventions: Supplementation of high doses of Vitamin
E or reduced ambient light exposure is not associated with
reduced incidence of ROP. In neonates with initial stages of ROP,
administration of supplementation oxygen to achieve oxygen
saturation in supraphysiological range and to reduce retinal hypoxia
is not associated with halt in progression of ROP.

Quality Improvement
Protocolized Approach
• All units caring for babies at risk of ROP should have a written
protocol for screening and treatment of ROP. The neonatologists
have the responsibility of followingup the babies discharged from
the unit till ROP screening is complete.
• If babies are transferred either before ROP screening is initiated or
when it has been started but not completed, it is the responsibility
of the consultant neonatologist to ensure that the neonatal team
in the receiving unit is aware of the need to start or continue
ROP screening.
• Whenever possible, ROP screening should be completed prior
to discharge. There should be a record of all babies who require
review and the arrangements for their follow-up.
• For babies discharged home before screening is complete, the
first follow-up out-patient appointment must be made before
hospital discharge and the importance of attendance explained
to the parents.
 Retinopathy of Prematurity 391

Auditing
Following outcomes should be regularly audited in units with ROP
screening and treatment program.

• Completenest stone regan Perinage of eligible babies

• Timing of first screen: Percentage of eligible babies receiving first
ROP screening exam by 4 weeks of postnatal age.
• Timing of treatment: Percentage of babies needing ROP treatment
who are treated within 48 hours of the decision to treat being
made.

REFERENCES
1. Tekchandani U, Katoch D, Dogra MR. Five-year demographic profile of
retinopathy of prematurity at a tertiary care institute in North India. Indian
J Ophthalmol 2021;69:2127-31.
2. Kumar P, Sankar MJ, Deorari A, Azad R, Chandra P, Agarwal R, et al. Risk
factors for severe retinopathy of prematurity in preterm low birth weight
neonates.Indian J. Pediatr.2011;78:812-6.
3. Sivanandan S, Chandra P, Deorari AK, Agarwal R. Retinopathy of Prematurity:
AlIMS, New Delhi Experience.Indian Pediatr.2016;53 Suppl 2:123-8.
4. Maheshwari R, Kumar H, Paul VK, Singh M, Deorari AK, Tiwari HK.Incidence
and risk factors of retinopathy of prematurity in a tertiary care newborn unit
in New Delhi.Natl. Med J India. 1996;9:211-4.
5. Narayan S, Aggarwal R, Upadhyay A, Deorari AK, Singh M, Paul VK.Survival
and morbidity in extremely low birth weight (ELBW) infants.Indian
Pediatr.2003;40:130-5.
6. Charan R, Dogra MR, Gupta A, Narang A. The incidence of retinopathy of
prematurity in a neonatal care unit.Indian J. Ophthalmol. 1995;43:123-6.
7. Dutta S, Narang S, Narang A, Dogra M, Gupta A. Risk factors of threshold
retinopathy of prematurity.Indian Pediatr.2004;41:665-71.
8. Vinekar A, Dogra MR, Sangtam T, Narang A, Gupta A. Retinopathy of
prematurity in Asian Indian babies weighing greater than 1250 grams at
birth: ten year data from a tertiary care center in a developing country.Indian
J. Ophthalmol.2007;55:331-6.
9. Rekha S, Battu RR. Retinopathy of prematurity: incidence and risk factors.
Indian Pediatr. 1996;33:999-1003.
10. Gopal L, Sharma T, Ramachandran S, Shanmugasundaram R, Asha V.
Retinopathy of prematurity: a study.Indian J. Ophthalmol. 1995;43:59-61.
11. Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Chan RP. Berrocal
A, et al. International classification of retinopathy ofprematurity.
Ophthalmology.2021;128(10):51-68.
12. Fierson WM, American Academy of Pediatrics Section on Ophthalmology.
American Academy of Ophthalmology, American Association for Pediatric
Ophthalmology and Strabismus, American Association of Certi ed
fi
• Miscellaneous
392 AliMS Protocols in Neonatology

Orthoptists. Screening Examination of Premature Infants for Retinopathy rd

Prematurity. Pediatrics.2018;142(6):20183061.
13. Sun X, Lemyre B, Barrowman N, O'Connor M. Pain managerent during eye.
examinations for retinopathy of prematurity in preterm infants: a systematic
review.Acta Paediatr.Oslo Nor. 1992. 2010;99:329-34.
14. Stevens B, Yamada J, Ohlsson A, Haliburton 5, Shorkey A. Sucrose for
analgesia in newborn infants undergoing painful procedures. Cochrane
Database Syst. Rev. 2016;7:CD001069.
15. Dempsey E, McCreery K. Local anaesthetic eye drops for prevention of
pain in preterm infants undergoing screening for retinopathy of prematurity.
Cochrane Database Syst. Rev. 2011;CD007645.
16. Athikarisamy SE, Patole S, Lam GC, Dunstan C, Rao S. Screening for
retinopathy of prematurity (ROP) using wide-angle digital retinal photography
by non-ophthalmologists: a systematic review.Br. J. Ophthalmol.
2015;99:281-8.
17. Good WV, Early Treatment for Retinopathy of Prematurity Cooperative Group.
Final results of the Early Treatment for Retinopathy of Prematurity (ETROP)
randomized trial. Trans. Am.Ophthalmol.Soc. 2004;102:233-248;discussion
248-500.
18. Andersen CC, Phelps DL.Peripheral retinal ablation for threshold
retinopathy of prematurity in preterm infants. Cochrane Database Syst. Rev.
2000;CD001693.
19. Madathil S, Thomas D, Chandra P, et al. 'NOPAIN-ROP' trial: Intravenous
fentanyl and intravenous ketamine for pain relief during laser photocoagulation
for retinopathy of prematurity (ROP) in preterm infants: A randomised trial.
BMJ Open 2021;11:046235.
20. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor
(VEGF) drugs for treatment of retinopathy of prematurity.Cochrane Database
Syst Rev. 2018 08;1:CD009734.
21. Stahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF, et al.
Ranibizumab versus laser therapy for the treatment of very low birthweight
infants with retinopathy of prematurity (RAINBOW): an open label
randomised controlled trial. The Lancet.2019 ;S0140673619313443.
22. Deorari A, Darlow BA. Preventing sight-threatening ROP: a neonatologist's
perspective. Community Eye Health.2017;30(99):50-52.
23. York JR, Landers S, Kirby RS, Arbogast PG, Penn JS. Arterial oxygen
fluctuation and retinopathy of prematurity in very-low-birth-weight infants.).
Perinatol. Off.J. Calif. Perinat. Assoc. 2004;24:82-7.
24. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal
Research Network, Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, et
al. Target ranges of oxygen saturation in extremely preterm infants.N. Engl.
J. Med. 2010;362:1959-69.
 CHAPTER

36
Hearing Screening

The hearing threshold of more than 25 decibels (dB) at the

frequencies (500, 1000, 2000 and 4000 Hertz) which are important
for speech recognition can result in significant auditory deficits.
Hearing loss can be slight, moderate, severe or profound hearing
loss based on the average threshold (Table 36.1).
Hearing loss may be conductive, sensorineural or mixed based
on the site of lesion.
1. Conductive hearing loss presents in the outer or middle ear
restricting the sound waves to propagate to the inner ear. It can
be due to deformity in outer / middle ear such as micotia/anotia,
atresia, ossicular deformity etc or due to transient obstruction of
middle ear with fluid.
2. Sensorineural hearing loss ceases the conduction and processing
of acoustic signals in the inner ear secondary to damage to
cochlea, auditory nerve or central auditory pathway itself. It can
be further subdivided into sensory loss wherein the hair cells in
the cochlea are damaged and neural loss in which the auditory
nerve and the neural pathway are affected.
3. Auditory neuropathy occurs when the auditory signal is either
absent or processed abnormally in the auditory nerve, brainstem,
or cerebral cortex.

Table 36.1: Grade of hearing impairment

Grade of Impairment Corresponding audiometric value in decibels (dB)
0. No impairment 25 or better
1. Slight impairment 26-40
2. Moderate impairment 41-60
3. Severe impairment 61-80
4. Profound impairment 81 or greater
including deafness

393
394 AIMS Protocols ie Neonatology

4. Mixed hearing loss is the condition when conductive component

is present along with the sensorineural component.

HEARING SCREENING 1-3

Implementation of hearing screening programme ensures early

diagnosis of hearing impairment. The average age of identification
of bilateral profound hearing loss has been estimated to be
24 months and impairment of lesser degree has been noted to
be 48 months. This can be significantly reduced to 12 months or
lesser with execution of neonatal hearing screening. It can be either
"universal" or "high risk". However, high risk focused screening
programmes have shown to miss out almost 50% of the congenital
hearing loss cases. Therefore, several authorities have proposed to
implement universal hearing screening protocol.
Two techniques are used for screening:
1. Otoacoustic emissions: Otoacoustic emissions (OAE) are an
objective, efficient and noninvasive tool to assess cochlear
function. They are the reflected acoustic vibrations from the
cochlea in response to the stimulus given through the testing
probe. They are obtained as a result of cochlear sensory cells,
primarily outer hair cell movement, and are obtained at
frequencies essential for speech acquisition.
The OAE screener consists of a probe that is placed inside
the ear. The probe houses a small microphone along with the
speakers. The click stimuli in case of transient evoked otoacoustic
emissions (TEOAEs) or tones in case of distortion product
otoacoustic emissions (DPOAE) are given through speakers and
the microphone receives the reflected sound from the cochlea
for SNR (Signal to noise ratio). It gives the result as 'PASS' or
'REFER'.
2. Automated auditory brainstem response: Automated auditory
brainstem response (AABR) is a screening tool to record electro-
physiological response against the auditory stimulus given at the
threshold level. The AABR method produces a simple 'PASS' or
'REFER' result without requiring interpretation. It is important
to note that both AABR and auditory brainstem response (ABR)
are different. ABR being a diagnostic test gives the detailed
information such as type and degree of hearing loss. However,
AABR is a screening test that measures the response and gives
the result as 'PASS' or 'REFER'. In high risk infants, OAEs alone
 Hearing Screening 395

can assess the sound conduction through middle ear and cochlear
function but will miss the condition such as Auditory Neuropathy
(AN). Therefore, it is recommended to perform AABR along with
OAE in such cases.
AABR screening device measures the surface signals by placing
electrodes on the forchead, mastoid, and the nape of the neck. For
all the high-risk infants, AABR is essentially to be used as part of
screening.
Execution of screening programme can give targeted results if
it follows the 1-3-6 principle (Fig. 36.1). States who meet the 1-3-6
benchmark (screening completed by 1 month, audiologic diagnosis
by 3 months, enrollment in early intervention by 6 months) should
strive to meet a 1-2-3 month timeline, 5,6
• The hearing screening should be performed by one month of age
either before or after discharge for all the newborns.
• The babies who fail initial and follow-up screening should
undergo diagnostic audiological evaluation to confirm the degree
and type of hearing loss by the age of three months.
• After the diagnosis of hearing loss, the children identified with
congenital hearing loss should be intervened with appropriate
medical management or amplification devices such as hearing
aids or cochlear implants by the age of 6 months.

SCREENING PROTOCOLS,7

A two-step screening programme is the most effective and widely

accepted arrangement to ensure high sensitivity of the testing
protocol (Fig. 36.2). In this the babies are screened initially within
24-48 hours of birth and in case they get REFER result, they are
re-screened preferably before discharge or on subsequent visit to
the hospital. This reduces the number of false-positive cases due to
presence of fluid in the ear during initial hours of birth.
In high-risk babies, initial screening should be carried out with
both OAE and AABR. Considering the greater incidences of hearing
impairment in children falling under the high-risk category, it
is imperative to perform OAE as well as AABR to ensure neural
hearing loss is not missed in these children. Also, to decrease false-
positive results it is advisable that hearing screening is done after 34

1 month 3 months 6 months

Fig. 36.1: 1-3-6 Principle for hearing screening

 396 AlIMS Protocols in Neonatology

Hearing screening

High risk
Low risk

OAE OAE and AABR

Pass Refer Pass Refer

Counselling OAEJAABR Counselling AABR

Pass Refer Pass Refer

Diagnostic ABR Diagnostic ABR

Fig. 36.2: Screening protocol for low-risk and high-risk babies

ABP: Auditory brainstem response; AABR: Automated ABR; AE: Otoacoustic emission

weeks postmenstrual age for premature infants born at <34 weeks

of gestation age (Fig. 36.2).

Evidence of two-step screening protocol and AABR for high-risk infants*

A retrospective study has advocated the use of two step screening protocol including
Automated ABR (auditory brainstem response)/OAE (otoacoustic emissions) for well
babies and inclusion of AABR along with OAE for high-risk babies.

IMPLEMENTATION

The hearing screening programme needs resources such as

appropriate instrumentation, isolated and less-noisy area for testing
and manpower for successful implementation. Also, the execution of
UNHS is majorly dependent on attitude and belief of physicians at
the medical facilities involved in neonatal care. They should ensure
hearing screening of all the neonates along with the appropriate test
battery for well babies and high-risk infants. Counselling of parent/
caregivers to increase awareness regarding importance of hearing
Section
screening and its implication is imperative to warrant the success
• | of screening programme.
 Hearing Screening 397
FOLLOW-UP

All the children failing two-stage hearing screening should undergo

diagnostic evaluation by 3 months of age. The test battery includes:
1. Medical evaluation: To examine the outer and middle ear and
check for the presence of impacted wax or fluid.
2. Tympanometry to assess the middle ear function.
3. Otoacoustic emissions to differentially diagnose sensorineural
hearing loss and auditory neuropathy.
4. Auditory brainstem responses (ABR): It is the gold standard test
for threshold estimation and site of lesion analysis and also to
help to determine the management option suitable.
Along with ear examination and audiological evaluation, bilateral
congenital hearing loss should also prompt for genetic work-up.
The genetic testing may give the opportunity to predict the possible
course of impairment. It can help to establish the connection
of auditory impairment with other congenital anomalies and
differentiate between underlying syndrome or an isolated hearing
loss.

LIMITATIONS

One of the major limitations of UNHS that poses a great challenge

for the medical professionals is delayed-onset hearing loss. The late-
onset progressive hearing loss, mostly associated with the known
risk factors such as congenital cytomegalovirus (CMV) infection,
hyperbilirubinemia, etc. can be identified with parental awareness
and follow-up. However, the impairment with delayed onset and
without associated risk factor can fail the purpose of screening as
they cannot be captured with UNHS. The pass UNHS results may
give false reassurance to parents resulting in missed or delayed
identification.

How to Manage®
In accordance with the recommendation of WHO the rehabilitation
for hearing impairment should be initiated by six months
of age. It should be a multidisciplinary approach including
otorhinolaryngologists, audiologists and parents. Based on the
type and degree of loss, appropriate management options should
be communicated to parents or caregiver. The habilitation process
may include speech and language therapy along with the following
options (Fig. 36.3):
 398 AlIMS Protocols in Neonatology

Hearing loss

Mixed
Conductive Sensorineural

Medical and Mild to severe Severe profound Hearing aid

surgical
intervention
Hearing aid Hearing aid
Implantable
devices,
Hearing aid, Assess candidacy Cochlear assess candidacy
BAHA' for CI implant for Cỉ
Fig. 36.3: Management of hearing loss post-diagnostic evaluation
BAHA: Bone-anchored hearing aid; CI: Cochlear implant

1. Medical and surgical intervention: Effective medical treatments

are available for variety of conditions causing conductive hearing
loss like middle ear effusion, chronic otitis media and acute
otitis media. Some conditions like chronic tympanic membrane
perforation, ear atresia and congenital ossicle abnormalities
can be effectively managed by surgical correction. Immediate
attention to these conditions and intervention can help to avoid
delay in speech development.
2. Hearing aids: They can be suggested in cases of hearing loss with
sensorineural component. Aids can be prescribed for hearing
impairment ranging from mild to severe degree with the adequate
amplification and appropriate programme. A strong follow-up
and re-evaluation are critical to ensure the benefit.

3. Bone-anchored hearing aid (BAHA): In cases of permanent

conductive hearing loss, BAHA can be suggested. It is most
suitable in cases of congenital malformations of middle and
external ears or chronically discharging ear. Surgical implantation
should be planned considering the age of the child.

4. Cochlear implant (CI): In cases of severe to profound hearing loss

cases, cochlear implants are the most suitable intervention option.
Children with no or inadequate benefits with amplification
devices can be surgically implanted with cochlear implants.
The surgery performed by twelve months of age or during the
JELIVII critical period results in significant improvement and near normal
development of speech and language skills.
 Hearing Screening 399

Evidence of benefits from universal neonatal hearing screening

A prospective study of large cohort of children indicated towards significant
benefit from early detection and intervention of hearing impairment followed
by improved language outcomes.

OUTCOMES°

Hearing impairment when diagnosed and treated in early years of

development can minimize its effects on communication skills of
the child. The timely medical intervention and use of appropriate
amplification device will assist children with hearing loss in
achieving speech and language skills at par with their normal
hearing counterparts. It will also be helpful in attaining normal
cognitive development and social integration.

REFERENCES
1. Holster IL, Hoeve LI, Wieringa MH, Willis-Lorrier RM, de Gier HH.
Evaluation of hearing loss after failed neonatal hearing screening. J Pediatr.
2009;155:646-50.
2. Thompson DC, McPhillips H, Davis RL, Lieu TL, Homer CJ, Helfand
M. Universal newborn hearing screening: summary of evidence. JAMA.
2001;286(16):2000-10.
3. Wrightson AS. Universal newborn hearing screening. American family phys.
2007;75:1349-52.
4. Lin HC, Shu MT, Lee KS, Ho GM, Fu TY, Bruna S, Lin G. Comparison
of hearing screening programs between one step with transient evoked
otoacoustic emissions (TEOAE) and two steps with TEOAE and automated
auditory brainstem response. Laryngoscope. 2005;115:1957-62.
5. Bachmann KR, Arvedson JC. Early identi cation and intervention for children
fi
who are hearing impaired. Pediatrics in Review. 1998;19:155-65.
6. Joint Committee on Infant Hearing. Year 2019 Position Statement: Principles
and Guidelines for Early Hearing Detection and Intervention Programs. The
Journal of Early Hearing Detection and Intervention 2019;4(2):1-44.
7. Unlu I, Guclu E, Yaman H. When should automatic auditory brainstem
response test be used for newborn hearing screening?. Auris Nasus Larynx.
2015;42:199-202.
B. World Health Organization. Hearing screening: Considerations for
implementation.Geneva: World Health Organization; 2021.

cellaneous
CHAPTER

37
Umbilical Cord
Blood Banking

Blood from the umbilical cord is a rich source of hematopoietic stern

cells. These cells from the umbilical cord blood (UCB) can be used
to treat certain malignancies and metabolic and immunological
conditions. The process by which the umbilical cord and placental
blood are salvaged at birth and stored by cryopreservation for
future use is known as UCB banking. The umbilical cord blood
transplantation (UCBT) may be autologous when the patient's own
UCB is used or allogeneic when the donated UCB-either from
relatives or unrelated donations—is used for UCBT. In either case,
the UCB is obtained from a UCB bank, where it has been preserved
and stored.
Cord blood banks can be classified as private, public, or hybrid.
Banks that store a child's UCB for future use for herself or one of the
family members are known as private cord blood banks. The banks
accepting UCB donations and making them available for anyone
needing a transplant are public banks. The newly emerging model
is the hybrid model, where a bank offers public donations after the
family makes an informed decision.

COLLECTION OF UMBILICAL CORD BLOOD

The collection of cord blood should not interfere with the baby's
delivery while maintaining sterility and maximizing the yield
of hematopoietic stem cells. Cord blood can be collected in utero
(before delivery of the placenta in the delivery room) or ex utero
(after delivery of the placenta).
The umbilical vein is cannulated via a sterile IV catheter and
tubing, and the UCB flows by gravity into a sterile collection bag
containing anticoagulant solution till the flow stops, which usually
takes 2-5 min.' A total volume of at least 40 ml of blood must be
collected to ensure sufficient stem cells.
400
 Umbilical Cord Blood Banking 401

Following this, the bag is transported to the cord blood bank,

where it undergoes testing followed by cryopreservation, i.e. stored
in liquid or vapor phase nitrogen. UCB can be cryopreserved and
stored for over 15 years, transported to the transplant center, and
thawed before use.

CLINICAL BENEFITS

1. UCB is helpful for all those who need allogeneic hematopoietic

stem cell transplantation (HSCT) with the advantage of ease of
procurement, rapid availability, expanded donor pool, no harm to
the neonate, low immunogenicity, decreased chronic graft-vs-host
disease (GVHD) compared to conventional HSCT from peripheral
blood and bone marrow, and low relapse rate in minimal residual
disease (MRD).?
2. UCB can be used for the allogeneic transplantation of an awaiting
family member (biological parents or sibling only) who is
confirmed to be suffering from an illness that allogeneic HSCT can
cure. Thalassemia is an example where UCB from an unaffected
matched sibling donor can be used for transplant.

LIMITATIONS OF UCB USE

1. When the disease exists in the donor's own cells, e.g.

hemoglobinopathies, storage disorders, hemophagocytic
lymphohistiocytosis, and primary immunodeficiencies, using
one's own UCB stem cells is contraindicated.
2. In low-risk families, the risk of having a disease curable by
autologous transplant is low—0.04-0.0005%. Even when there is a
remote chance of having a condition where autologous stem cells
are curative, e.g. in certain high-risk solid tumors, stem cells can
be readily taken from the patient's marrow or peripheral blood,
which provides similar results to that of using UCB.
3. Increased risk of infection following UCBT." Delayed neutropenia,
particularly following myeloablative regimens, increases
significant vulnerability to bacterial and fungal infections.
Delayed acquired immune reconstitution raises concerns about
viral complications.
4. In certain hematological malignancies, the graft-versus-leukemia
reaction is harnessed as a therapeutic benefit to kill the leukemia
cells. UCB may have a limited role in these conditions, and allogenic
stem cells from peripheral blood or bone marrow may be preferred.
402 AlIMS Protocols in Neonatology

5. UCB is costly, and its cost comprises testing, processing, and

storage.
6. The role of UCB in diseases like BPD and HIE, where the
regenerative property of the stem cells is utilized, is still under
research. The use of UCB for such purposes should be limited to
clinical trials.
7. A single UCB unit may not contain enough stem cells to be
helpful in adults because the cell dose per kg body weight
may be insufficient. A double unit umbilical cord blood
transplantation has been attempted with limited benefit to
mitigate this. To expand functional UCB cells in vitro, using
nicotinamide as part of the ex vivo expansion of UCB cells has
been shown to achieve faster engraftment, reduced infections,
and shortened hospital stays compared with an unmanipulated
UCB product."

RECOMMENDATIONS

The American Academy of Paediatrics, 2017, ACOG 2016; American

Medical Association, 2007; American Society for Blood and Marrow
Transplantation (ASBMT) 2008; and most recently, the Indian
Academy of Paediatrics (LAP) consensus statement 2018 recommend
the following:
1. The general public should be provided accurate information
about the clinical limitations and benefits of UCB banking
and transplantation (allogeneic versus autologous) as per the
currently available evidence.
2. The parents of the neonate should be informed clearly that,
currently, there is no scientific data to prove that autologous cord
blood is of any value for regenerative medical purposes (e.g. in
conditions like HIE and BPD).
3. To ensure that UCB is stored in sufficient numbers and made
available for patients needing HSCT, public banking of UCB is
encouraged where possible.
4. Because of the limitations of autologous UCB, storing cord blood
for personal use is not recommended.
5. UCB can be stored for personal use if siblings or biological parents
suffer from a disease curable by allogeneic HSCT.
At AIMS, we do not encourage routine UCB banking; we undertake it
only in speci c instances, as mentioned.
fi
 Umbilical Cord Blood Banking 403

REFERENCES
1. Cord blood banking for potential future transplantation: subject review.
American Academy of Pediatrics. Work Group on Cord Blood Banking.
Pediatrics 1999;104:116-8.
2. Milano F. Gooley T, Wood B, et al. Cord-blood transplantation in patients
with minimal residual disease. N Engl | Med 2016;375:944-53.
3. Delaney C, Gutman IA, Appelbaum FR. Cord blood transplantation for
haematological malignancies: conditioning regimens, double cord transplant
and infectious complications. Br | Haematol 2009;147:207-16.
4. Wang L, Gu ZY, Liu SF, Ma DX, Zhang C, Liu C), Gao R, Guan LX, Zhu CY,
Wang FY, Gao C), Wei HP. Single- Versus Double-Unit Umbilical Cord
Blood Transplantation for Hematologic Diseases: A Systematic Review.
Transfus Med Rev. 2019;33:51-60.

phase 3 randomized study. Blood 2021;138:1429-40.

 Section
11
Diagnostic Modalities
and Procedures

38. Neonatal Chest X-ray

39. Arterial Blood Gase: Interpretation
40. Blood Culture and CSF Examination
41. Umbilical Cord Blood Sampling
42. Central Vascular Access
 CHAPTER

38
Neonatal Chest X-ray

The chest X-ray is the most frequently ordered radiological

investigation in neonatal intensive care units. It is indispensable
for diagnosing pulmonary disorders in preterm and term neonates.
It should ideally be performed in the neonatal ICU using portable
X-ray equipment. In most cases, an anteroposterior view of the chest
would provide sufficient diagnostic information. Lateral views of
the chest and abdomen should only be included with a clinical
indication.1,2

INDICATIONS'

1. For evaluating the initial cause of respiratory distress (such as

preumonia, pulmonary hemorrhage, collapse, airway or lung
malformations).
2. For suspected cardiac or pericardial disease.
3. To check the position of the endotracheal tube, umbilical venous or
arterial lines, peripherally inserted central catheters or chest tubes.
4. For evaluating the cause of worsening respiratory distress in a
ventilated neonate after ruling out mechanical problems (tube
block/ secretions / dislodgement) or ventilator dysfunction.
Some conditions where X-rays are not indicated include:
1. Routine/ daily X-rays in ventilated neonates.
2. Routine pre- or post-extubation X-rays.
3. After re-intubation in a neonate where the optimal "tip-to-lip"
distance is known based on the initial X-ray.
4. Evaluation of an isolated episode of desaturation/ apnea.

INTERPRETATION

All X-rays should be interpreted considering the clinical scenario.

While describing an X-ray, the following vital observations need
to be made:
407
408 AlMS Protocols in Neonatology

• Projection (AP vs. PA lm)

fi
• Exposure (hard vs. soft films)
• Rotation
• Soft tissue/bone
• Lungs:
- Expansion
- The appearance of lung parenchyma
- Cardiac and diaphragmatic margins
• Cardiac:
- Cardiothoracic ratio/ cardiac size
- Pulmonary vascular markings
- Specific chamber enlargement

Projection
The following features distinguish AP from a PA lm:

fi
• In PA films, the scapulae lie posterolaterally and are away from
the lung fields, whereas they tend to overlap the lungs in AP
films.
• Due to its anterior placement, the heart appears larger in AP
than in PA film.
• The cervicothoracic vertebral end plates are tangential to the AP
projection beam, making them prominent in the AP view, while
the lamina appears more prominent in the PA view.
• The ribs appear more horizontally placed in AP than in PA view:
Practical Tip: Most neonatal chest X-rays are AP films unless the
baby is made to lie in a prone position.

Exposure
• Lucency of soft tissue shadow-the darker the soft tissue, the
more exposure.
• Ease of visibility of retrocardiac vertebrae—if the retrocardiac
vertebrae are easily seen, the film is overexposed.
• Relative lucency of lung fields.

Rotation
The chest X-ray is said to be rotated if
• The distance between the posterior ends of the ribs from the
midline of the spine is unequal on either side. The lm is rotated
fi
to that side on which the distance appears greater.
 Neonatal Chest X-ray 409

• The medial end of the clavicles is not equidistant from the

midline.
Usually, the side to which the chest is rotated appears more
hyperlucent than the other; hence, it should be interpreted
cautiously.
Soft Tissue and Bones

Carefully examining the bones cannot be overemphasized,

especially for picking up changes in osteopenia and fractures. This
is not discussed in detail here.

Thymus: Normal and Abnormal

The thymus may create some challenges in the interpretation of
neonatal chest X-rays. Typically, the thymus appears as a bilateral,
smoothly outlined superior mediastinal fullness blending with the
cardiac silhouette. Some normal variants of the thymus are:
• Notch sign: Uniform thymus enlargement on both sides with a
prominent notch on the inferior left border (corresponding to the
junction of the inferior aspect of the normal thymus gland and
cardiac silhouette).
• Sail sign: Characteristic sail-like border of the normal thymus,
commonly seen on the right side.
• Wavy thymus sign: Undulating waviness of the lateral border
of the thymus due to indentation of the ribs.

Interpretation of Lung Fields

Lung Expansion
Normal lung expansion: Up to six ribs anteriorly and eight ribs
posteriorly. This follows the normal position of the diaphragm
between the 5th and 7th anterior ribs. The radiological features of
hyper-expansion are the presence of more than six anterior and
eight posterior ribs, flattening of the diaphragm, increased lucency
of lung fields (blackness), air under the heart, herniation of lung to
the opposite side, and ribs more horizontal.
However, the evaluation of lung expansion by counting the
number of ribs (or intercostal spaces) above the diaphragm can be
tricky in newborns due to two reasons:
1. This technique represents the expansion in two dimensions
only. But newborns, unlike older infants and children, have a
highly compliant thoracic cage, which can quickly expand in the
anteroposterior dimension. • Diagnotic Modalities and Procedures
410 AlIMS Protocols in Neonatology

2. Lesser diaphragmatic excursions occur during inspiration in

neonates as compared to older children.

Common Disease Conditions.2

Respiratory Distress Syndrome
The condition is caused by the de ciency of surfactant production

fi
by type Il alveolar cells, which results in alveolar collapsibility
with overinflation of larger alveoli and resultant transudation
of proteinaceous fluid into alveoli, creating the classical hyaline
membranes. The radiological features of the condition are:
• Under-aerated lungs
• Diffuse granularity
• Reticulogranularity (presence of air in the distended terminal
bronchioles and alveolar ducts against a background of alveolar
atelectasis).
• Air bronchograms (As the disease progresses, distal airways
collapse, leaving the proximal bronchi, which stand out as air
bronchograms. Note that the air bronchograms may be absent
in an expiratory film).

• In severe cases or expiratory films, white-out lungs may replace

these findings due to diffuse alveolar atelectasis.

The severity of RDS has been classified based on radiological

findings as follows:

Mild: Normal/ decreased aeration, reticulo-granularity

Moderate: Decreased aeration, air bronchograms, and indistinct
diaphragm and heart borders
Severe: Confluent pacification of lungs with loss of mediastinal
and diaphragmatic borders

RDS mimickers: A few congenital heart disorders, such as total

hypoplasic elmear yeone un, pinion reinate pate

seen in RDS due to interstitial pulmonary edema.

Transient Tachypnoea of the Newborn (Retained Fluid Syndrome)

This results from the delayed clearance of fetal lung fluid,
overloading the interstitium, lymphatics, and cardiovascular
system. X-ray picture is characterized by:
• Prominent hilum with perivascular streaky shadows
 Neonatal Chest X-ray
411
• Prominent interlobar fissure
• Small pleural effusion
• There may be mild cardiomegaly
• Normal to increased lung volume
Radiographic findings usually resolve in 12-24 hours.
Pulmonary Interstitial Emphysema (PIE)
It is caused by the dissection of air from alveoli into the parenchyma
and interstitium of lungs and perivascular sheaths of vessels
tracking towards the hilum. X-ray appearance is characterized by:
• Radiolucent streaks- linear or irregular, branching/ cystic spaces
(honeycomb-like) or pneumatoceles; seen radiating from the
hilum toward the periphery of the lung.
• PIE may present with linear or cystic changes. Linear lucencies
of PIE may be differentiated from air bronchograms as the latter
are generally smooth and branching in contrast to interstitial air,
which is coarse and nonbranching.

Pneumothorax
This results from the dissection of extra-alveolar air to the hilum,
followed by rupture into pleural space. Increased radiolucency of
the ipsilateral lung and sharpness of the mediastinal border are the
earliest signs of pneumothorax.
The characteristic X-ray ndings are:
fi
• Clear border of a collapsed lung.
• Absent lung markings beyond the collapsed lung border (This
differentiates pneumothorax from vertical skin folds).
• It may or may not be accompanied by a mediastinal shift.
• Herniation of the pneumothorax bounded by parietal pleura into
the contralateral side.
• The thymus is compressed by pneumothorax, whereas it is
elevated by pneumomediastinum.

Pneumomediastinum
The presence of air adjacent to the heart outlines the thymus and
elevates it.

Meconium Aspiration Syndrome (MAS)

The radiological appearance may range from hyper-expansion to
collapse
 412 AlIMS Protocols in Neonatology

• Gross hyper expansion of lungs.

• Bilateral coarse patchy nodular opacities (This represents areas
of focal alveolar atelectasis with focal alveolar over-distension).
• Sometimes, a large piece of meconium can obstruct the bronchus
leading to emphysema of one lung/lobe and compression of the
other.
Pneumonia
The radiological picture is variable and may range from reticulo.
granularity to lobar or segmental consolidation
• Asymmetry of reticulogranular pattern with air bronchograms
may be seen.
• Coarse granular patchy infiltrates with irregular areas of
hyperinflation.

Pleural Effusion
• It was detected by the blunting of the posterior followed by lateral
costophrenic angle (only in the erect lm).
fi
• In supine radiographs, the lung has decreased translucency with
preserved pulmonary vascular markings.
• If enough fluid is present, it is seen as a peripheral band
separating the lung and lateral chest wall.

Bronchopulmonary Dysplasia (BPD)

The radiological appearance is variable and depends on the
postnatal age. (Northway et al.)3
• Stage I (2-3 days): Air bronchograms, reticulo-granularity
(similar to RDS).
• Stage II (4-10 days): Opacification; coarse irregular densities.
• Stage III (10-20 days): Small generalized radiolucent cysts.
Stage IV (1 month): Dense fibrotic strands, generalized cystic
areas, hyper-inflated lungs.

"ypes of Bubbles in Chest X-ray

Type I bubbles are seen in RDS. They are small, uniform, rounded,
and nearly 1-2 mm in diameter. They are more prominent in lung
bases. They occur due to overdistension of the terminal airways
and become less pronounced on expiration.
Section 11
• Type II bubbles are seen in pulmonary interstitial emphysema
(PIE), are nodular and tortuous in shape, and are nearly 2-3 mm
 Neonatal Chest X-ray 413
in diameter. They are peribronchial and perivascular in location
and do not empty on expiration.
• Type III bubbles are seen in focal hyper-aeration syndrome, e.g.
bronchopulmonary dysplasia, and are larger than the first two
types of bubbles. They are irregularly shaped and become less
pronounced, like type I bubbles, on expiration.
Congenital Dlaphragmatic Hernia
Bochdalek defects present with a well-defined dome-shaped soft
tissue opacity usually on the left chest. They are dynamic and may
"come and go" in serial films. Importantly, intestinal loops may
be gasless in the first few hours of life. The herniated abdominal
contents appear opaque with ipsilateral lung hypoplasia and
contralateral mediastinal shift. The classical appearance of gas-filled
loops in the chest may appear only a few hours after birth.
Morgagni hernias are seen as opacities adjacent to the right
costophrenic angle.
Tracheoesophageal Fistula
A soft rubber tube is better than an infant feeding tube for the
radiological diagnosis of TOF. The X-ray shows the coiling of the
tube in the upper esophagus. If one desires to delineate the extent
of the gap between the upper and lower pouch, a lateral X-ray is
preferable. Absent stomach gas suggests associated esophageal
atresia.

Interpretation of the Cardiac Shadow on Chest X-ray*

The most important features to be noted are:
1. Cardiac size
2. Pulmonary vasculature
3. Shape and size of different chambers/ cardiac situs

Cardlac Size
This may be assessed simply by measuring the cardiothoracic (CT)
ratio. CT ratio is the heart's largest transverse diameter divided by
the chest's maximum internal diameter. A CT ratio of more than 0.6
suggests cardiomegaly in newborns.
Pulmonary Vasculature

•
Appreciating pulmonary vascular markings in the lateral third of
the lung fields and the lung apices is usually challenging. Increased
Diagnotic Modalities and Procedures
 414 AlIMS Protocols in Neonatology

Table 38.1: Causes of decreased and increased pulmonary blood dow

nconates
Causes of decreased PBF Causes of increased PBF

Tricuspid valve Acyanotic defects

• Tricuspid atresia • Ventricular septal defect

• Ebsteinid atresia • Patent ductus arteriosus

• Ostium primum/secundum ASD
Right ventricle
• Pulmonary stenosis (PS) Cyanotic defects
• Tetralogy of Fallot • Admixture lesions without PS
Arterial • Transposition of great arteries
• Peripheral pulmonary stenosis • Total anomalous pulmonary venous
• Pulmonary atresia drainage
• Persistent truncus (type IV) • Persistent truncus
• Single ventricle
• Eisenmenger syndrome

pulmonary vascularity is visible as pulmonary vessels are seen in the

lateral third of the film or the lung apices, or if the right pulmonary
artery (visible in the right hilus) appears wider than the trachea.
Decreased pulmonary blood flow (PBF; oligemia) is diagnosed
by the relative blackness of lung fields with small lung hilum
(Table 38.1).

Specific Chamber Enlargement

Prominent pulmonary vascular markings left atrial and ventricular
enlargement may be seen in the ventricular septal defect. In an AP
view, the right heart border is formed (from above downwards)
by the superior vena cava (SVC), ascending aorta (AA), right atrial
appendage (RAA), and right atrium (RA). The left heart border
is formed by the aortic arch (AoA), main pulmonary artery (PA),
left atrial appendage (LAA), and left ventricle (LV). This forms the
basis for diagnosing various chamber enlargements. Note that the
right ventricle (RV) does not contribute to either of the borders and
usually presents with an upturned apex when enlarged, left atrial
enlargement results in splaying of the carina and a double left heart
border appearance. Prominent main pulmonary artery left atrial and
ventricular enlargement may be seen in patent ductus arteriosus.
Reverse three sign along the upper left heart border- hypoplastic
aortic knob and left ventricular prominence; inferior rib border
notching usually seen in co-arctation in pediatric age group and not

• Section 11
in neonates. Other congenital heart conditions are listed in Table 382.
 Neonatal Chest X-ray 415

Table 38.2: Speci c X-ray picture of congenital heart lesions

fi
X-ray picture
Heart lesion
Tetralogy of Fallot "Coeur en sabol"* (boot-shaped) heart-caused
by a small pedicle (atretic PA) with an upturned
apex due to RV hypertrophy; Pulmonary oligemia.
Truncus arteriosus Narrow pedicle, frequently accompanied by an
absent thymus.
Total anomalous "Snowman" appearance caused by the dilated
pulmonary venous vertical vein, innominate vein, and SVC, pulmonary
connection (supracardiac) plethora.
Transposition of great "Egg on the side" appearance due to the narrow
arteries pedicle created by the parallel orientation of the
aorta and pulmonary artery.
•Note: The characteristic X-ray picture may not be evident in the immediate
neonatal period.

Line Positions
Umbilical arterial line:
• High: Between T6 and T9 thoracic vertebrae.
• Low: Between L3 and L4 vertebrae.
Umbilical venous line: 0.5-1 cm above the diaphragm.
Endotracheal tube tip: Between the lower border of T1 to the upper
border of T2 thoracic vertebrae. (Note: Position of the baby's head
and neck may alter ETT position).
Percutaneous central line (PICC): When inserted from the upper
limb, the line must have crossed the first rib and passed medially,
with the tip lying between T3 and T6 vertebrae.
Practical Tips5
While Doing an X-ray
• Follow aseptic precautions. Adequate hand hygiene is a must for
all, including the radiographer. _1111

• Always discuss the exposure settings with the radiographer to

optimize the image quality. A rough guide is to use 30-50 KV (kilo
Volts) and 4-10 mA (milliamps).
• Avoid direct contact with the X-ray plate with the baby to prevent --

hypothermia. Always place the X-ray plate in the tray meant for
that purpose.
416 AlIMS Protocols in Neonatolosy

• In small babies, beware of hypothermin as the radiant warmer is

tilted away during the X-ray and provide an additional heat source
if necessary. An X-ray can be safely done through an incubator.
• Instruct healthcare providers to wear a lead apron. A safe distance
of 2 meters should be maintained for healthcare professionals
when an X-ray is filmed to prevent radiation hazards.
• Expose only the area of interest and remove any chest leads,
tubings, etc. from the field.
• Make sure the baby is not rotated.
• As far as possible, quieten the baby to avoid swings in respiratory
depth.
While Reading an X-rays
• Read the X-ray schematically. Significant findings may be missed
while jumping to the diagnosis.
• Correlate the findings with clinical details.
• Note the neonate's age in hours/days and interventions done
before (such as surfactant administration) and after the X-ray
(pulling out a deeply placed endotracheal tube).
• The use of a view box and the magnifying glass is ideal.
• Writing serial numbers chronologically on the films is helpful
When multiple X-rays have been performed on the same baby. If
the positions of the ET tube or central lines have been changed,
the changed place should be marked.
• Neonatal X-rays should be read by the neonatologist; relying on
a pediatric radiologist (who may not be reading neonatal films
regularly) as a routine is not advisable.

REFERENCES
1. Deorari A, Kumar P, Murki S. Workbook on CPAP: Science, evidence and
practice. ed. New Delhi: 2011. Neonatal chest X-ray interpretation; p.59-64.
2. Swischuk LE. Imaging of the newborn, infant, and young child. 5th ed
Philadelphia: Lippincott Williams and Wilkins: 2004. Respiratory system;
р.1-108.
3. Northway WH, Rosan RC, Porter DY. Pulmonary disease following respirator
therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl
J Med. 1967 Feb 16;276(7):357-68.
4. Abdulla R. Heart Diseases in Children: A Pediatrician. Respiratory system; inger
2011. Chapter 2, Cardiac Interpretation of Pediatric Chest X-Ray; p.17-34.
5. Jones J, Bell D, Bickle I, et al. Neonatal chest radiograph in the exam setting
Reference article, Radiopaedia.org (Accessed on 17 Apr 2023) https://doi.
org/10.53347/rID-16903.
 CHAPTER

39
Arterial Blood
Gases: Interpretation

Arterial blood gas (ABG) can be obtained directly from indwelling

include the umbilical artery and radial artery. 12 Blood gas analyzers
measure pH, PCO, and PO, using separate analytical electrodes.
The serum bicarbonate concentration is then calculated using the
Henderson-Hasselbach equation.?

pH = 6.10 + log ([HCO3-] + [0.03 x PaCO2])

Current blood gas analyzers also report lactate concentrations,

hemoglobin, electrolytes, oxyhemoglobin, carboxyhemoglobin, and
methemoglobin concentrations.

TERMINOLOGIES USED

The terminologies used to de ne acid-base disorders are based on

fi
the principles of the Henderson-Hasselbach equation.
• Acidemia: An arterial pH less than 7.35.
• Alkalemia: An arterial pH greater than 7.45.
• Acidosis: A process lowering the pH of extracellular uid by low
fl
serum HCO; concentration or increased PaCOz.
• Alkalosis: A process raising the extracellular fluid pH by either
elevating serum HCO concentration or reducing PaCOz.
• Metabolic acidosis: A disorder that decreases the pH and serum
HCO; concentration.
• Metabolic alkalosis: A disorder that raises pH and serum HCO;
concentration.
• Respiratory acidosis: A disorder that raises PaCO, and thus
reduces the pH.
• Respiratory alkalosis: A disorder that decreases PaCO, and
increases the pH.
T.ME/NEONATOLOGY
417
418 AliMS Protocols in Neonatology

• Simple acid-base disorder: The presence of a single condition,

as mentioned above, with appropriate respiratory or renal
compensation for that disorder.
• Mixed acid-base disorder: When more than one acid-base
disorders are present concurrently. Suspect mixed acid-base
disorders if there is a less- or more-than-expected compensatory
(respiratory or renal) response.
• Buffers are substances that help attenuate the change in pH
occurring if an acid or base is added to the body system. They
act within minutes to bring the pH to be normal. The principal
physiological buffers include bicarbonate, hemoglobin, and
proteins.
• Buffer base: Normal BB is 48-49 mmol/L. BB is contributed by
bicarbonate (50%), hemoglobin buffer (25%), and 25% by other
buffers (proteins, phosphate, sulfate).
Tables 39.1 and 39.2 provide typical and targeted values of
different ABG parameters in neonates.

Table 39.1: Normal ABG values in newborn

Parameter Normal values
pH 7.35-7.45
PaCO? 35-45 mm Hg
PaO, 50-70 mm Hg
HCO, 20-24 mEq/L
Base excess ‡5
PaCO,: Partial pressure of carbon dioxide in arterial blood; PaO,: Partial pressure of oxygen
in arterial blood; HCO,: Bicarbonate concentration

Table 39.2: Target blood gas values in neonates*

<28 weeks 28-40 Term infant with lofant

GA weeks GA
pulmonary hypertension with BPD
pH >7.25 >7.25 7.30-7.45 7.35-7.45
PaCO? 45-55
45-55 35-45 55-65
(mm Hg)

PaO, 45-65 50-70 80-120 50-80

(mm Hg)
PaCO,: Partial pressure of carbon dioxide in arterial blood; PaO,: Partial pressure of oxygen
in arterial blood; GA: Gestational age; BPD: Bronchopulmonary dysplasia
 T.ME/NEONATOLOGY

Arterial Blood Gases: Interpretation 419

Stepwise Approach to the Interpretation of ABG5.6

1. Clinical evaluation
2. Assess the pH
3. Assess the primary component
4. Assess the compensation status
5. Identify the possible etiology of the acid-base imbalance
6. Assess the oxygenation status
Step 1. Clinical Evaluation
Arterial blood gases should never be interpreted without other
clinical information. Various symptoms and signs, such as the
patient's vital signs (indicating shock or sepsis), neurological status,
gastrointestinal symptoms (vomiting, diarrhea), etc. can provide
clues towards identifying the underlying acid-base disorder. Intake
of certain medications like diuretics can also affect the acid-base
status. Previous blood gases are also reviewed to see the trends.
Step 2. Assess the pH
Check if there is acidemia (pH <7.35) or alkalemia (pH >7.45). This
is usually the primary disorder (refer to Figs 39.1 and 39.2).
Note: Acidosis or alkalosis may be present even if the pH is within
the normal range (7.35-7.45).
Step 3. Assess the Primary Component
The next step is to identify the primary component-respiratory
or metabolic. In primary respiratory disorders, the pH and
PaCO, change in opposite directions (i.e. if pH increases, the
PaCO, decreases), whereas in primary metabolic disorders, the pH
and HCO, change in the same direction. edures

Respiratory acidosis: pH/PaCO,7

Respiratory alkalosis: pH†PaCO,
Metabolic acidosis: pH/HCO>
Metabolic alkalosis: pHTHCO; T
Step 4. Assess the Compensation Status
During the initial phase of acid-base disturbance (uncompensated
stage), the pH and PaCO, (or HCO3 ) are abnormal. Compensation
occurs to normalize the pH, which depends on the renal system,
the lungs, and the intracellular and extracellular buffers. The pH is • Diagnotic Modalities
420 AlIMS Protocols in Neonatology

normal in a fully compensated stage, but the PaCO, or HCO, are

altered. In response to primary metabolic disturbance, respiratory
compensation occurs within hours by changes in the respiratory
rate resulting in a new steady state PaCO. In primary respiratory
disturbances, metabolic balance occurs by the renal buffering system
resulting in a new constant state concentration of bicarbonate, which
usually takes 2-5 days.
The following formulas are used for calculating compensation:"
A. Calculate the projected PaCO, concentration required for
compensating metabolic disorder:
• Metabolic acidosis (Winters formula)

- PaCO2 = 1.5 (HCO;) + 8 ‡ 2 mm Hg

- Complete compensation occurs within 12-24 hours.
• Metabolic alkalosis
- PaCO, = 0.7|(HCO3) -20] + 40 ‡ 2 mm Hg
If the PaCO, is lesser or greater than predicted, there is
superimposed respiratory alkalosis or acidosis, respectively.
Complete compensation occurs within 24-36 hours.

B. Calculate the projected HCO; concentration required for

compensating respiratory disorder:
• Respiratory acidosis

Acute: For every 10 mm Hg increase in PaCO, above

40 mmHg, HCO5 increases by 1 mmol/L.
Chronic: For every 10 mm Hg increase in PaCOz
above 40 mm Hg, HCO; increases by 4-5 mmol/L.
• Respiratory alkalosis
Acute: For every 10 mm Hg decrease in PaCO, below
40 mm Hg, HCO; decreases by 2 mmol/L.
Chronic: For every 10 mm Hg decrease in PaCO, below
40 mm Hg, HCO; decreases by 4-5 mmol/L.
If the bicarbonate is greater or lesser than predicted, there is
superimposed metabolic alkalosis or acidosis.

Step 5 identity the Possible Etiology of the Acid-base Imbalance

The next step in interpreting ABG in metabolic acidosis is to
calculate the anion gap (AG). The anion gap is the difference
between the charges of anions and cations and is calculated by
the formula.
AG = Na* + (CT + HCO5)
 Arterial Blood Gases: Interpretation 421

Elect neutrality must be maintained in vivo so the difference

re ects the unmeasured ions. The normal anion gap is 12 + 4 mm Hg.
fl
Step 6. Assess the Oxygenation Status
The oxygenation status of the baby can be assessed by the
following:
A. The partial pressure of oxygen (PaO,): Normal values
for Pa02 in term infants are 50-70 mm Hg; in preterm are
45-65 mm Hg. PaO, values >90-100 mm Hg are referred
to as hyperoxemia and should be avoided, especially in
preterm neonates. The presence of below-normal PaO, levels
is referred to as hypoxemia. It should be differentiated from
hypoxia which is inadequate tissue oxygenation and can
result from several factors apart from hypoxemia, such as
anemia, heart failure, etc.
Note: Always identify whether the sample is preductal or
postductal before interpreting PaO, values. In newborns
with patent ductus arteriosus, especially in pulmonary
hypertension, PaO, levels in preductal are higher than
postductal blood.
B. Alveolar arterial oxygen tension difference (AaDO2): The

and real coed heapsisinguise the puminty causeot

hypoxemia from extrapulmonary causes. The formula gives
alveolar oxygen.

PA02 = (Ps - PH20) × (FiO,) - PaCO,

PB is barometric pressure, PHO is water vapor pressure,
FiO, is a fraction of inspired oxygen, and R is respiratory
quotient (assumed to be 0.8). Typically the AaDO, is about
5-10 mm Hg in healthy individuals. This can be as high as
25-35 mm Hg in neonates due to higher physiological dead
space. Conditions associated with high AaDO:: Cyanotic
congenital heart disease, meconium aspiration syndrome,
chronic lung disease, pneumonia, pulmonary edema,
aspiration, pulmonary embolism. Conditions with normal
AaDO2: Respiratory center depression (encephalitis, narcotics
use), neuromuscular disorders, kyphoscoliosis.
Table 39.3 describes sources of errors found in interpreting Diagnotic Modalities and Procedures

arterial blood gases.

422 AIMS Protocols in Neonatology

Table 39.3: Sources of error in arterial blood gas analysis

Error Effect
Excess dilution with heparin ¡PaO, IPaCO, 1k°, INa'. ICal, Tch.
flush solution IGlu, ILac
Admixture with venous blood ‡PaO,, TPaCO, ‡Sa0,
Presence of air bubble TpH, TPaO, (150 mm Hg), IPaCO,, TSa02
Delayed processing IpH, JPaO, TPaCO,, TCa*, 1Glu, TLac
Hemolysis TK*, INa', Ica?•
PaO, Partial pressure of oxygen in arterial blood; PacO,: Partial pressure of carbon dioxide
in arterial blood; SaO,: Oxygen saturation of arterial blood; K*: potassium ion; Na* sodium
ion; Ca'*: Calcium ion; Glu: glucose; Lac: lactate

Acidemia pH <7.4

HCO; <24 mmol/L PaCO, >40 mm Hg

Metabolic acidosis Respiratory acidosis

Look for compensation Look for compensation

Expected PaCO,= • 1 mmol/L in HCO; for every
1.5(HCO;) + 8 + 2 mm Hg 10 mm Hg increase in PaCO, above
Observed PaCO, < Calculated Paco,: 40 mm Hg: Acute respiratory acidosis
Additional respiratory alkalosis [<1 mmo/L n HCO; : Additional
fi
metabolic acidosis]
• 4-5 mmol/L Tin HCO; for every

40 m He chronic repao, above

Calculate anion gap acidosis [>5 mmol/L Tin HCO; :
Na - (Cĩ + HCO; ) additional metabolic alkolosis]

Calculate AaDO,
Normal anion gap High anion gap
metabolic metabolic
acidosis acidosis
Example: Renal Example: Lactic
bicarbonate losses acidosis, advanced AaDO, <35 mm Hg AaDO, >35 mm Hg
(renal tubular renal failure, late Hypoventilation Hypoventilation
acidosis, early onsel metabolic without intrinsic with intrinsic
renal failure, acidosis, inborn pulmonary disorder pulmonary disorder
acelazolamide); GI errors of
losses (diarrhea) metabolism

Fig. 39.1: Evaluation of acidemia

 Arterial Blood Gases: Interpretation 423

Alkalemia pH >7.4

PaCO, <40 mm Hg
HCO; >24 mmol/L
Metabolic alkalosis Respiratory alkalosis

Look for compensation Look for compensation

Expected PaCO,= 0.7 • 2 mmol/L t in HCO; for every 10 mm
[(HCO; )-24] + 40 ‡ 2 mm Hg
40 mim Pa ce respiratory alkalosis
Observed PaCO,< Calculated
PaCO,: Additional respiratory alkalosis [<2 mmol/L ‡ In HCO; : Additional
Observed PaCO,> Calculated metabolic alkalosis]
PaCO; Additional respiratory acidosis • 4-5 mmol/L 1 in HCO; for every 10
mm Hg 1 In Paco, above 40 mm Hg:
Chronic respiratory alkalosis
Estimate urinary chloride 1>5 mmol/L 1 in HCO; additional
metabolic acidosis]

Chloride Chloride resistant Calculate AaDO,

responsive Urinary Chloride
Urinary chloride <40 mmol/l
<20 mmol/ e.g. Bartter
e.g. vomiting syndrome, AaDO, <35 mm Hg AaDO, <35 mm Hg
Gitelman syndrome Hyperventilation Hyperventilation
without intrinsic with intrinsic
pulmonary pulmonary
disorder disorder

Fig. 39.2: Evaluation of alkalemia

C. Oxygenation index: The oxygenation index assesses the

severity of hypoxemia and the response to treatment.

01 = MAP × FiO 2 × 100

Postductal PaOz
Where MAP is mean airway pressure; OI >25: Indication
for inhaled nitric oxide; OI >40: Indication for ECMO
(extracorporeal membrane oxygenation)

REFERENCES
1. Smith AD. Arterial blood sampling in neonates. Lancet. 1975 Feb
1;1(7901):254-5.
2. Shaw JC. Arterial sampling from the radial artery in premature and full-term
infants. Lancet. 1968:2;389-90. • Diagnotic Modalities and Procedures
 424 AlIMS Protocols in Neonatology

3. Gomez H, Kellum JA. Understanding Acid-Base Disorders. Crit Care Clin.

2015:31;849-60.
4. Goldsmith J, Karotkin E, Keszler M, Suresh G. Assisted ventilation of the
neonate. Philadelphia, PA: Elsevier. 2017.
5. Berend K, de Vries API, Gans ROB. Physiological Approach to Assessment
of Acid-Base Disturbances. Ingel nger JR, editor. New England Journal of

fi
Medicine. 2014:371;1434-45.
6. Sood P, Paul G, Puri S. Interpretation of arterial blood gas. Indian Journal of
Critical Care Medicine. 2010:14;57-64.
7. Wennecke, G. and Knudby, M. Avoiding preanalytical errors - in capillary
blood gas testing. Bronshoj: Radiometer. 2011.
8. Baird G. Preanalytical considerations in blood gas analysis. Biochemia
Medica. 2013:23;19-27.

section 11
 CHAPTER

40
Blood Culture and
CSF Examination

BLOOD CULTURE

Blood culture remains the gold standard for the diagnosis of sepsis.
It identifies the causative pathogen and its sensitivity to antibiotics.
Proper blood sampling is critical to ensure the optimum growth of
the pathogenic organism and prevent the growth of contaminants.'
A. Blood sampling
• Select the appropriate vein for sampling.
• Wear sterile gloves.
• A 5 cm skin patch at the proposed venipuncture site is
disinfected with 70% isopropyl alcohol, povidone-iodine,
and isopropyl alcohol.
• The skin should be allowed to dry for at least 60 sec before
taking the sample.
• The arterial sample offers no added advantage and is
hence avoided
• Taking a sample from a freshly inserted peripheral venous
cannula is acceptable. However, culture should be taken
from a fresh venipuncture for patients with indwelling
vascular lines. Additional samples for blood culture can
be sent from the vascular catheter in cases of suspected
catheter-related bloodstream infection (CRBSI).
• The sample must be taken before the 1st antibiotic dose.
• Clean the top of the blood culture bottle with an antiseptic.
• Changing the needle between venipuncture and injecting
it into the culture bottle is not recommended.
B. Volume of blood
• At least 1 ml sample should be taken for blood culture
in neonates, although the minimum volume specified in
some pediatric blood culture systems is 0.5 ml." Infectious

425
426 AlIMS Arotocols in Neonatology

Disease Society of America (IDSA) recommends a

minimum volume of 2 ml.
• All attempts should be made to obtain an adequate
amount of blood.
• Ablood-to-broth dilution ratio of 1:5 to 1:10 is considered
optimal, even though it has not been consistently proven.
The dilution ratio enables the dilution of the antibacterial
agents in the blood and the binding of the residual
antibiotics by the resins.

C. Blood culture system

• Brain heart infusion (BHI) broth has been used as the
standard media for blood culture, with pediatric culture
bottles having smaller amounts of broth to ensure an
appropriate blood-to-broth ratio. Automated blood culture
systems are increasingly being used, such as BACTEC and
BACT/ALERT. These systems are based on the principle
of detecting CO2 produced by growing organisms by
utilizing carbohydrate substrates in the culture medium.
These systems estimate the CO, level (based on pH,
colorimetry, or fluorescence) every 10-15 minutes and can
detect microbial growth within 12-24 hours of inoculation.
• Once culture broth is inoculated with the blood sample, it
should be kept in an incubator at 37°C. If an incubator is
not available, some automated culture bottles can be kept
at room temperaturefor up to 36 hours after inoculation.
Never put the inoculated culture bottle in the refrigerator.
Once growth is indicated, subcultures are obtained and
inoculated on culture media. Gram's staining is done from
the subculture. Timely Gram's stain results can enable the
administration of more targeted antibiotics.
All blood cultures should be observed for at least 72 hours,
preferably 120 hours, before reporting it as sterile.
• Evidence suggests that over 95% of blood cultures obtained
in cases of early-onset neonatal sepsis before initiating
antibiotics show growth within the first 24 hours.*
• Only aerobic cultures are routinely sent in the case of
neonates. However, in cases where an anaerobic grow th
is likely, such as necrotizing enterocolitis, cellulitis, and
maternal chorioamnionitis, it may be preferable to send
separate anaerobic cultures too.
 Blood Culture and CSF Examination 427

D. Interpretation
• In the presence of compatible clinical symptoms, the
growth of even a single pathogenic organism in the blood
culture suggests sepsis.
• However, the possibility of the growth of a contaminant
organism may be kept in cases with clinical presentation
not compatible with the diagnosis of sepsis, common
contaminant organisms like coagulase-negative
Staphylococcus species (CONS), and delayed growth in
the culture medium.
• On the other hand, the growth of an organism within
48 hours, with a higher colony count, or with the growth
of organisms like Neisseria or Candida, is usually taken as
clinically significant.
• It is vital to have good communication between the clinical
and the microbiology teams, with prompt reporting of any
growth in blood culture.
• Antibiotic sensitivity is ascertained most commonly
by the disc diffusion method. Commercially available
antibiotic discs are used. Based on the size of the
"zones of inhibition," the organism is classified into
susceptible, intermediate, or resistant to a given antibiotic.
"Susceptible" implies that the organism is inhibited by the
usually achievable antibiotic concentration in the body by
administering the usual dosage. "Intermediate" category
drugs may achieve inhibition, but with poor response
rates, while "resistant" antimicrobials would not inhibit
the agent in usually achievable concentration.
• In addition, some organisms are intrinsically resistant to
certain classes of antimicrobials, for example, Pseudomonas
aeruginosa to amoxicillin, cefotaxime, tigecycline,
cotrimoxazole, etc.
• Despite a poor blood culture positivity rate in clinical
sepsis in neonates, it is essential to send blood culture in
all suspected cases of sepsis.
• A positive blood culture with antimicrobial sensitivity
can guide targeted antibiotic therapy, while a negative
blood culture can enable early discontinuation of
antibiotic therapy. Trends of positive cultures and their
antimicrobial sensitivity also helps in determining Diagnotic Modalities and Procedures

empirical antimicrobial choice at a given center.

428 AlIMS Protec * in Necutology

Practice tip
At least 1 mL sample should be laken for blood culture in neonates.

CEREBROSPINAL FLUID (CSF) EXAMINATION

The incidence of neonatal meningitis in resource-poor countries
varies from 0.8 to 6.1 per 1000 live births. It increases with increasing
postnatal age and is associated with significant mortality (40-58%)
and long-term neuromorbidities." However, it may be clinically
silent or present with non-specific signs, especially in the first week
of life, precluding reliance on clinical diagnosis alone. Hence, the
CSF exam is included as an essential investigation in the evaluation
of neonatal sepsis. Lumbar puncture is an invasive procedure with
a risk of complications, necessitating a careful selection of neonates
requiring a lumbar puncture.
A. Indications and contraindications
• The indications and contraindications for performing a
lumbar puncture for evaluation of neonatal meningitis
have been depicted in Table 40.1.5
• LP may be safely omitted in case of initiation of antibiotics
solely based on risk factors, with no symptoms of sepsis
and in preterm neonates with respiratory distress only but
no other systemic signs.

B. Patient position
• Various patient positions have been described for
performing a lumbar puncture, including lateral recumbent
with or without hip flexion and sitting position with or
without hip flexion.
• Lateral recumbent position with hip flexion has been used
most commonly for neonatal lumbar puncture.

Table 40.1: Indications and contraindications for lumbar puncture

Indications of LP Contraindications for LP

• Clinical features suggestive of • Coagulopathy and/or thrombocy-

sepsis. topenia (platelet count <50,000/mm').

• Blood culture positive • Increased intracranial pressure

• Late-onset neonatal sepsis • Cardiorespiratory instability

• Clinical deterioration or failure • Local infection at the LP site
to show an improvement despite
48-72 hours of antibiotics therapy
 Blood Culture and CSF Exarmination 429

• Sitting position with hip exion provides the maximum

fl
interspinous distance and may be equivalent or superior to
lateral recumbent position, with equivalent clinical safety?
• Ultrasound-guided lumbar puncture has also been
successfully used to provide real-time guidance in
challenging cases." Our unit uses a lateral recumbent
position with maximum hip exion.

fl
C. Normative ranges for CSE parameters
• Various studies have evaluated the normal values of CSF
parameters in term and preterm neonates (Table 40.2)?
• A combination of CSI protein, glucose, and WBC count
values provides a higher diagnostic yield than any
individual parameter. Broadly, a CSF WBC count of
20 cells/ mn' (both term and preterm) and CSF protein
level of 170 mg/dl (in preterm) and 120 mg/dl (in term)
has a reasonable diagnostic accuracy.
• With increasing postnatal age, CSF protein level decreases,
CSF glucose remains similar, while CSF TLC shows a less
predictable trend. 10
• NNF India Clinical Practice Guidelines 2021 recommend
using CSF WBC count and protein estimation, but not
CSF glucose, for the diagnosis of suspected meningitis in
neonates." CSF culture remains the gold standard test for
diagnosis of meningitis. Around 30-40% of CSF culture-
positive meningitis may have sterile blood culture.
• Around 30-46% of the lumbar punctures done in neonates
may be traumatic.! However, correcting the WBC count
in case of traumatic LP is not recommended. CSF protein
increases by around 1.9 mg/ dl for every 1000 RBCs in CSF
and does not require correction.

Table 40.2: Normal CSF parameters

CSF components Term neonates Preterm neonates

WBC counts (cells/mm?) 8 (0-32) 9 (0-29)
Imean (range)l

Protein (mg/dl) 90 (20-170) 115 (65-150)

Imean (range)l
Glucose (mg/dl) 52 (34-119) 50 (24-63)
Imean (range)l
430 AlIMS Protocols in Neonatology

• Although even a few hours of antibiotic exposure may

result in sterile CSF cultures, CSF biochemistry can
still enable a diagnosis of meningitis. CSF WBC counts
remain the most reliable parameter in such a scenario,
followed by CSF protein level, which decreases but
usually remains above the cut-off range. CSF glucose
may normalize rapidly after antibiotic exposure.
Lumbar puncture should not be omitted because of prior
antibiotic therapy.10,11
• Gram's stain is a highly specific test for meningitis but
has limited sensitivity. Given the low cost and rapidity of
results, Gram's staining of the CSF sample is recommended
in every case.
• CSF Latex agglutination has modest sensitivity and good
specificity. It may be considered in cases of negative
Gram stain and/or in patients who have received prior
antibiotics.12 Recently, broad-range CSF PCR which
primarily detects conserved regions of the bacterial 16S
RNA gene, has been made available. This method has
a sensitivity and specificity approaching 100%. Cost
and availability remain limiting, especially in resource-
poor settings. Other emerging markers, including CSF
procalcitonin, IL-1ß, lactate, lipocalin 2, NGAL, etc. are
yet to find a routine clinical application.

REFERENCES
1. Buttery J. Blood cultures in newborns and children: optimising an everyday
test. Arch Dis Child Fetal Neonatal Ed. 2002 Jul;87(1):F25-8.
2. Huber S, Hetzer B, Crazzolara R, Orth-Höller D. The correct blood volume
for paediatric blood cultures: a conundrum? Clin Microbiol Infect Off Publ
Eur Soc Clin Microbiol Infect Dis. 2020 Feb;26(2):168-73.
3. Kirn T), Weinstein MP. Update on blood cultures: how to obtain, process,
report, and interpret. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol
Infect Dis. 2013 Jun; 19(6):513-20.
4. Marks L, de Waal K, Ferguson JK. Time to positive blood culture in early onset
neonatal sepsis: A retrospective clinical study and review of the literature
/ Paediatr Child Health. 2020 Sep;56(9):1371-5.
5. Thaver D, Zaidi AKM. Burden of neonatal infections in developing countries:
a review of evidence from community-based studies. Pediatr Infect Dis I
2009 Jan;28(1 Suppl):S3-9.
6. Aleem S, Greenberg RG. When to Include a Lumbar Puncture in the
Evaluation for Neonatal Sepsis. NeoReviews. 2019 Mar;20(3)e124-34.
 Blood Culture sna CSt Examination
431
7. Had C. Thompson A. Morany P. QUESTION 2: Is the lateral decubitus
position best for successful paediatric lumbar puncture? Arch Dis Child.
2016 Aug 1:10100:774-7
8. Muthusami P. Robinson Al, Shroff MM. Ultrasound guidance for ditticult
lumbar puncture in children: pearls and pitfalls. Pediatr Radiol. 2017
lun:4717:822-30.

Pediatt. 1976 Mar;88131:473-7.

10. Srinivasan 1, Harris MC, Shal SS. Lumbar puncture in the neonate:
challenges in decision making and interpretation. Semin Perinatol. 2012
Dec; 36(6):445-53.
11. Diagnosis and Management of Neonatal Sepsis. NNF India Evidence-based
Clinical Practice Guidelines December 2021.
12. Tunkel AR. Hartman BI, Kaplan SL, Kaufman BA, Roos KI., Scheld WM, et
al. Practice Guidelines for the Management of Bacterial Meningitis. Clin
Infect Dis. 2004 Nov 1:39(9):1267-84.
CHAPTER

41
Umbilical Cord
Blood Sampling

Umbilical cord arterial blood (UCAB) normally reflects fetal acid

base balance while venous blood reflects a combination of maternal
acid-base status and placental function. Paired umbilical artery and
venous samples should ideally be taken for optimal interpretation
as it gives insights into the etiology of acidosis. Practically, however,
we take UCAB for knowing fetal acid-base balance.
INDICATIONS
American College of Obstetricians and Gynecologists (ACOG) and
American Academy of Pediatrics (AAP) recommends UCAB to be
taken in all high-risk deliveries! We take UCAB in following neonates:

1. Gestation below 32 weeks.

2. Evidence of fetal distress such as fetal heart abnormalities,
meconium-stained liquor.
3. Sentinel events such as cord prolapse and antepartum hemorrhage.
4. Requiring positive pressure ventilation.
Umbilical cord gas and neonatal outcomes: What is the evidence?
In a meta-analysis (51 studies, 4, 80,000 neonates), a pH threshold of 7.0 had
a strong association with neonatal morbidity (OR 12.5, 95% Cl 6.1 - 25.6), and
a pH threshold of 7.1 with mortality (OR 7.1, 95% Cl 3.3-15.3).'
In a case control study (n = 174 infants), moderate to severe encephalopathy
occurred in 10% Of neonates with umbilical arterial base de cit between
fi
12-16 mmol/L and in 40% of those with base de cit >16 mmol/L.?
fi
In a retrospective review (n= 56,574 infants), the combined outcome of death or
cerebral palsy was 3%, 10% and 40% at lowest pH of 6.9-6.99, 6.8-6.89 and
<6.8 respectively; and 8%, 14% and 59% at base de cit of 12-15.9, 16-19.9
fi
and 20.0 mmolL or more, respectively.?

PROCEDURE (FIG, 41.1)

• Immediately after the birth, approximately 20 cm of the cord

should be isolated between two sets of clamps. The baby is then
handed over to the newborn team for post-birth care.
432
 Umbilical Cord Blood Sampling 433

Cut between each pair of clamps

Placenta

Site for cold blood sampling

Fig. 41.1: Site for umbilical arterial blood sampling

• The blood in this segment of the cord is reflective of fetal acid

base status that is not affected by postnatal changes in the neonate
or the mother.
• The sample must be taken from both umbilical artery and
umbilical vein. Umbilical vein is large and easy to sample whereas
the umbilical artery is thin and difficult to sample. When a single
sample is obtained due to sampling difficulty, it is likely to be
venous.
• Blood is sampled into a pre-heparinized syringe. Use one ml
syringe with a 21-gauge needle. Draw one drop of heparin in
it, move the plunger up and down expelling residual heparin.
• Withdraw a minimum of 0.2 ml blood. Expel all air bubbles and
cap the syringe before mixing the sample.
• Label the syringe and process the sample within 30 minutes.
Document in records.

INTERPRETATION

• The normal values for umbilical cord gases are given in Table 41.1.
Umbilical venous blood gas has higher pH and lower pCO, than
arterial blood. The venous-arterial pH difference ranges from 0.02
to 0.49 units, median 0.09, while the PCO, difference ranges from
0.5 to 9.9 kPa; median 1.9 kPa.* Progressive widening of umbilical
arterial and venous blood gas values is seen in restriction of
umbilical blood flow (nuchal cord), whereas, the difference is
small in impairment of placental perfusion (abruption).? • Diagnotic Modalities and Procedures
434 AIMS Protocols in Neonatology

Table 41.1: Normal values for umbilical cord blood gaus

pH 7.18-7.38 7.25-7:65
PO, (mm Hg) 5.6-30.4 174-41.0
PCO, (mm Hg) 27.0-49.4
32.4-66.0
BDECF (mmol/l.' 4.79 (3.46) 4.0 (3.5)
•Ranges based on mean ‡ 2 SD

• Umbilical cord arterial pH varies with gestational age.

It decreases with increasing gestational age possibly due to
increased placental oxygen consumption with advancing age.
• The current evidence states that cord arterial pH of <7.0 and
base deficit of >12 mmol/L is associated with increased risk of
adverse neurological outcomes and hence these values are taken
to be indicative of fetal hypoxia significant enough to cause
neurological deficit.
• Isolated respiratory acidosis (elevated pCO,) is seldom associated
with adverse outcomes and is usually due to short lived
impairment in circulation.
• Delayed cord clamping has small or no effect on cord blood acid
base balance.3

REFERENCES
1. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No.
348, November 2006: Umbilical cord blood gas and acid-base analysis.
Obstet Gynecol 2006; 108(5): 1319-22.
2. Armstrong L, Stenson BJ. Use of umbilical cord blood gas analysis
in the assessment of the newborn. Arch Dis Child Fetal Neonatal Ed
2007;92(6):F430-4.
3. Nudelman MJR, Belogolovsky E, Jegatheesan P, Govindaswami B, Song D
Effect of Delayed Cord Clamping on Umbilical Blood Gas Values in Term
Newborns: A Systematic Review. Obstet Gynecol 2020;135(3):576-82.
4. Westgate J, Garibaldi JM, Greene KR. Umbilical cord blood gas
analysis at delivery: a time for quality data. Br / Obstet Gynaecol. 1994
Dec; 101(12):1054-63.
5. Yeomans ER, Hauth JC, Gilstrap LC, Strickland DM. Umbilical cord pH,
PCOz, and bicarbonate following uncomplicated term vaginal deliveries
Am J Obstet Gynecol 1985;151 (6):798-800.
6. Wiberg N, Källén K, Olofsson P. Base de cit estimation in umbilical cord
fi
blood is in uenced by gestational age, choice of fetal uid compartment.
fl
fl
and algorithm for calculation. Am J Obstet Gynecol 2006;195(6):1651-6.
 CHAPTER

42
Central Vascular Access

The commonly sed cert cularcaheter Ve ir de.

and peripherally inserted central catheter (PICC). Though not a
CVC, we have also included peripheral arterial cannulation here.

UMBILICAL ARTERY CATHETERIZATION

Indications
1. Continuous monitoring of arterial blood pressure in sick and
ventilated babies.
2. Arterial blood gas (ABG) analysis in ventilated babies.
3. Isovolumetric exchange blood transfusion (in unstable neonates).

Contraindications
1. Omphalitis/ omphalocele.
2. Vascular compromise in lower limbs.
3. Necrotising enterocolitis.
4. Age >3 days (beyond day 1, UAC insertion is technically
challenging).
Length of Insertion
Table 42.1 provides formulae for estimating the length of insertion.
As the formulae give a rough estimate, always con rm the tip
fi
position by chest X-ray, including the abdomen and upper thighs.
ÜAC is seen as having a looping course in the abdomen on the X-ray

Two Positions
1. High: The tip of the catheter lies between T6 and T9 vertebrae.
A high position is preferred due to a lower incidence of vascular
complications.
435
436 AlIMS Protocols in Neonatology

Table 42.1: UAC insertion length (cm)

Methods
Dunn Measure shoulder umbilical length (SUL; the distance from
the tip of the shoulder to a point vertically below till the
level of the umbilicus.!
Shukla and Ferrera 13 x weight (kg)l + 9 cm
(Preferred in infants with birth weight > 1500 gi
Wright 14 x weight (kg)l + 7 cm
(Preferred in infants with birth weight s1500 g)
"Add umbilical stump length to the estimated insertion length.

2. Low position: The tip of the catheter lies between the L3 and 14
vertebrae.
The high position of UAC: What is the evidence?
A high position compared to a low position of UAC is associated with a lower
incidence of clinical vascular complications (RR 0.53, 95% CI 0.44-0.63)
but no difference in intraventricular hemorrhage, death rates, and necrotizing
enterocolitis.

Recommended Catheter Size

• Infants ≤1.2 kg: 3.5 Fr
• Infants >1.2 kg: 5 Fr

Catheter Type and Material

End-hole catheters are preferred to the side-hole to decrease the risk
of complications. No clinically relevant differences exist between
standard polyvinyl chloride (PVC) catheters and other materials
like polyurethane.

Practical tip
• Attempt UAC insertion rst (followed by UVC, if required) unless it is an
fi
emergency•
• Dilate the artery lumen for around 60 seconds using iris forceps' before
attempting the insertion of a catheter (Fig. 42.1)
• If one gets a "Popping" sensation rather than relaxation during insertion:
- UAC may have created a false channel; remove the catheter and use the
second artery.
(Contd.)
 Central Vascular Access 437

(Contd.)

- Resistance may be felt after - 6-8 cm catheter insertion as the umbilical

artery angles around the bladder towards the internal iliac artery. Applying
gentle and steady pressure for 30-60 sec, flexing the hip, and tilting the
infant to the side of the catheterized artery may help.
• Never advance an in situ catheter.
• If it is low for the high position (between T10 and L2), withdraw an equal
length of the catheter by measuring the distance between the actual and
appropriate position on the radiograph.
• Once the correct position is confirmed, secure the catheter.
• Run a low-dose heparin infusion (0.5-1.0 U/ml) at 0.5 ml/hour to maintain
the patency of the catheter. Account for this fluid volume in total, particularly
in ELBW neonates.
• Document the date and time, indication, number of attempts, depth of
insertion, and position on X-ray.

Recommended duration: 5-7 days

Iris
forceps

• Umbilical vein

• Umbilical arteries

Fig. 42.1: Umbilical arteries are smaller, thick walled and may protrude slightly
from cut surface. Umbilical veins are larger, thin walled seen usually at 12
o'clock position at the base of the stump.

Complications
1. Vascular complications (most common)
a. Arterial vasospasm leads to blanching and cyanosis of
the buttocks, legs, ngers, and toes. If the leg blanches,
fi
• Diagnotic Modalities and Procedures
438 AlIMS Protocols in Neonatology

rewarm the opposite leg with a warm (not hot) towel, which
causes reflex vasodilatation. Apply topical nitroglycering
(2% ointment; ribbon length of 4 mm/ kg) 1-2 cm proximal to
the ischemic site. If there is no return of normal color within
5 minutes, remove the catheter.5
b. Thromboembolism involving renal, mesenteric, iliac, and
other vessels presenting as NEC, hypertension, hematuria,
renal failure, pallor/coldness of extremities. The catheter
should be removed in all such cases. It is seen days or weeks
after insertion.
c. Aortic thrombus, aneurysm
2. Creation of false passage, hematoma, peritoneal perforation, and
vessel perforation
3. Catheter breakage
4. Infection (cellulitis, omphalitis, sepsis)
5. Line migration
Removal of the Catheter
1. Remove once the catheter is no more needed. Any complication
may require catheter removal earlier.
2. Stop heparinized saline infusion 30 min before removal. Pull the
catheter slowly with gentle traction over 30-60 seconds to avoid
bleeding.
UMBILICAL VENOUS CATHETERIZATION (UVC)
Indications
1. Emergency vascular access during resuscitation at birth.
2. Central venous pressure (CVP) monitoring (the UVC must pass
through the ductus venosus, and the tip must rest in the inferior

vena cava).
3. Exchange transfusion.
4. Administration of TPN, blood products, and hyperosmolar
solutions.

Contraindications
1. Omphalitis/ omphalocele
2. Necrotizing enterocolitis
3. Age > 5 days beyond 24 hours as in UAC, technically challenging
to place. Use of saline-soaked gauze may facilitate ease of
insertion)
 Central Vascular Access
439

Table 42.2: Methods to estimate the UVC insertion length (cm.)

Formula
Dunn By measuring shoulder umbilical length (SUL)'
Shukla 13 × weight (kg))
+1+9
Verheij 13 x weight (kg)l + 9
2
Real-time Probe: Small sectorial probe 7-8 MHz
ultrasonography View: Subcostal longitudinal view
(RT-USG)' Procedure: Visualize the tip as it passes through the
umbilical vein, the ductus venous, and the IVC. It is
followed until it reaches the junction of IVC and the right
atrium. A normal saline flush (0.5-1 ml) can improve the
visualization.
'For exchange transfusion and emergency vascular access, the catheter is advanced until
the point of good blood ow (usually 2-5 cm).
fl
Length of Insertion
UVCs often get malpositioned due to complex portal venous
anatomy. The formulae based on the length and birth weight have
a low success rate for UVC. Real-time ultrasonography (RT-USG)
has yielded better success rates in the proper position. RT-USG
is accurate, safe, and cost-effective but needs significant training
(Table 42.2).
Con rmation of Tip Position
fi
1. X-ray: The UVC tip position should be con rmed with an
fi
anteroposterior chest X-ray, including the abdomen. The
preferred catheter tip position is 0.5-1 cm above the right
diaphragm (UVC tip at thoracic vertebrae T8-T9 corresponds to
cavo-atrial junction) (Fig. 42.2).
2. RT-USG: Helps in accurate localization of catheter tip and
reduces radiation exposure. If using RT-USG, the catheter should
pass beyond the ductus venosus and at the junction of the inferior
vena cava (IVC) and right atrium.?
Catheter Size
• Infant's birth weight <1.5 kg: 3.5 Fr
• Infant's birth weight >1.5 kg: 5 Fr
Recommended duration of UVC: 10-14 days •
Diagnotic Modalities and Procedures
440 AliMS Protocols in Neonatology

Fig. 42.2: Anteroposterior radiograph of chest and abdomen showing satisfactory

position of UAC (red arrow) and UVC (blue arrow). UAC can also be identi ed

fi
by its looping course (block arrow).

Practice tip
• Identify the umbilical vein by its 12 o'clock location in the umbilical cord
cut section and by its thinner wall and wider lumen.
• "Popping" sensation during insertion may indicate the catheter entering the
portal venous system. Do the following:
- Withdraw the catheter for about 2-3 cm, and push it again while rotating
the catheter clockwise to get through ductus venous
- Double catheter technique: Passing a new catheter into the same vessel,
leaving a misdirected catheter in situ avoid in ELBW neonates due to
risk of vessel damage)
- Placing the neonate in the right lateral decubitus position.
• Secure catheter
• Never advance an in situ catheter
• Avoid infusion of hypertonic solutions if the catheter tip is not in IVC.
• Document the date & time, indication, number of attempts, insertion depth,
and position on the X-ray.

Complications
1. Infection (most common): Sepsis, cellulitis, omphalitis, endocarditis,
septic emboli, liver abscess. Any evidence of central line-associated
blood stream infection (CLABSI) warrants catheter removal.
2. Line malposition
a. Heart and major vessels: Pericardial effusion, cardiac
tamponade, arrhythmia, endocarditis, left atrial thrombus.
Cardiac complications are rare but life-threatening.
 Central Vascular Access 441

b. Portal system: Portal vein thrombosis, NEC, hepatic necrosis,

hepatic abscess."
3. Blood loss
a. From umbilical stump
b. Accidental UVC disconnection

hemorrhage, hepatic necrosis, abscess, and calcification. Removal

of the catheter is indicated.
5. Catheter breakage
Percutaneously Inserted Central Catheter
A percutaneously inserted central catheter (PICC) is a soft, exible

fl
catheter inserted into a peripheral vein and directed into the central
vein. Neonatal PICC are small bore catheters (1-2.7 Fr) suitable for
low flow infusion rates in neonates (1-3 ml/ min).
Indications
1. Preterm neonates needing parenteral nutrition when UVC is
contraindicated (refer above).
a. All neonates <1000 g and not on significant feeds.
b) Birth weight 1000-1499 g and not likely to receive significant
feeds for 3 or more days.
c. Birth weight more than 1500 g and not likely to receive
significant feeds for 5 or more days.
2. Prolonged intravenous access (usually more than 5-7 days) in
gastrointestinal/ surgical disorders, congenital cardiac conditions,
etc.
3. Hyperosmolar intravenous fluid/medication (dopamine,
dobutamine, calcium gluconate) administration.
4. Difficult intravenous access.
Vein Selection
Upper limb: Cephalic, basilic, median cubital, or axillary vein.
Lower limb: Saphenous vein, popliteal vein.
Scalp veins (temporal and posterior auricular veins)and external
jugular veins can rarely be used.
Length of Insertion
The desired insertion length for PICC is calculated using
surface landmarks for both upper and lower limbs (Table 42.3). • Diaanotic Modalities and Procedures
442 AIIMS Protocols in Neonatology

Table 42.3: Estimation of length of insertion for PICC

Estimating distance of insertion Optimum tip position

Upper limb: Measure the distance PICC tip is considered to be correctly
from the insertion point along positioned if it meets all of the following
the venous pathway to the three parameters: First, it crosses the first
suprasternal notch to the right costochondral junction of the same side,
3rd intercostal space (Fig. 42.3). second after crossing the first costochondral:
junction, it should have progressed medially
and downwards and should have stayed
above the heart base. The point where the
right atrial hump straightens towards SVC
on contrast radiography was considered the
heart base (Fig. 42.4).
Lower limb: Measure the distance The inferior vena cava (IVC) is below the
from the point of insertion to diaphragm (T9-T10) and above the L4-LS
the umbilicus and then to the vertebrae level.
xiphisternum.

Fig. 42.3: Estimating the desired length Fig. 42.4: Anteroposterior radiograph
of PICC insertion in upper limb. of chest showing satisfactory position
of PICC line (red box) inserted in the
right upper limb.

The malposition rate is high when anatomical landmarks are

used for calculating the length to be inserted, with a tendency to
overestimate the actual length.

Con rmation of PICC Tip Position

fi
1. X-ray: Always con rm the tip position of the catheter by an X-ray
fi
(see above); preferably, both anteroposterior and lateral views are
 Central Vascular Access 443

to be taken in case of lower limb PICC for better visualization.

Radio-opaque contrast (0.3-0.5 ml) helps assess the location of
the catheter tip in small-size catheters.
2. Real-time ultrasound (RT-USG): High parasternal, subcostal,
bicaval, and apical views can be used to localize the PICC tip
during the procedure. The tip should be manipulated to lie at
the SVC - RA junction."

Recommended Catheter Size

• Infant's birth weight ≤1.0 kg: 1 Fr (28 G)
• Infant's birth weights >1.0 kg: 2 Fr (24 G)

Practical tip
• Prefer upper limb PICC as they are associated with fewer complications.
• Do not use PICC for blood sampling or central venous pressure monitoring.
• Packed cell transfusions should be avoided due to the risk of catheter
occlusion.

PICC Maintenance
1. Use transparent occlusive dressings to allow easy visualization of
the catheter site. Change the dressing only when visibly soiled,
damp, or loosened. For optimum sterility, two persons should
change the dressing.
2. Assess the catheter site and review the need for a central catheter
daily. Remove the catheter at the earliest when it is no longer
needed.
3. Always "scrub the hub" for at least 15 seconds before initiating
any infusion to prevent contamination of the central line.
4. For surveillance, use quality indicators such as catheter dwell
time and central line-associated bloodstream infections (CLABSI).
Use CLABSI Bundle (Table 42.4).

Table 42.4: A bundled approach for prevention of CLABSI®

1. Proper hand hygiene is the single most crucial intervention.
2. Best CVC practices: optimal insertion using a checklist, daily maintenance,
timely removal.
3. Real-time surveillance and reporting of infection.
Complications
1. Catheter-related sepsis: Higher chance of multiple insertion
attempts, hub manipulation, etc. Coagulase-negative
staphylococci are the most common pathogen. It is also the most
common healthcare-associated infection in NICU. Bundled care
approach helps in reducing CLABSI; Table 42.5).
2. Line migration: Cardiac arrhythmia, pericardial effusion,
pericardial tamponade, tissue extravasation, pleural effusion.
Ascending lumbar vein (ALV) migration is a common complication
of lower limb PICCs.
3. Thrombosis (more in lower extremity lines): It includes
deep venous thrombus, renal vein thrombus, and intracardiac
thrombus. It is responsible for 90% of venous thromboembolic
events in neonates.
4. Catheter breakage or dysfunction

5. Phlebitis
In rare situations when PICC placement is not possible, and there
is no other venous access, central venous access can be established
by centrally inserted central catheters (CICC) (using internal jugular
vein (IJV), subclavian vein and femoral vein)

PERCUTANEOUS ARTERIAL CATHETERIZATION

Indications
1. Continuous monitoring of invasive blood pressure in critically
sick babies.
2. Need for frequent samplings, such as the need for repeated
arterial blood gases in ventilated babies.
3. Inability to insert a UAC/ removal of UAC due to complications.

Table 42.5: Central: line associated bloodstream infection (CLABSI) definition

Presence of all
1. Occurrence of laboratory-con rmed bloodstream infection (LCBI).
fi
2. Duration of central line (CL) or umbilical catheter (UC) for 2 or more
calendar days on the occurrence of CLABSI, with a day of catheter insertion
being the rst day.
fi
3. The line must be in place either on the day of CLABSI or the day before.
The term catheter related blood stream infection (CRBSI) is used when the same
organism is recovered from percutaneous blood culture and from culture of
catheter tip with a 3-fold colony count in the latter.
 Central Vascular Access 445

Preferred Site
Radial artery or posterior tibial artery as they have good collateral
circulation. The axillary artery, femoral artery, dorsalis pedis artery,
and temporal artery should be avoided.

Practical tip
• Perform modified Allen's test (Table 42.6) before cannulation of the radial
artery to establish patency of ulnar artery circulation.
• Use transillumination with a cold light for better visualization of the artery
(Fig. 42.5).
• Always fix the cannula allowing good visibility of fingers and toes.
• Maintain patency of catheter using low-dose heparin infusion(0.5 U/ml).

Complications
1. Vascular—vasospasm/ thrombosis/ embolism: Most common;
can lead to blanching of extremity, skin necrosis, gangrene, and
loss of digits. The catheter should be removed immediately once
evidence of ischemia is seen.
2. Hemorrhage/hematoma at the puncture site
3. Infection
4. Air embolism
Table 42.6: Modified Allen test
• Apply pressure on the palm and fingers of the infant to blanch.
• Apply pressure using your fingers to both the radial and ulnar arteries of the
infant to obstruct blood ow.
fl
• Release the occlusive pressure only on the ulnar artery.
- Positive test If hand ushes within 5-15 seconds (good ow in the ulnar
fl
fl
artery).
• Negative test - If the hand does not ush within 5-15 seconds, there is poor ow
fl
fl
in the ulnar artery. Do not puncture the radial artery puncture in such cases.

Fig. 42.5: Radial artery cannulation using transillumination • Diagnotic Modalities and Procedures
 446 AilMS Protocols in Neonatology

_REFERENCES
1. Dunn PM. Localization of the umbilical catheter by post-morten
measurement. Arch Dis Child. 1966;41(215):69-75.
2. Shukla H, Ferrara A. Rapid estimation of insertional length of umbilical
catheters in newborns. Am | Dis Child. 1986 Aug: 140(8):786-8.
3. Wright IM, Owers M, Wagner M. The umbilical arterial catheter: a formula
for improved positioning in the very low birth weight infant. Pediat Crt
Care Med. 2008 Sep; 9(5):498-501.
4. Barrington KJ. Umbilical artery catheters in the newborn: effects of position
of the catheter tip. In: The Cochrane Collaboration, ed. Cochrane Database
of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 1999.
doi:10.1002/14651858.CD000505.
5. Samiee-Zafarghandy S, van den Anker IN, Ben Fadel N. Topical nitroglycerin
in neonates with tissue injury: A case report and review of the literature.
Paediatr Child Health. 2014 Jan; 19(1):9-12.
6. Barone G, Pittiruti M, Biasucci DG, Elisei D, lacobone E, La Greca A,
Zito Marinosci G, D'Andrea V. Neo-ECHOTIP: A structured protocol
for ultrasound-based tip navigation and tip location during placement
of central venous access devices in neonates. J Vasc Access. 2021 Apr
5:11297298211007703.
7. Kishigami M, Shimokaze T, Enomoto M, Shibasaki J, Toyoshima K.
Ultrasound-Guided Umbilical Venous Catheter Insertion With Alignment
of the Umbilical Vein and Ductus Venosus. J Ultrasound Med. 2020
Feb; 39(2):379-83.
8. Butler-O'Hara M, D'Angio CT, Hoey H, Stevens TP. An evidence-based
catheter bundle alters central venous catheter strategy in newborn infants.
J Pediatr. 2012;160(6):972-7.e2. doi:10.1016/j-jpeds.2011.12.004.

ection 11
 Section
12
Therapeutic Modalities

43. Oxygen Saturation Policy in the NICU

44. Surfactant Replacement Therapy in Neonates

45. Fluid and Electrolyte Management

46. Continuous Positive Airway Pressure

47. Heated Humidi ed High Flow Nasal Cannula Therapy

fi
48. Nasal Intermittent Positive Pressure Ventilation
49. Parenteral Nutrition
50. Peritoneal Dialysis
51. Blood Component Therapy
52. Kangaroo Mother Care
53. Pain Assessment and Management
54. Donor Human Milk
55. Developmentally Supportive Care
 CHAPTER|

43
Oxygen Saturation
Policy in the NICU

Oxygen is a drug and oxygen toxicity can have signi cant adverse

fi
have a policy for targeting oxygen saturation in neonates and

implementationer such guidelines has shown reduction in the

Evidence on oxygen saturation targeting
Five major randomized controlled trials, the SUPPORT Study, the Benefits of
Oxygen Saturation Targeting (BOOST Il) trial and the Canadian Oxygen Trial
(COT) compared two SpO, target ranges—low (85-89%) vs. high (91-95%) -
involving around 5000 preterm neonates of <28 weeks of gestation. The results
have been pooled in a meta-analysis called the NEOPROM? project which
showed no signi cant difference between the lower and higher Spo, target
fi
range on the primary composite outcome of death or major disability at a
corrected age of 18-24 months. However, neonates randomized to the lower
SpO, target range had a higher risk of death and necrotizing enterocolitis, but
a lower risk of retinopathy of prematurity. This study suggests that an SpO
target range of 91-95% may be safer compared to 85-89% in extremely preterm
infants due to a higher risk of death associated with the lower range.

IMPLICATIONS FOR PRACTICE

• The National Neonatology forum (NNF) clinical practice

guidelines (CPG) recommend an oxygen saturation target
of 91-95% in all neonates (both 34 weeks and >34 weeks of
gestational age) requiring respiratory support.3
• The NNF-CPG also recommends a similar oxygen saturation
target (91-95%) for preterm neonates with evolving or established
BPD and requiring respiratory support.
• Oxygen therapy should always be administered based on pulse
oximeter based continuous SpO, monitoring.

449
450 AlIMS Protocols in Neonatology

• The alarm limits should be set no more than 1 or 2% above or

below the chosen target range and should always be 'on'. The
upper alarm limit should always be 95% and it can be increased
to 100% if the neonate is on 21% FiO, on respiratory support to
decrease alarm fatigue."
• The alarm delay should not be longer than 20 sec to ensure that
significant events are not missed.
• Small incremental changes (1-5%) in FiO, are preferred to avoid
fluctuations in SpO, unless oxygen saturation is below 70% or
associated with apnea or bradycardia.
• Routine preoxygenation (up to 100%) for procedures such as
endotracheal suction, venous cannulation, or other painful

• Predures our peroxia is indicated by the monitor, respond

to the neonate first and the monitor next. The evaluation should
include:
- Ascertaining if there is bradycardia, apnea, or cyanosis
by a clinical examination, which may warrant immediate
intervention.
- Assessing air-way patency and clear secretions, if any.
- Ensuring if the pulse oximeter probe is attached correctly and
there are no motion artifacts.
- Adjusting the FiO, in small incremental steps to achieve the
target saturation and
- Addressing the underlying disease problem.
• Discuss the percentage time spent within and outside the target
SpO, range if oxygen saturation histograms are downloadable
from pulse oximeters and the frequency of desaturations over the
preceding 24-hour period with the healthcare providers during
daily rounds.
• Quality improvement initiatives targeting caregiver education,
implementation of guidelines for oxygen administration and
targeting, bedside availability of histograms, and event review
during rounds can result in better oxygen saturation targeting
and improved clinical outcomes.4

REFERENCES
1. Lau YY, Tay YY, Shah VA, Chang P, Loh KT. Maintaining optimal oxygen
saturation in premature infants. Perm J. 2011;15(1)e108-13.
2. Askie LM, Darlow BA, Finer N, Schmidt B, Stenson B, Tarnow-Mordi W, et al.
Neonatal Oxygen-ation Prospective Meta-analysis (NeOProM) Collaboration.
 Oxygen Saturation Policy in the NICU
451

Association Between Oxygen Satu-ration Targeting and Death or Disability

in Extremely Preterm Infants in the Neonatal Oxygena-tion Prospective
Meta-analysis Collaboration. JAMA. 2018;319(21):2190-201.
3. NNF India Evidence-based Clinical Practice Guidelines. Oxygen therapy in
neonates. December 2021. Available at: https://www.nn .org/assests/upload/

fi
usefull-links-pdi/Oxygen_therapy_in_neonates_NNFL_CPG_Dec2021 pdf
Accessed 18-04-2023.
4. Shivananda S, Thomas 5, Dutta S, Fusch C, Williams C, Gautham KS. Care
Bundle to Improve Oxygen Maintenance and Events. Pediatr Qual Saf.
2023;8(2):639.
CHAPTER

44
Surfactant Replacement
Therapy in Neonates

Respiratory failure secondary to surfactant de ciency is a signi cant

fi
fi
cause of morbidity and mortality in preterm neonates. Exogenous
surfactant therapy substantially reduces mortality and respiratory
morbidities in them.

SURFACTANTS (Table 44.1)

Dosage
Term infants usually have a surfactant storage pool of approximately
100 mg/kg, whereas preterm infants have an estimated pool of only
4-5 mg/kg at birth. Exogenous surfactant therapy rapidly increases
pool size and improves pulmonary gas exchange until endogenous
surfactant is released. A minimum of 100 mg/kg of surfactant should

Table 14.1: Commonly used surfactant preparations

Natural Minced lung 1. Beractant (Survanta®

extract 2. Poractantalfa (Curosurf®)
3. Surfactant TA (Surfacten®

Lung lavage 1. Bovine LipidExtract Surfactant (BLES)

extract 2. Calfactant (Infasurf®)
3. SF-RI1 (Alveofact*)

Newer New synthetic 1. Lucinactant (Surfaxin)-SPB analogues.

synthetic (protein

(nati second 2. Sec

generation sitatan Venicute: SPC analogues,
Lusupultide
Third generation CHF 5633 (SP-B and SP-C enriched synthetic
surfactant)
1. Bovine minced lung extracts contain less than 10% of the SP-B found in the bovine
lung lavage extracts.
2. Synthetic surfactants do not have the theoretical concerns associated with animal-
derived surfactants like transmission of microorganisms, exposure to animal proteins
and in ammatory mediators, and susceptibility to inactivation.
fl
3. First-generation protein-free synthetic surfactants are no longer used.

452
 Suffactant Replacement Therapy in Neonates 453

Table 44.2: Common brands of surfactant avallable in India and dotage

Surfactant Survanta Curosurf Neosurt
(Abbie) (Nicholas) (Cipls)
Dose 4 ml/kg 2.5 ml/kg 5 ml/kg
Phospholipids (100 mg/kg) (200mg/kg) (135 ng/kg)
Available + ml and 8 ml 1.5 ml and 3 ml 3 ml and 5 ml
formulation
Cost INK 8800 and INR 11780 and INR 4900 and
14500 20790 7950

be administered to preterm infants with RDS. Doses of 50 mg/kg to

200 mg/kg have been studied. A higher dose of poractant (200 mg/
kg) has been found to be superior in reducing mortality and BPD
compared to low-dose poractant or beractant (Table 44.2).

Indications for Surfactant Therapy

Surfactant replacement is done mainly for RDS. But it can be
used in other conditions where the surfactant is inactivated,
such as meconium aspiration syndrome, pneumonia, pulmonary
hemorrhage, congenital diaphragmatic hernia, and acute respiratory
distress syndrome.
In extreme or very preterm neonates, the surfactant can be
administered prophylactically or as rescue therapy (Fig. 44.1).
1. Prophylactic surfactant: Surfactant is administered within
15-30 min of birth, irrespective of the signs of RDS. Prophylactic
surfactant therapy should be used with caution as recent evidence
suggests an increased risk of BPD/mortality compared to
selective surfactant administration. It may be considered only in
neonates born before 28 weeks of gestation with no/incomplete
antenatal steroids or required intubation and mechanical
ventilation immediately after birth. 1-5
Rationale: Administration of surfactant to a previously
unventilated or minimally ventilated lung will diminish acute
lung injury. Acute lung injury results in alveolar-capillary
damage, leakage of proteinaceous fluid into the alveolar space,
and release of inflammatory mediators, resulting in decreased
response to surfactant replacement.
2. Early rescue: Surfactant is administered in an infant with features
of RDS within 2 hours. Early administration of surfactant is • Therapeutic Modalities
 AIMS Protocols in Neonatology
454

[* 28 weeks*] [ 28 weeks or more |

Intubation at birth or Respiratory distress

No/ Incomplete antenatal steroids* al birth

May consider prophylactic Mechanical ventilation

CPAP with FIO,
surfactant after stabilization of 0.3 or more with FIO, of 0.3 or more

Early rescue surfactant within 2 hours

Good spontaneous respiration and

no hemodynamic Instability

Yes No
Insure to Continued on
nasal СРАР mechanical ventilation)

Consider giving repeat dose after 12 hours of Initial dose

I FiO, 0.4 or more or CPAP failure"

'Individualised decision to be taken for giving prophylactic surfactant in this group

*Duration might vary based on the proparation

Fig. 44.1: Surfactant replacement therapy

advantageous as the presence of lung fluid helps in the uniform

distribution of the surfactant. It also ensures that surfactant
is administered before widespread atelectasis develops in the
lungs. Early rescue surfactant therapy following a trial of CPAP
is preferred over prophylactic treatment because it reduces the
amount of surfactant used with comparable immediate outcomes.
3. Late rescue: Surfactant is administered in an infant with features
of RDS after 2 hours. It is usually done in outborn neonates who
are Iransported late to referral centers.
Procedure for Surfactant Administration via InSurE
The standard method of surfactant administration is through the
endotracheal tube after intubation of the infant (Table 44.3).

Methods of Surfactant Administration

Surfactant preparations must spread uniformly throughout the lung
into the air-liquid interface once instilled in the proximal airways.
 Surfactant Replacement Therapy in Neonates 455

Table 44.3: Procedure for surfactant administration

1. A physician or a nurse experienced in surfactant administration should
administer the surfactant.
2. Warm the surfactant prior to administration (for 8 minutes if the vial is held
between the palms of the hands or for 20 minutes at room temperature.) The
vial should not be heated, and it should not be kept on radiant warmer. It
should not be kept in room air for more than 30 min as it increases viscosity.
3. Do not shake the surfactant.
4. Intubate the baby with appropriate size endotracheal tube.
5. Assess breath sounds for equality. Chest X-ray is not mandatory for
con rmation of ET tube position.
fi
6. Infant should be connected to a pulse oximeter and oxygen saturation and
heart rate must be monitored throughout the procedure.
7. Administer the surfactant through the feeding tube inserted in the ET tube
or through the side port of the ET tube (if available).
8. Surfactant is given as bolus instillation in four aliquots of the total dose.
9. Connect the infant to ventilator or the T-piece resuscitator with set PIP and
PEEP and ventilate carefully till saturation and heart rate stabilizes before
administering the next aliquot.
10. Consider increasing PIP by 10% for about 5 min after surfactant
administration if chest rise is inadequate.
11. No position change of the infant is required between the aliquots.
12. Suctioning of ET tube should be avoided for at least 2 hours following
surfactant administration
Strict asepsis should be carried out throughout the procedure

1. Slow infusion versus rapid bolus administration: Surfactant

can be administered either by slow tracheal infusion or rapid
bolus administration. Natural surfactant works best if given
by a rapid bolus into the lungs as it leads to the homogeneous
distribution of surfactant and results in rapid improvement
in oxygenation. On the other hand, it can also cause ET tube
obstruction, transient bradycardia, hypotension, and changes
in cerebral blood flow. Slow infusion results in nonhomogenous
distribution of surfactant. Currently, the rapid bolus technique is
the recommended method of surfactant administration.
2. Through endotracheal tube (InSurE-Intubate - Surfactant -
Extubate to CPAP): InSurE comprises intubation, surfactant
administration, a brief period of ventilation (usually <1 hour),
and rapid extubation to nasal CPAP to prevent ventilation
induced lung injury (VILI). In infants with signs and symptoms
of RDS, InSurE to nasal CPAP results in a decreased duration of
456 AIIMS Protocols in Neonatology

mechanical ventilation, air leak, and less incidence of BPD. InSur:

technique may not be successful in neonates with severe birth
asphyxia, lack of complete course of antenatal steroids, extreme
prematurity, delayed administration of surfactant, and shock.
3. Through a thin catheter (Less invasive surfactant administration
[LISA]/Minimally invasive surfactant therapy [MIST): Due
to the risks associated with ET tube placement and ventilation,
newer techniques with less invasive surfactant therapy have
emerged. LISA involves the administration of surfactant through
a feeding tube (4-5 Fr catheter) inserted into the trachea using
Magill forceps under direct laryngoscopy without intubation. In
contrast, in MIST, a slightly stiff catheter (e.g. surfcath, angiocath
16G) is used to administer surfactant without using Magill
forceps. CPAP is continued during surfactant administration to
facilitate alveolar recruitment, which helps distribute surfactant
and avoids positive pressure ventilation. LISA technique, as
compared to InSurE, has been shown to reduce the risk of death
or BPD, the need for mechanical ventilation, and pneumothorax.
Nowadays, dedicated LISA catheters have become available.
Personnel practicing LISA should be adequately trained
regarding the use of Magill forceps and the depth of insertion of
the catheter. Poractant is preferable for LISA/MIST as the volume
instilled is lesser than beractant.

4. Through laryngeal mask airway: A few trials that used LMA for
surfactant therapy in infants of more than 1000 g showed less
need for mechanical ventilation. Surfactant reflux and coughing
are more frequently seen in these infants. There is a lack of solid
evidence to recommend using LMA for surfactant administration
in preterm neonates.

5. Nebulized surfactant delivery: It is a genuinely noninvasive

technique. Practical issues like loss of surfactant in the
upper airway / esophagus, inactivation of surfactant, and
nonhomogenous distribution need to be addressed before
nebulized surfactant can be adopted in routine clinical practice.
Repeat Dose of Surfactant
Multiple doses of surfactant have a more signi cant effect than a
fi
single dose on air leaks. Repeat doses of surfactant may be required
in an infant if the administered surfactant is inhibited by edema
fluid, soluble proteins, or inflammatory mediators present in the
alveoli after lung injury due to mechanical ventilation, delayed
 Surfactant Replacement Therapy in Neonates 457

surfactant administration, or sepsis. Using a higher threshold for

r-treatment with surfactant is as effective as a low threshold and
can result in significant cost savings. Infants may require repeat
dose(s) of surfactant if they require FiO, of 0.4 or more on CPAP
and mechanical ventilation to maintain target saturation. Infants
with lower gestational age, male sex, lack of antenatal steroids, and
initial requirement of higher FiO, might require repeated doses
of surfactant. Administering more than three doses has not been
shown to have a benefit.
Poor Response to Surfactant
Some infants may not show the expected response to the surfactant
administered ('RDS plus'). These non-responders usually have
lung injury either before birth (infection) or after delivery but
prior to treatment (volutrauma and barotrauma), asphyxia,
sepsis / pneumonia, meconium aspiration, the severity of disease,
pulmonary hypoplasia, or hemodynamic instability (shock).
Intratracheal Administration of Corticosteroids and Surfactant
Corticosteroids (systemic and inhaled) have been used to prevent
and treat BPD. Early intratracheal administration of corticosteroids
(especially budesonide) has been hypothesized to reduce the
incidence of BP'D by suppressing lung inflammation. But trials on
intratracheal administration of steroids alone have not shown any
proven benefit. Meta-analysis of trials comparing intratracheal
steroids with surfactant as a vehicle compared to surfactant alone
have shown to decrease the risk of BPD and BPD/mortality at
36 weeks. But due to the heterogeneity of trials, additional cost, and
feasibility of preparing the mixture, intratracheal administration of
steroids with surfactant is currently not recommended.
Adverse Reactions of Surfactant Administration
Surfactant replacement therapy is much safer, and side effects
are usually transient. Hypoxia and bradycardia can occur during
surfactant instillation due to acute airway obstruction. Other less
common acute adverse effects are reflux of surfactant into the
pharynx, increased PCO2, gagging, and mucous plugging of the
ET tube. There is an increase in the risk of pulmonary hemorrhage
following surfactant therapy which is more common with natural
surfactants (5-6%) than with newer-generation synthetic surfactants
(1-3%). Pulmonary hemorrhage typically occurs within 72 hours
and is due to improved lung compliance after surfactant therapy,
458 AIMS Protocols in Neonatology

which promotes an increase in left-to-right shunt through the PDA,

resulting in increased blood ow and congestion. Evidence suggests

fl
that surfactant therapy reduces the risk of mortality, air leak, or BID.

LONG-TERM OUTCOMES

Improved or equivalent results on pulmonary function testing but

no significant differences in the long-term neurodevelopmental
outcomes have been reported in infants treated with surfactant
compared to those treated with placebo.
Evidence6-13
Prophylactic versus selective surfactant
Studies conducted prior to the routine application of CPAP demonstrated
a decrease in the risk of air leak and neonatal mortality associated with
prophylactic administration of surfactant. However, when all studies were
evaluated together, no benefits of prophylactic surfactant could be demonstrated
and there is higher incidence of BPD or death in prophylactic surfactant group
(RR1.13; 95% Cl 1.02-1.25) (Cochrane 2012).
Early rescue versus late rescue surfactant
Early rescue surfactant reduces the risk of neonatal mortality (RR 0.84; 95% CI
0.74-0.95), BPD (RR 0.69; 95% Cl 0.55-0.86), and overall air leak syndromes
(RR 0.61; 95% Cl 0.48-0.78) (Cochrane 2012).
InSurE
InSurE compared with surfactant administration followed by continued
mechanical ventilation and extubation from low respiratory support was
associated with a lower incidence of need for mechanical ventilation [RR 0.67,
95% Cl 0.57-0.79], air leak syndromes |RR 0.52, 95% Cl 0.28-0.96] and BPD
IRR 0.51, 95% Cl 0.26-0.99] (Cochrane 2007).
Surfactant replacement therapy (SRT) in LMIC
Systematic review on SRT in preterm with RDS from LMICs showed a signi cant
fi
reduction in mortality (RR 0.67; 95% Cl 0.57-0.79) and air leaks (RRO.51;
95% CI 0.29-0.90).

New synthetic versus animal-derived surfactant

Protein containing synthetic surfactant compared with animal-derived surfactant
did not demonstrate any signi cant reduction in risk of mortality (RRO.81, 95%
fi
Cl 0.64-1.03) or BPD (RR 0.99, 95% Cl 0.84-1.18) (Cochrane 2007).
Single dose versus multiple doses of surfactant
Repeat dose of surfactant administration results in a lower incidence of
pneumothorax (RR 0.51, 95% Cl 0.30-0.88) and a decreased trend towards
mortality (RRO.63, 95% Cl 0.39-1.02) (Cochrane 2009).
(Contd.!
 Surfactant Replacement Therapy in Neonates 459

(Contd.)
Less Invasive Surfactant Administration (LISA)
Metanalysis of 6 trials comparing the LISA technique with intubation for
suriactant delivery demonstrated the reduced composite outcome of death or
BPD at 36 weeks (RR 0.75; 95% Cl 0.59-0.94), BPD at 36 weeks (RR 0.72;
95% Cl 0.53-0.97) or need for mechanical ventilation anytime during NICU
stay (RR 0.66; 95 % Cl 0.47-0.93).

REFERENCES
1. Polin RA, Carlo WA, Committee on Fetus and Newborn, American Academy
of Pediatrics. Surfactant replacement therapy for preterm and term neonates
with respiratory distress. Pediatrics. 2014 Jan; 133(1):156-63.
2. Ng EH, Shah V. Guidelines for surfactant replacement therapy in neonates.
Paediatr Child Health. 2021;26:35-49.
3. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, te Pas A, et al.
European Consensus Guidelines on the Management of Respiratory Distress
Syndrome - 2019 Update. Neonatology. 2019 Jun; 115(4):432-50.
4. Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, Somanath SH, Shaik
NB, Pullattayil AK, et al. Interventions to Prevent Bronchopulmonary
Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews
and Metaanalyses. JAMA Pediatrics. 2022.
5. National Neonatology Forum India Clinical Practice Guidelines [Dec 2021
update]. Surfactant Replacement therapy in neonates. Available from www.
nn .org/cpg.
fi
6. Rojas-Reyes MX, Morley C), Soll R. Prophylactic versus selective use of
surfactant in preventing morbidity and mortality in preterm infants. Cochrane
Database Syst Rev. 2012 Mar 14;(3):CD000510.
7. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for
neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2012
Nov 14;11:CD001456.
8. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal
Research Network, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, et
al. Early CPAP versus surfactant in extremely preterm infants. N Engl | Med.
2010 May 27;362(21):1970-9.
9. Stevens TP, Harrington EW, Blennow M, Soll RF. Early surfactant
administration with brief ventilation vs. selective surfactant and continued
mechanical ventilation for preterm infants with or at risk for respiratory
distress syndrome. Cochrane Database Syst Rev. 2007 Oct 17(4):
CD003063.
10. Sankar MJ, Gupta N, Jain K, Agarwal R. Ef cacy and safety of surfactant
fi
replacement therapy for preterm neonates with respiratory distress syndrome
in low- and middle-income countries: a systematic review. ) Perinatol.
2016;36 Suppl 1:536-48.
 460 AIMS Protocols in Neonatology

11. Pfister RH, Soll RF, Wiswell T. Protein containing synthetic surfactant
versus animal derived surfactant extract for the prevention and treatment
of respiratory distress syndrome. The Cochrane Database Syst Rev
2007(41:CD006069
12. Soll R. Ozek E. Multiple versus single doses of exogenous surfactant for the
prevention or treatment of neonatal respiratory distress syndrome. Cochrane
Database Syst Rev. 2009 Jan 21;(1):CD000141.
13. Aldana-Aguirre IC, Pinto M, Featherstone RM, Kumar M. Less invasive
surfactant administration versus intubation for surfactant delivery in preterm
infants with respiratory distress syndrome: a systematic review and meta.
analysis. Arch Dis Child Fetal Neonatal Ed. 2017;102(1):F17-F23.

Section 12
 CHAPTER

45
Fluid and Electrolyte
Management

The goal of fluid and electrolyte management is to maintain fluid

homeostasis, which can be altered by the physiological immaturity
of organ systems involved in maintaining homeostasis or various
systemic illnesses in neonates.
Adaptation to extrauterine life consists of three phases of fluid
balance. In the first week of life, there is a decrease in the total body
water by shrinkage of the extracellular fluid (ECF) compartment.'
Loss of the excess ECF and evaporative water loss from immature
skin results in physiological weight loss during this period. This
phase of transition ends with maximum weight loss. Since the ECF
compartment is larger in more preterm neonates, the weight loss is
greater in preterm neonates. During the second phase, the insensible
water loss reduces as the skin barrier matures, urine volume falls
to less than 2 ml/kg/hour, and sodium excretion becomes low. The
third phase consists of stable growth characterized by continuous
weight gain with a positive net balance for water and sodium.

RENAL FUNCTION

Neonates have a limited capacity to excrete either concentrated

(due to immaturity of the distal nephron with an anatomically
shortened loop of Henle) or diluted urine (due to physiologically
low glomerular filtration rate). The physiological range of urine
osmolality varies from a lower limit of 50 mmol/L to upper limits
of 600 mmol/L in preterm neonates and 800 mmol/L in term
neonates23 An acceptable osmolality range of 300-400 mmol/L
corresponds to a daily urine output of 2-3 ml/kg/hr.

SODIUM BALANCE
Neonatal kidneys have a limited capacity to excrete or conserve
sodium. The maturity of sodium handling depends on the gestation
and postnatal age.* Normally, there is salt and water diuresis in
461
462 AIMS Protocols in Neonatology

the first 48-72 hours of life. Therefore, sodium supplementation

should be started after ensuring initial diuresis or at least 5-6%
weight loss. Preterm neonates have a limited tubular capacity
to reabsorb sodium due to tubular immaturity and reduced
responsiveness to aldosterone and hence have increased urinary
losses." Failure to supplement sodium after the first week of life
can result in low body stores of sodium and poor weight gain.'
Very low birth weight infants on exclusive breastfeeding may need
sodium supplementation in addition to breast milk till 32-34 weeks
corrected age?$

FLUID LOSSES

In addition to water loss by the kidneys and gastrointestinal system

('sensible' loss), additional water losses occur due to evaporation
from the skin and respiratory tract. This water loss is termed
insensible water loss (IWL). IWL tends to be higher in preterm
infants (Table 45.1).

Evaporative loss through the skin usually contributes to 70%

of IWL.' The remaining 30% is contributed by losses from the
respiratory tract. The fluid management of neonates should focus
on prevention rather than replacement of increased IWL.
The strategies to reduce insensible water loss include the
following:
• Antenatal corticosteroids aid in accelerated skin maturation in
preterm babies.'
• Double-wall incubators with humidification.
• Covering the bassinette of the radiant warmer with cling wrap. 10
• Covering the head and extremities with caps and socks.
• Topical application of emollient or coconut oil or safflower oil
(50%).11,12
• Use of warm and humidified inspiratory gas for babies on
respiratory support.

Table 45. 1; Insensible water loss according to birth weight on day 1

Birth weight (g) Insensible water loss (ml/kg/day)

<1000 60-80
1000-1500 40-60
>1500 20
 Flud and Electrolyte Margement 463
Guidelines for Fluid and Electrotyte Therapy
First week of postnatal life: The goals for uid and electrolyte

fl
administration during the first week are to:
a. Allow contraction of ECF (without compromising intravascular
fluid volume and cardiovascular function) with a negative fluid
balance of not more than 10%.
b. Allow a negative net balance for sodium of 2-5 mmol/kg/day
to maintain normal serum electrolyte concentrations.
c. Avoid oliguria (0.5-1.0 ml/kg/hour) for longer than twelve
hours, and
d. Avoid excessive transepidermal water loss. Once the transition
period is over, the goals are to attain a weight gain of 15-20
g/kg/day and progressively increase oral feeds.
The amount of actual fluid intake to be prescribed from the
recommended range for each day (Table 45.2) is decided based on
the clinical examination and laboratory parameters—the neonate
should have physiological (not excessive) weight loss, normal tissue
perfusion, normal serum electrolytes, and adequate urine output
(see below).

Physiological Basis for Fluld Requirements in the First Week of Life

Term and Preterm Neonates with a Birth Weight of 1500 g or more
Day 1: These neonates must excrete a solute load of about 15 mOsm/
kg/day through the kidneys. To excrete this solute load at a urine
osmolarity of 300 mOsm/kg/day, they need a minimum of 50 ml/
kg of free water. Allowing for an additional IWL of 20 ml/kg, the
initial fluids should be 60-70 ml/kg/day.
Day 2-7: As the neonate grows and receives enteral milk feeds,
the solute load presented to the kidneys increases, and the infant
requires more fluid to excrete the solute load. Water is also
needed for fecal losses and growth purposes. Therefore, the fluid
requirements increase by 15-20 ml/kg/day up to 150 ml/kg/day.

Preterm Very Low Birth Weight Neonates

Day 1: The urine output in these neonates is likely to be similar
to that of term neonates. However, their fluid requirement will be
higher due to increased IWL and weight loss (extracellular fluid
loss). Using caps, socks, and plastic barriers (cling wrap) under Theraneutic Modalities

the radiant warmer is recommended to reduce the IWL rather than | •

464 AIMS Protocels in Neonatology

Table 45.2: Parenteral fluid and clectrolyte requirements during the first wi.
after birth

Parenteral fluid in ml/kg/day

Day after birth

6 5
Term 60-80 80-100 100-120 120-140 140-160 140-160 140-160
neonates
AND
Preterm
neonates
with birth
weight
>1500 g
Preterm 80-90 100-110 120-130 130-150 140-160 150-170 150-180
neonates
with birth
weight
<1500 g

Electrolyte requirement (mEq/kg)

Sodium 3-4 (careful adjustment needed in neonates weighing <1000 g)
Potassium 1-2 (start after the onset of diuresis)
Chloride 3-4
No electrolyte supplementation is required in the initial 48 hours of life.
NB:
• Dextrose infusion should be maintained at 4-6 mg/kg/min; ELBW neonates are at high
risk of hyperglycemia-blood glucose should be monitored frequently to titrate the
glucose infusion rate.
• Calcium may be used in a dose of 4 ml/kg/day (40 mg/kg/day) of calcium gluconate for
the rst 3 days in certain high-risk situations (see the protocol on 'hypocalcemia"').
fi
unduly increase the uid intake. With the measures to reduce IL
fl
(see above), managing VLBW neonates with a fluid intake of 80 mL /
kg/day on day 1 of life is possible. The fluid requirement on the
first day of life in extremely preterm neonates is discussed below
(see 'Specific clinical conditions').
Day 2-7: As the skin matures in preterm neonates, the IWL
progressively decreases and becomes like that of term neonates by the
end of the first week. Hence, their fluid requirement is not different
from that of term neonates during this period. Fluid intake needs to
be increased by 15-20 ml/kg/day up to 150-180 ml/kg/day.
 Fluid and Electrolyte Management 465
After the First Postnatal Week
The goals in stable neonates after the first week of life are to maintain
water and electrolyte homeostasis and provide enough additional
fluids and electrolytes to build new tissue at intrauterine growth
rates (Table 45.3).

Restricted uids in preterm neonates: what is the evidence?

fl
A review of ve randomized studies with different levels of uid intake during
fi
fl
the rst week of life concluded that uid restriction reduces the risk of patent
fi
fl
ductus arteriosus and necrotizing enterocolitis with trend towards reduction
in risk of bronchopulmonary dysplasia, intracranial hemorrhage, death, and
increased risk of dehydration. 13

MONITORING OF FLUID AND ELECTROLYTE STATUS

Body weight: Serial weight measurements can be used to estimate

the fluid deficit in neonates. Term neonates lose 1-2% of their
weight daily, with a cumulative loss of 7-10% in the first week of
life. Preterm neonates lose 2-3% of their birth weight daily, with
a cumulative loss of 10-15% in the first week of life. Failure to
lose weight in the first week of life indicates the need for possible
fluid restriction. On the other hand, excessive weight loss in the
first 7 days would merit additional fluids to ensure normal fluid
homeostasis.
Clinical examination: The usual physical signs of dehydration are
unreliable in neonates. Neonates with 10% (100 ml/kg) dehydration
may have sunken eyes and fontanelle, cold and clammy skin, poor
skin turgor, and oliguria. Those with 15% (150 ml/kg) or more
dehydration would have signs of shock (hypotension, tachycardia,
and weak pulses) in addition to the abovementioned features.
Dehydration warrants the correction of fluid and electrolytes
gradually over the next 24-48 hours.
Serum biochemistry: Serum sodium and plasma osmolarity
help assess the hydration status. Serum sodium values should be

Table 45.3: Parenteral fluid and electrolyte requirements after the first
postnatal week
Fluid Sodium Potassium
(ml/kg/day) (mmol/kg/day) (mmol/kg/day)
Term neonates 140-160 2-3 1-3
Preterm neonates 150-180 3-5 (up to 7) 4 • Theraneutic Modalities
466 AliMS Protocols in Neonatology

maintained between 135-145 mEq/L. Hyponatremia with weight

loss suggests sodium depletion and merits sodium replacement.
Hyponatremia with weight gain indicates water excess and
necessitates uid restriction. Hypernatremia with weight loss

fl
suggests dehydration and the need for fluid correction over
48 hours. Hypernatremia with weight gain suggests salt and water
overload and the need for fluid and sodium restriction.
Urine output, specific gravity (SG), and osmolarity: The capacity
of the newborn kidneys to either concentrate or dilute urine is
limited. Nevertheless, the estimation of urine SG helps guide fluid
therapy. The acceptable ranges of urine output, specific gravity, and
osmolarity are 1-3 ml/kg/hour, 1.005-1.012, and 100-400 mOsm/L,
respectively. Specific gravity can be checked by a dipstick or by
a hand-held refractometer. Osmolarity is estimated by a freezing
point osmometer.
Blood gas analysis: Blood gases are not needed routinely for
fluid management. However, they are helpful in the acid-base
management of neonates with poor tissue perfusion and shock.
Hypoperfusion is associated with metabolic acidosis.

LABORATORY GUIDELINES FOR FLUID AND ELECTROLYTE THERAPY

Fluid intake should be increased in the presence of:

a. Increased weight loss (>3%/ day or a cumulative loss >15-20%).
b. Increased serum sodium (Na> 145 mEq/L).
c. Increased urine specific gravity (>1.020) or urine osmolality (>400
mOsm/ L), or
d. Decreased urine output (<1 ml/kg/hour).
Fluids should be restricted in the presence of:
a. Decreased weight loss (<1%/ day or a cumulative loss <5%).
b. Decreased serum sodium (Na <130 mEq/L) in the presence of
weight gain.
c. Decreased urine specific gravity (<1.005) or urine osmolality
(<100 mOsm/L), or
d. Increased urine output (>3 ml/kg/hour).
Speci c Clinical Conditions
fi
Extreme prematurity (gestation <28 weeks): They have extremely
high insensible water loss (WL) in the initial few days of life,
which may be 10-15 times that of term neonates. Moreover, there
 uid and Electrolyte Management 467

fl
is a considerable variation in the IWL, making it necessary to rely
on frequent monitoring instead of assumptions alone. The fluid
requirement can be minimized considerably by implementing
strategies to reduce IWL (see above). Most guidelines recommend
administering around 90-120 ml/kg/day fluids on day 1 of life,
with frequent revision of fluid rate in the subsequent days based
on urine output, change in weight, and serum sodium level (which
predominantly depends on fluid status rather than sodium intake in
the rst week of life). It is desirable to allow around 2% weight loss per
fi
day, with a cumulative weight loss of 6-12%, to allow physiological
contraction of extracellular fluid. Sodium supplementation is not
recommended in the initial 24-48 hours of life and is added at 3-4
miq/kg/day thereafter. After the first week of life, a higher sodium
intake of around 5-7 mEq/kg/day is recommended to maintain a
positive sodium balance. Potassium should be added at 2-3 mEq/
kg/day after 48 hours of life. Hyperkalemia of prematurity (serum
potassium up to 6.5 mEq/L) is relatively common till 72 hours of life
and does not usually require treatment. The stratum corneum of these
neonates matures rapidly in 1-2 weeks; therefore, fluid requirements
become comparable to larger infants by the end of the second week.

Perinatal asphyxia: Perinatal asphyxia may be associated with

the syndrome of inappropriate ADH (SIADH) secretion and renal
failure. However, fluid restriction (e.g. two-thirds of daily intake) is
not routinely recommended. It should be done only in the presence
of oliguric hyponatremia. Renal parenchyma injury from perinatal
asphyxia may result in acute tubular necrosis (ATN) accompanied
by oliguria or anuria. In case of oliguric renal failure, fluid intake
should be restricted to replenishing IWL and metabolic water
requirement (400 ml/m? or 40 ml/kg) and any other losses (urine
output, gastric secretions, etc.). During the recovery phase of ATN,
there can be large urinary sodium and potassium losses, which
should be estimated and replaced.
Diarrhea: Neonates develop dehydration quickly because of the
limited concentrating ability of their kidneys. The fluid deficit is
corrected over 24 hours in neonates with diarrhea. Ongoing losses
need to be assessed and corrected 6-8 hourly.

REFERENCES
1. Bell EF, Oh W. Fluid and electrolyte management. In: Avery GB, Fletcher
MA, MacDonald MG, eds. Neonatology: Pathophysiology of the Newborn.
5th ed. Philadelphia: Lippincott Williams and Wilkins; 1999:345-61.
468 AlIMS Protocols in Neonatology

2. Chevalier RL. Developmental renal physiology of the low birth weight pre-
term newborn. | Urol 1996;156:714-9.
3. Modi N. Renal function, uid and electrolyte balance, and neonatal renal

fl
disease. In: Rennie IM, Roberton NRC, eds. Textbook of Neonatology. 3td
ed. Edinburgh: Churchill Livingstone; 1999:1009-36.
4. Nakamura KT, Paul Matherne G, McWeeny OJ, Smith BA, Robillard JE. Renal
Hemodynamics and Functional Changes during the Transition from Fetal to
Newborn Life in Sheep. Pediatr Res 1987.
5. Bueva A, Guignard JP. Renal function in preterm neonates. Pediatr Res
1994;36(5):572-7.
6. Al-Dahhan J. Haycock GB, Nichol B, Chantler C, Stimmler L. Sodium
homeostasis in term and preterm neonates. III. Effect of salt supplementation.
Arch Dis Child 1984;59:945-50.
7. Ayisi RK, Mbiti MJ, Musoke RN, Orinda DA. Sodium supplementation in
very low birth weight infants fed on their own mother's milk I: Effects on
sodium homeostasis. East Afr Med J 1992;69:591-5.
8. Segar DE, Segar EK, Harshman LA, Dagle JM, Carlson S), Segar IL.
Physiological Approach to Sodium Supplementation in Preterm Infants. Am
| Perinatol 2018.
9. August D, Kandasamy Y. The effects of antenatal glucocorticoid exposure
on fetal and neonatal skin maturation. | Perinat Med 2017;45(8):969-75.
10. Kaushal M, Agarwal R, Aggarwal R, et al. Cling wrap, an innovative
intervention for temperature maintenance and reduction of insensible
water loss in very low-birthweight babies nursed under radiant warmers: a
randomized, controlled trial. Ann Trop Paediatr 2005;25:111-8.
11. Nangia S, Paul VK, Chawla D, Agarwal R, Deorari AK, Sreenivas V. Topical
coconut oil application reduces trans-epidermal water loss (TEWL) in very
low birth weight (VLBW) neonates: A randomized clinical trial. In: Pediatric
Academic Society. Toronto; 2007:7933.21.
12. Lane AT, Drost SS. Effects of repeated application of emollient cream to
premature neonates' skin. Pediatrics 1993;92:415-9.
13. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing
morbidity and mortality in preterm infants. Cochrane Database Syst Rev
2014.
 CHAPTER

46
Continuous Positive
Ainway Pressure

Continuous positive airway pressure (CPAP) refers to the application

of positive pressure to the airway of a spontaneously breathing
infant throughout the respiratory cycle. CPAP predominantly
helps by preventing the collapse of the alveoli. Preterm infants
have difficulty establishing and maintaining lung volumes due
to surfactant deficiency, muscle hypotonia, slow clearance of lung
fluid, and a compliant chest wall. CPAP results in the recruitment
of alveoli, thus increasing the functional residual capacity (FRC)
and preventing alveolar collapse.'

COMPONENTS

The components of a CPAP system are:

1. Gas source: To provide a continuous supply of warm, humidified,
and blended gases, i.e. air and oxygen.
2. Pressure generator: To create positive pressure in the circuit.
3. Patient interface/delivery system: To connect the CPAP circuit
to the infant's airway.

Devices Used for Pressure Generation

The pressure sources of CPAP can be broadly grouped into two types
(Fig. 46.1):7 We use continuous flow CPAP by both conventional
ventilators and bubble CPAP devices in our unit.

Devices Used for CPAP Delivery (Patient Interface)

Various devices used for CPAP delivery include:
1. Nasal prongs (single / double or binasal)
2. Long (or) nasopharyngeal prongs
3. Nasal cannula
4. Nasal masks

469
470 AlIMS Protocols in Neonatology

CPAP pressure generators

Continuous ow devices Variable ow devices

fl
fl
Desired CPAP pressure is Desired CPAP level is generated
usually generated by by varying the ow

fl
obstruction of a xed ow of

fi
fl
gas by a valve or water column

1. Infant ventilator/ stand-alone CPAP Common examples:

machines: Pressure is generated by
the exhalation valve and adjusted by Vase Sie dryer (IFD)
varying the expiratory ori ce size.
fi
2. Bubble CPAP: Pressure is CPAP pressure is generated at the
generated by submerging the airway proximal to the infant's
expiratory limb into a water chamber nares.
and adjusted by altering its depth.

Fig. 46.1: Surfactant replacement therapy

Hudson, Argyle, IFD prongs, and RAM cannula are the commonly
used short binasal prongs in neonates. A study comparing RAM
cannula, Hudson prongs, and nasal masks found that the nasal
masks delivered oropharyngeal pressure closer to the set CPAP?
Also, nasal masks may reduce the risk of treatment failure and
nasal injury compared to nasal prongs.^ On the other hand, the
ToNIL study revealed that leakages are common for both masks
and prongs, but the degree of the leak was significantly higher with
prongs. Leakage can be significantly decreased using corrective
measures such as adjusting the interface seal by external pressure,
closing the mouth, changing interface size, and adjusting the cap
and patient position. We use Argyle prongs, RAM cannula, or nasal
masks to deliver CPAP.

INDICATIONS FOR CPAP

The common clinical indications of CPAP have been listed in

Table 46.1.
We use CPAP predominantly in preterm infants (<35 weeks
and birth weight <1800 g) with respiratory distress, apnea of
prematurity, delayed adaptation, and pneumonia; also, we extubate
VLBW infants to CPAP routinely. We occasionally use CPAP in late
preterm and term infants with respiratory distress secondary to
TTNB, pneumonia, meconium aspiration syndrome, etc.
 Continuous Positive Airway Pressure 471

Table 46.1: Indications for CPAP

Common indications
1. Respiratory distress syndrome (RDS)
2. Apnea of prematurity
3. Post-extubation in preterm VLBW infants
4. Transient tachypnea of the newborn (TTNB)
Other indications
1. Pneumonia
2. Meconium aspiration/other aspiration syndromes
3. Pulmonary edema/pulmonary hemorrhage
4. Laryngomalacia/tracheomalacia/bronchomalacia

CONTRAINDICATIONS OF CPAP

The important contraindications for CPAP include:

1. Progressive respiratory failure with PaCO, levels >60 mm Hg or
inability to maintain oxygenation (PaO, <50 mm Hg).
2. Congenital malformations of the airway (choanal atresia, cleft
palate, tracheoesophageal fistula, congenital diaphragmatic
hernia, etc.)
3. Severe cardiovascular instability (hypotension).
4. Poor respiratory drive not improved by CPAP.

GUIDELINES FOR CPAP THERAPY

When to Initiate Cpap?

Early CPAP: It is important to note that CPAP helps mainly by
preventing an alveolar collapse in preterm neonates with surfactant
de ciency. Once atelectasis and collapse have occurred, CPAP
fi
might not help much. Therefore, all preterm infants (<35 weeks of
gestation) with any sign of respiratory distress (tachypnea/chest
in-drawing/grunting) should be started immediately on CPAP.
Infants of 32-34 weeks of gestation can have a little higher threshold
(say, silverman score of at least 3-4 or RR of 70 bpm+) for initiating
CPAP than infants <32 weeks of gestation (in whom CPAP must be
started early for any distress or tachypnea).
Prophylactic CPAP: The Cochrane review that compared
prophylactic CPAP with supportive care in preterm infants (mostly
29-32 weeks of gestation) concluded that there is insufficient
evidence for any additional benefit with prophylactic CPAP? • Therapeutic Modalities
472 AIMS Protocols in Neonatology

However, in preterm neonates born at or before 28 weeks of

gestation, prophylactic CPAP administered immediately after birth
in the delivery room (i.e. delivery room CPAP) has been found to
reduce the need for mechanical ventilation and surfactant and also
reduce the incidence of BPD when compared to intubation and
mechanical ventilation."
We do not practice prophylactic CPAP for preterm infants born
after 28 weeks of gestation. However, we generally employ delivery
room CPAP in preterm infants born at or before 28 weeks.

PROTOCOL FOR CPAP THERAPY

Table 46.2 outlines the protocol for CPAP therapy in the three most
common neonatal conditions.

MONITORING WHILE ON CPAP

The following parameters need to be monitored while the infant
is on CPAP:
1. Regular monitoring of respiratory rate, heart rate, SpO
2. Serial monitoring of:
a. Severity of respiratory distress by using Downe's or
Silverman score.
b. Arterial blood gases (ABGs).
c. Perfusion —CFT, BP, peripheral pulses, urine output.
d. Abdominal girth.
e. Nasal injury
During CPAP therapy, the target saturation and blood gases are
SpO, 90-95%; PaO, 50-70 mm Hg; PaCO, 40-50 mm Hg.

HAZARDS/COMPLICATIONS OF CPAP

CPAP, though less invasive and generally safer than IMV, is not
free of side effects.
1. Nasal irritation, damage to the septal mucosa, or skin damage
and necrosis from the xing devices are the most common
fi
adverse effects of CPAP. A nasal injury scoring system helps
monitor skin integrity, septum, and other anatomic structures.
Use of appropriate-size nasal prongs and proper nursing
care, including frequent instillation of saline drops in the
nostrils, ensuring an adequate gap between the prongs and the
 (Contd.)

H,O to reach a maximum of 7-8 ст H20

pre-extubation FiO, maximum of 0.6

• Increase in steps of 1-2 cm

• Same or 0.05 above the • Increase in steps of 0.05 to a
Post extubation • Start at 4-5 cm H,O
Same as for RDS

warranted usually -may lead

(further increase is not

to hyperinflation)

• FiO, increase does not help much Recurrent episodes of apnea requiring PPV

• 0.21-0.4 (as decided by • Increase up to 5 cm H20

• Start at 4 cm H20
Apnea of prematurity

reach a maximum of 8 cm H,0

Indications RDS • Increase in steps of 1-2 cm H,0 to

hypoxemia (PaO, <50 mm Hg), or
and FiO, of 0.5-0.6
hypercarbia (PaCO, >60 mm Hg)despite CPAP pressure of 7-8 cm H,O

• Start at 5-6 cm H20

• 0.3-0.5 (titrate based on SpO,)

Pressure
Initiating CPAP FiOr What to do if there Pressure
is no improvement?
FiOr
474 AlIMS Protocols in Neonatology

Post extubation Likely to occur in ELBW

infants and sepsis/pneumonia,
PDA, metabolic acidosis, and collapse • Same as for RDS

desaturation/bradycardia at
for least 12-24 hours

Likely to occur in infants with central apnea and apnea

secondary to sepsis/pneumonia • Same as for RDS
Apnea of prematurity

Cor CPAP therapy in the three common neonatal conditions (Contd.)

H2O (infant's clinical conditionguide

will the speed of weaning). pressure wean (decreasing pressure a we a goratored in neonates

Indications RDS RDS with delay in initiation administration

Likely to occur in infants with severe of CPAP/ soris, cined ANSW infants who have
of suríactant, associated
and SpO,/blood gases are normal

• Preen data segus havin and

• When there is no respiratory distress • No episodes of apnea/

Tabre

Failure of CPAP CPAP

Weaning from • When to wean?
• How to wean?
 Continuous Positive Airway Pressure 475

columella, and maintaining optimal humidity and temperature

in the circuit would help minimize nasal injury. In some infants,
protective barriers such as 'cannulaide, hydrocolloid dressing,
and alternating between nasal masks and prongs might also be
considered to reduce the risk of injury?
2. Pulmonary air leaks are the most severe adverse effects of CPAP
They occur following over-distension of the lungs caused by
inappropriately set high pressures.
3. Decreased cardiac output due to reduced venous return, decreased
right ventricular stroke volume, and altered dispensability of the
left ventricle."
4. Impedance of pulmonary blood flow with increased pulmonary
vascular resistance (with inappropriately high CPAP pressure).
5. Gastric distension and 'CPAP belly syndrome.' Routine use of an
orogastric tube minimizes the risk.

REFERENCES
1. Sankar MJ, Deorari AK. CPAP - A gentler mode of ventilation. J Neonatol
2007; 21:160-5.
2. Courtney SE, Barrington KJ. Continuous positive airway pressure and
noninvasive ventilation. ClinPerinatol. 2007;34:73-92.
3. Sharma D, Murki S, Maram S, Pratap T, Kiran S, Venkateshwarlu V, et al.
Comparison of delivered distending pressures in the oropharynx in preterm
infant on bubble CPAP and on three different nasal interfaces. Pediatr
Pulmonol. 2020 Jul;55(7):1631-9.
4. Prakash R, De Paoli AG, Oddie S), Davis PG, McGuire W. Masks versus
prongs as interfaces for nasal continuous positive airway pressure in preterm
infants. Cochrane Database Syst Rev. 2022 Nov 14;1 1(11): CD015129.
5. Falk M, Gunnarsdottir K, Baldursdottir S, Donaldsson S, Jonsson B,
Drevhammar T. Interface leakage during neonatal CPAP treatment: a
randomized, cross-over trial. Arch Dis Child Fetal Neonatal Ed. 2021
Nov; 106(6):663-7.
6. Subramaniam P, Ho JI. Davis PG. Prophylactic nasal continuous positive
airway pressure for preventing morbidity and mortality in very preterm
infants. Cochrane Database Syst Rev. 2016 Jun 14;(6): CD001243.
7. Alsop EA, Cooke J, Gupta S, et al. Nasal trauma in preterm infants receiving
nasal continuous positive airway pressure. Archives of Disease in Childhood
2008; 93:23.
8. Hall RT, Rhodes PG: Pneumothorax and pneumomediastinum in infants with
idiopathic respiratory distress syndrome receiving CPAP. Pediatrics 55:493,
1975.
476 AlIMS Protocols in Neonatology

9. Tittley JG, Fremes SE, Weisel RD, Christakis GT, Evans PJ, Madonik MM, et
al. Hemodynamic and myocardial metabolic consequences of PEEP. Chest
1985;88:496-502.
10. Pillai MS, Sankar MJ, Mani K, Agarwal R, Paul VK, Deorari AK. Clinical
prediction score for nasal CPAP failure in pre-term VLBW neonates with
early onset respiratory distress. | Trop Pediatr2011;57:274-9.
11. Murki S, Kandraju H, Oleti T, Saikiran, Gaddam P. Predictors of CPAP
Failure-10 years' Data of Multiple Trials from a Single Center: A Retrospective
Observational Study. Indian J Pediatr. 2020 Nov;87(11):891-6.
12. Jensen CF, Sellmer A, Ebbesen F, et al. Sudden vs. Pressure Wean From Nasal
Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of
Gestation: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(9):824-31.
 CHAPTER

47
Heated Humidi ed High

fi
Flow Nasal Cannula Therapy

In recent years, the heated, humidified high-flow nasal cannula

(HFNC) has emerged as an alternative to CPAP among neonates.
Its popularity is related to ease of application and maintenance, less
nasal trauma, better infant tolerance, and, most importantly, better
access to neonates for caregiving, skin-skin care, and feeding.!
HFNC therapy refers to administering blended oxygen and air
to neonates via nasal cannula at higher flow rates (>1 L/minute)-
typically between 2 and 8 L/ minute. Just as a CPAP, the delivery of
gas flow rates between 2 and 10 L/minute to the nasopharynx has
been shown to develop positive distending pressure in both preterm
and term infants. However, the pressure delivered is unpredictable
depending on the size of the nasal cannula, gas flow rate, size of
the patient's airway, and the amount of air egress around the nares
and mouth.

MECHANISMS OF ACTION
1. The washout of nasopharyngeal dead space is an important
mechanism that promotes alveolar ventilation and improves CO2
elimination.
2. Higher gas flow rates provide CPAP to the airway, recruit alveoli
and stabilize both the alveoli at end-expiration, maintaining the
FRC. This, in turn, improves oxygenation and decreases the work
of breathing.
3. Splints the pharynx and upper airways.

4. Threaten and reverses he dryes and ecost soiry at

would otherwise occur at high gas flow rates.

EQUIPMENT
Optiflow Junior (Fisher & Paykel, New Zealand) and the Precision
Flow (Vapotherm, Exeter, NH, USA) are the common devices
477
478 AIMS Protocols in Neonatolosy

used. The essential parts of a Fisher and Paykel HFNC system are
described below.
1. Oxygen and air source.
2. Blender: FiO, can be adjusted in increments of 1% from 21 to 100%.
3. Flow meter: standard 0-15 L/minute flow meter is used. In
HFNC systems, circuit flow is adjusted according to the level of
respiratory distress, and in neonates, the maximum flow used
is 8 L/minute. Although a pressure relief valve is used in some
circuits, the internal circuit pressure is not routinely measured.
4. Humidifier: Should be set at 37°C. The length of the circuit from
temperature probe to nares will result in temperatures dropping
to a comfortable level while maintaining optimal humidity. At
flow rates of 1-4 L/minute, both Optiflow and Vapotherm devices
achieve an oro-pharyngeal temperature of 33-34°C and relative
humidity (RH) of >96%. At high flow rates, the temperature
and RH achieved by these devices are less than bubble CPAP or
ventilator CPAP.*
5. Circuit tubing to attach to the humidifier.
6. Nasal cannula (prongs): The nasal cannula of HFNC is small and
thin, does not occlude the nostrils, and mandatorily has a leak
around it.
7. Water bag for the humidifier.

INDICATIONS
1. Post-extubation support: This is a common indication for HFNC
use. Studies comparing HFNC versus CPAP for post-extubation
support in preterm infants showed no significant differences in
treatment failure
treated with HFNC rates,
hadreintubation, death,
reduced nasal or BPD.?
trauma Neonates
rates by 36%.
Though the treatment failure rate was similar across different
gestational groups, relatively few extremely preterm neonates
were enrolled in the studies.

2. To aid in weaning from CPAP in preterm neonates: Although

the best way to wean CPAP is to take the neonate off CPAP and
to reinstate the therapy if indicated, HFNC has been used in the
interim as a bridge to transition neonates to room air. Two studies
(149 infants) found that preterm infants randomized to HFNC
had a reduced duration of hospitalization compared with infants
who remained on CPAP with no difference in weaning success
or other morbidities.?
 Heated Humidi ed High Flow Nasal Cannula Therapy 479

fi
3. As an alternative to CPAP in stable preterm neonates at risk
of or have established nasal trauma or for better nursing care to
promote mother-infant bonding, kangaroo care, and oral feeding.
. As a primary mode of support in preterm neonates with RDS:
A recent systematic review that included 10 studies (1830 infants)
noted 1.34-fold higher treatment failure than CPAP but no
difference in intubation rates and lesser nasal trauma." In our
unit, we prefer CPAP as the primary mode of respiratory support
in preterm neonates with RDS.* If HFNC is to be considered as
the primary support due to nasal trauma or ease of care, its use
should be restricted to neonates above 28 weeks of gestation,
and the units should have access to CPAP or NIPPV to manage
treatment failures.5

CONTRAINDICATIONS

Severe RDS, neonates with recurrent apnea, pneumothorax, and

cranial and airway anomalies

Initiation, Escalation, and Weaning of HFNC

1. Choosing an appropriately sized nasal cannula: Nasal cannula
should occupy less than 50% of the area of the nostril aperture to
allow ample egress of expired gas. A snugly tting or tight nasal
fi
cannula can lead to inadvertently high distending pressures in
the nasopharynx.
2. Setting ow rates: An initial ow rate of 4-6 L/minute is
fl
fl
recommended. Our unit policy is to begin flows based on the
current weight of the neonate as follows: for 1000-1999 g = 3 L/
minute, for 2000-2999 g = 4 L/ minute, and ≥3000 g = 5 L/minute.

3. FiO: Begin at 30% or FiOz, similar to ventilatory or CPAP

settings. A pulse oximeter should be used to titrate FiO, to target
oxygenation.
4. Conditioning of respiratory gases: The humidifier should be set
at 37°C in the invasive mode. However, if there is condensation
in the circuit at flow rates < 4 L/minute, it may be necessary to
lower the set temperature to 34-35°C.

5. Monitoring during therapy: A neonate on HFNC requires the

same level of monitoring as a neonate on CPAP. Monitoring
should include respiratory rate, heart rate, chest retractions,
and degree of chest-in drawing. The use of an objective scoring
system like the Silverman and Anderson score is recommended. | • Theraneutic. Modalities
 480 AIMS Protocols in Neonatolory

6. Escalation of therapy: Flow rates can be increased in increments

of 1 L/minute up to a maximum of 8 L/minute in response
to increased chest retractions, tachypnea, and higher PiO,
requirement.
7. Failure of LIFNC: Increasing FiO requirement >50%, respiratory
acidosis (pH 7.2 and PCO, > 60 mm Hg), or recurrent episodes
of apnea requiring positive pressure ventilation should be
considered as a failure of HFNC and alternative respiratory
support (CPAP/intubation) is mandated.
8. Weaning of HENC: One can consider weaning when the neonate
is stable on HFNC for 12-24 hours. FiO, is weaned down to 30%
or lower, and then the flow rate in decrements of 1 L/minute
every 12 or 24 hours guided by work of breathing. Once a flow
rate of 2 L/minute is reached, HENC can be discontinued.
Neonates requiring minimal oxygen before discontinuation may
need to be placed on low-flow titrated oxygen therapy.

REFERENCES
1. Manley B). Nasal high flow: going viral? Arch Dis Child Fetal Neonatal Ed
2016;101:282-3.
2. Wilkinson D, Andersen C, O'Donnell CP, De Paoli AG, Manley B). High ow

fl
nasal cannula for respiratory support in preterm infants. Cochrane Database
Syst Rev. 2016;2(2):CD006405.
3. Bruet S, Butin M, Dutheil F. Systematic review of high-flow nasal cannula
versus continuous positive airway pressure for primary support in prelerm
infants. Arch Dis Child Fetal Neonatal Ed. 2022 (1):56-9.
4. Non-invasive respiratory support for newborns. NNF India. Evidence-based
Clinical Practice Guidelines. January 2020. Available at: http://www.nnfi.
org/assests/pdf/cpg-guidelines/NIV-CPAP.pdf. Last accessed 25-01-2023.
5. Sweet DG, Carnielli VP, Greisen G, Hallman M, Klebermass-Schrehof K,
Ozek E, Te Pas A, Plavka R, Roehr CC, Saugstad OD, Simeoni U, Speer CP,
Vento M, Visser GHA, Halliday HL. European Consensus Guidelines on the
Management of Respiratory Distress Syndrome: 2022 Update. Neonatology.
2023;120(1):3-23.
6. Roehr CC, Yoder BA, Davis PG, Ives K. Evidence Support and Guidelines
for Using Heated, Humidified, High-Flow Nasal Cannulae in Neonatology:
Oxford Nasal High-Flow Therapy Meeting, 2015. Clin Perinatol. 2016;
43:693-705.

ection 12
 CHAPTER

48
Nasal Intermittent Positive
Pressure Ventilation

Nasal intermittent positive pressure ventilation (NIPPV) is a non-

prie made higher

with intermittent proprays port the
pressures delivered using As idion
nasal masks or
nasal prongs. NIPPV is also called nasal intermittent mandatory
ventilation (N-IMV) or noninvasive pressure support ventilation
(NI-PSV).

PHYSIOLOGIC EFFECTS'

• Like CPAP, NIPPV stabilizes the alveoli, maintains alveolar

recruitment, and prevents airway collapse. It also supports the
inspiratory work of breathing, splints the nasopharynx, and
improves both central and obstructive apneic events.
• The application of peak inspiratory pressure (PIP) in NIPPV is
postulated to promote better ventilation by delivering positive
pressure breaths to the lower airways. However, the pressure
delivered at the nasopharynx is highly variable and does not
consistently reach lower airways or produce a chest rise. In the
non-synchronized mode, a tidal volume increase is noted only
when the PIP was delivered during the infant's spontaneous
inspiratory effort.
• Additional mechanisms of action include triggering an
augmented inspiratory reflex (Head's paradoxical reflex) in
preterm infants to support spontaneous breathing, chest wall
splinting, and better thoracoabdominal synchrony.
EQUIPMENT

Any mechanical ventilator can be used to provide nonsynchronized

NIPPV. When the peak pressure is delivered synchronized with
the infant's inspiration, it is called synchronized NIPPV. Most
neonatal ventilators can provide a wide range of set peak pressures
481
482 AlIMS Protocols in Neonatology

(10-25 cm H2O) at variable rates (10-60 per minute) and variable

inflation times (0.3-0.5 seconds).
Bilevel positive airway pressure (BiPAP), also called biphasic
CPAP system, delivers alternating high and low levels of CPAP
pressure. The flow-driver SiPAP and Infant Flow Driver Advance
(Care Fusion, USA) are examples of devices that can deliver BiPAP.
See Table 48.1 for differences between BiPAP and NIPPV.
Nasal interface: The most common interface used to deliver both
NIPPV and BiPAP breaths is the short binasal prongs, with the other
interfaces being nasal masks and long nasopharyngeal tubes.

SYNCHRONIZATION IN NIPPV
The peak pressure delivered in the NIPPV device can be
synchronized with the infant's respiratory efforts, similar to
synchronization in a ventilator. Synchronization can be achieved
using a pneumatic capsule, pneumotachograph (flow-trigger),
respiratory inductance plethysmography, or diaphragmatic
electromyogram (Table 48.2). Synchronized NIPPV was available
with the Infant Star ventilator, which is currently no longer in
production, and newer ventilators like Giulia (Giulia Neonatal
Nasal Ventilator, Ginevri Medical Technologies, Italy). In this
ventilator, synchronization is achieved using a fixed orifice
pneumotachograph placed between the nasal prongs and Y-piece.
Another ventilator, Maquet Servo-n from Getinge provide
synchronized NIPPV with help of Neurally adjusted ventilator
assist (NAVA) technology (Table 48.2).

INDICATIONS FOR NIPPV

NIPPV can be considered in the following situations:
1. Preterm neonates with RDS: The standard strategy involves
early use of CPAP with early selective surfactant administration.
NIPPV can be used as the primary mode of respiratory support,
in place of CPAP, in neonates less than 6 hours of age with RDS.
NIPPV has been compared to CPAP as the primary mode.'
An updated meta-analysis suggested a 37% relative reduction
in respiratory failure needing mechanical ventilation in the
first week of life." The benefits were found to be greater with
ventilator-derived NIPPV. There was also a reduction in mortalit;
BPD (22% relative reduction), and risk of air leaks compared to
CPAP (Table 48.3).4
 Nasal Intenmittent Positive Pressure Ventilation

Highpressureduration

ure ventilation

5 cm H,O 0 cm H,0

20 ст H,0 10 cm HO -5 cm H,0

Nasal Intermittent positive press

The inflation times (0.3-0.5 s) are shorter. PEEP of 5-8 cm H.O)

High pressure duration

5 cm H,O 0 cm H,0

10 cm H,O -5 cm H20

breathes independently.
BiPAP provides two nasal CPAP levels, over which the infant NIPPV mimics invasive ventilation in its setting. The high-pressure duration is longer Terate
(0.5-1.0 s).at or 10-prin). The rate refers to cycle The rates are variable from 10 10 60/min (generally 45 min
liged
Bilevel CPAP or BuP4P and 11-15 cm H2O for the SiPAP.

• Therapeutic Modalities
484 AlIMS Protocols in Neonatology

Table 48.2: Devices for synchronization in NIPPV

Devices for Mechanism
synchronization
Pneumotachograph This device measures inspiratory flow when the
gases flowing across a fixed resistance tube creates
a pressure difference. In NIPPV, leaks at the
mouth and nose can interfere with the accuracy.
The device requires frequent calibration and
changes in gas temperature, humidity, and water
condensation can affect performance.
Graesby capsule It is a pneumatic capsule that detects outward
abdominal movement due to diaphragmatic
contraction. Ventilators (Infant star) using these
capsules are no longer commercially available.
The SiPAP device uses a similar abdominal

Disadvantages: some breaths may be missed

in neonates with tachypnea and abdominal
distension
Respiratory inductance Measures respiration from body surface movements
plethysmography using abdominal and chest bands
Neurally adjusted NAVA uses a diaphragmatic electromyogram.
ventilator assist (NAVA) It synchronises in ations with inspiratory effort
fl
and provides pressure support proportional to the
infant's inspiratory effort. It requires nasogastric
insertion, and its sensors are expensive.

Table 48,3: Summary of evidence for NIPPV in neonates

• NIPPV is superior to CPAP as a primary mode in neonates with RDS and for
post-extubation in preterm neonates. NIPPV reduces the risk of treatment
failure and the need for additional ventilator support. NIPPV also reduces
mortality, BPD, and air leaks. In both scenarios, the observed bene ts were
fi
attributed to ventilator-generated, synchronized NIPPV.
• Ventilator derived NIPPV is superior to BiPAP. It is unknown if one would
get the same bene ts if the mean pressures generated by a CPAP device
fi
could match the mean pressures of NIPPV.
• No harm was noted with NIPPV use in neonates. However, care should be
taken to avoid nasal injury from the interface.

2. Prevention of post-extubation failure: When used after

extubation in preterm neonates, NIPPV resulted in a 22%
reduction of respiratory failure and less need for re-intubation
within the first week compared to CPAP.45
 Nasal Intermittent Positive Pressure Ventilation 485

‡ Treatment of apnea of prematurity: Studies that evaluated

the role of NIPPV in apnea of prematurity found beneficial
efforts in short-term outcomes, namely the incidence of apnea,
desaturations, and bradycardia episodes. However, there was no
difference in the need for intubation and mechanical ventilation.
NIPPV may augment the beneficial effects of CPAP in preterm
infants with frequent or severe apnea and can be considered
lefore initiating mechanical ventilation.
4. CPAP failure: NIPPV may be instituted as a bridge before shifting
to intubation and mechanical ventilation in neonates with CPAP
failure.
Although evidence favors synchronized NIPPV over CPAP as
a primary mode in neonates with RDS and after extubation from
invasive ventilation, it is challenging to implement it because of the
lack of availability of equipment providing synchronized NIPPV
and the need for more careful monitoring (compared to CPAP).
We do not routinely use NIPPV in all preterm neonates. We use
unsynchronized NIPPV preferentially in extreme preterm or extremely
how birth weight nconates at high risk of mortality and BPD.

SETTINGS AND MONITORING FOR PROVIDING NIPPV SUPPORT

1. NIPPV settings: The typical settings are provided in Table 48.4.

2 Monitoring: Monitor respiratory rate, Silverman score, Sp02, and
heart rate. Blood gas and chest X-ray should be done if there is
worsening respiratory distress.

Table 48.4: NIPPV settings in various scenarios

Parameter Settings when used as Settings for post-extubation

the primary mode
PIP 10 cm H,O above PEEP 2-4 cm H20 more than PIP
(Maximum 30) of ventilator at the time of
extubation
PEEP Same as PEEP of ventilator at
5-6 cm H20
extubation
(Maximum 8)
Rate 10-40/min 20-30/min
(Maximum 50)
Inspiratory time (Ti) 0.3-0.5
0.35-0.4 sec
Flow
8-12 Umin 8-12 L/min
Titrate to maintain SpO, 91-95%; maximum FiO, is
Theraneutic Modalities

60-70%
 486 AlIMS Protocols in Neonatology

3. Failure criteria (indication for reintubation):

a. Clinical: Severe and recurrent apnea (>4 apnea/hr requiring
tactile stimulation or >2 episodes requiring bag and mask
ventilation in a day), Silverman score >6, shock requiring
inotropes.
b. FiO, >60% to maintain target saturation.
c. Blood gas: pH <7.2 with PaCO, >60 mm Hg.
4. Weaning
a. Gradually decrease FiO, by 3-5% while maintaining target
SpO, in the range of 91-95% until it reaches 30%.
b. If there is no worsening of distress, taper PIP by 1-2 cm of
H2O till PIP is 15 cm H2O.
c. Rates are kept at 40/min until PIP is weaned and then
decreased in steps to 20/min.
d. Wean to nasal CPAP if settings are PIP 14 cm of H2O, PEEP
5 cm H2O, rate 20 bpm, and FiO, 30%.
SAFETY OF NIPPV

Although studies have not shown severe complications like

gastrointestinal perforation or necrotizing enterocolitis, most were
small studies and were not sufficiently powered to detect adverse
effects. Similarly, nasal injury due to NIPPV use has not been
adequately studied.

REFERENCES
1. Owen LS, Manley BJ. Nasal intermittent positive pressure ventilation in

Vera Mad: 1621en. evidence, and synchronization. Semin Fetal

2. Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive
pressure ventilation (NIPPV) versus early nasal continuous positive airway
pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev.
2016;12(12): CD005384.
3. Rüegger CM, Owen LS, Davis PG. Nasal Intermittent Positive Pressure
Ventilation for Neonatal Respiratory Distress Syndrome. Clin Perinatol.
2021;48(4):725-44.
4. Ramaswamy VV, More K, Roehr CC, Bandiya P, Nangia S. Efficacy of non-
invasive respiratory support modes for primary respiratory support in preterm
neonates with respiratory distress syndrome: Systematic review and network
meta-analysis. Pediatr Pulmonol. 2020;55(11):2940-63.
5. Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive
pressure ventilation (NIPPV) versus nasal continuous positive airway pressure
(NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev.
• Section 12
2017 Feb 1;2(2): CD003212.
 CHAPTER|

49
Parenteral Nutrition

The goal of nutrition management in neonates, especially very low

birth weight (VLBW) infants, is achieving postnatal growth at a rate
that approximates the intrauterine growth of a fetus and ensuring
optimal long-term neurodevelopment.! This is best achieved by

enera nutrition in is inadentral tonindicated Wis

especially crucial for extremely low birth weight neonates and
neonates with congenital gastrointestinal anomalies.

INDICATIONS

Parenteral nutrition (PN) should be considered in neonates who

are not expected to be on significant enteral feeds for more than
3-5 days or are anticipated to receive less than 50% of the total
energy requirement in the next 7 days (Table 49.1).

MACRONUTRIENTS
Energy
The total energy is provided by a combination of macronutrients
that include carbohydrates, fats, and proteins. It is preferable

Table 49.1: Indications of parenteral nutrition

• Birth weight less than 1000 g: TPN to be started on day 1 (MEN to be started
along with TPN if hemodynamically stable and no contraindication for
feeding like A/REDF).
• Birth weight 1000-1499 g and anticipated to be not on significant feeds for
3 or more days.
• Birth weight more than 1500 g and anticipated to be not on significant feeds
for 5 or more days.
• Surgical conditions: necrotizing enterocolitis, gastroschisis, omphalocele,
tracheoesophageal fistula, intestinal atresia, malrotation, short bowel
syndrome, meconium ileus, and others that prevent the initiation of enteral
feeds.

487
488 AIMS Protecols in Neonatology

to have a balance of energy from carbohydrates (60-75%), fats

(25-40%), and proteins (10-15%).2
A daily energy intake of 110-120 kcal/kg is needed to meet the
metabolic demands of a healthy preterm neonate and to allow
for a growth rate comparable to the intrauterine growth rate.!*
Energy requirement of term neonates is 90-100 kcal/kg/day. The
energy intake of sick neonates (e.g. those with acute respiratory
illness, chronic lung disease, necrotizing enterocolitis) is not
precisely known; it is likely to be near the upper limits of the energy
requirement of preterm infants.
Each gram of dextrose and lipid provides 3.4 kcal and 9 kcal,
respectively. If the non-protein energy is insulficient, amino acids
are catabolized for energy production. An adequate balance

bain: stir 100 and is protein en promote proper in nons

However, if the dextrose infusion is initiated at the physiological
rate (4-6 mg/kg/minute), starting with even 3-3.5 g/kg/day of
amino acids in the first few days of life may be beneficial. There is
no concrete evidence for monitoring the P: E; however, pragmatic
studies show the benefit of starting with higher amino acids in
better achieving lean body mass. A balance between carbohydrates
and fat is needed to prevent excessive fat deposition and excessive
production of COz.

Carbohydrates
Carbohydrates are the primary energy substrate for neonates
receiving PN. The amount of carbohydrate delivered as dextrose is
commonly initiated at the endogenous hepatic glucose production
and utilization rate of 4-6 mg/kg/min. This provides an energy
intake of 40-50 kcal/kg/d and preserves carbohydrate stores. Once
the glucose infusion rate (GIR) supports acceptable serum glucose
values, it is advanced in a gradual, stepwise fashion (2 mg/kg/min/
day) to a suggested maximum glucose oxidative rate for neonates of
12-13 mg/kg/min to support growth and maintained there unless
serum glucose values change significantly. In the first week of life, it
is advisable to be cautious in advancing GIR due to reduced insulin
sensitivity and glucose tolerance. Table 49.2 summarizes the GIR
recommendations as per various nutrition guidelines:
Insulin infusion should not be routinely used to increase the GIR.
However, it can be started if the infant develops high glucose levels
despite a GIR of 4-6 mg/kg/minute.
 Parenteral Nutrition 489

Table 49,2: CIR recommendation as per various nutrition guidelines

Day 1 Advancement Maximum rate
fmg/kg/min) (mg/kg/min) (mg/ kg/min)
NICE Preterm and term: - 6.25-11.1
4-6.25
ESPGHAN Preterm: 4-8 Advance over Preterm: 5-10 (max 12)
Term: 2.5-5 2-3 days Term: 8-10 (max 12)
ASPEN Preterm: 6-8 Advance over 10-14 (max 14-18)
Term: 6-8 7-10 days
NICE. National Institute for Health and Excellence; ESPGHAN: European Society for
Fediatric Gastroenterology, Hepatology, and Nutrition; ASPEN: American Society for
Parenteral and Enteral Nutrition

Carbohydrates in PN: Evidence

Excessive carbohydrate delivery above the amount that can be oxidized for
energy and glycogen storage can increase basal metabolic rate, fat deposition,
cholestasis, or hepatic steatosis. 6-8 Use of insulin to achieve a higher glucose
infusion rate and promote growth has been associated with lactic acidosis.?

LIPIDS
Fats are provided as intravenous lipid emulsions and should be
started on the rst day at a dose of 1.5 g/kg/d and then increased
fi
gradually by 0.5-1.0 g/kg/day stepwise to reach 3.5 g/kg/day.4
Evidence suggests that early initiation of lipids within the rst 48
fi
hours is well tolerated and improves cerebellar volume and retinal
growth, in addition to improving the nitrogen balance and linear
growth in preterm infants.
Specific concerns with the use of lipids have been observed,
including PNALD (parenteral nutrition associated liver disease)
and IFALD (intestinal failure associated liver disease). The newer
combined lipids with fish oil (SMOF) have been postulated to
reduce the associated hepatic damage. In preterm neonates with
hyperbilirubinemia in the range of exchange transfusion threshold,
lipids may be restricted to minimum amounts (1 g/kg/day) to
provide only the essential fatty acids.!
Intravenous lipid emulsions are available in two strengths:
10% and 20% (see Appendix of this chapter). Using 20% lipid
emulsions is preferable to decrease the risk of hypertriglyceridemia,
hypercholesterolemia, and hyperphospholipidemia." When lipids
are exposed to light, they form potentially toxic lipid hydroperoxides.
Hence lipid syringes and tubing should be covered by wrapping
them in aluminum foil. • Therapeutic Modalities
 490 AlIMS Protocois in Neonatology

Lipids in PN: Evidence

Even a short delay of 3-7 days in supplying lipids to parenterally fed pretentr
infants leads to biochemical EFA de ciency.!

fi
Type of Lipid Infusions
There have been three generations of intravenous lipid emulsions
which have been used to date:
First-generation lipid emulsions: The main component of these
lipids (e.g. IntraLipid by Fresenius Kabi) is soyabean oil or saf ower

fl
oil containing long-chain triglycerides (LCT), defined as having
16-18 carbon atoms. The risk of adverse effects (steatosis, cholestasis)
with these long-chain lipids mandated better preparations. The
concern of sepsis was also high with these lipid emulsions.
Second-generation lipid emulsions: They were marketed with the
intent of reducing the LCT content. These emulsions contain 50% of
medium-chain triglycerides (MCT) with 6-12 carbon atoms. These
emulsions do not require carnitine to enter the mitochondria and
are oxidized easily. Lipofundina (soybean oil and medium-chain
triglycerides), Clinoleic (soybean and olive oil), and Structolipid
(structured lipids) are some of the lipid emulsions of this generation.
None of these is being used in India.
Third-generation lipid emulsions: The main constituent of this
generation is the omega-3 fatty acids. Compared to omega-6,
omega-3 fatty acids have better immunomodulatory and
immunosuppressive effects. SMOFLipid (Fresenius Kabi; Soyabean
oil, medium chain triglycerides, olive oil, and fish oil), Omegaven
(100% refined fish oil emulsion), and Lipoplus (MCT, soyabean oil,
and fish oil) are included in this generation of lipid emulsions. Of
these, SMOFlipid is available in India.

SMOFlipid vs. Intralipid: Evidence

A meta-analysis of 14 studies, of which 9 studies compared different types of
lipid emulsions, concluded that emulsions that are not purely soyabean oil
based might be associated with a lower incidence of sepsis. 13-16 Beneficial
effects on growth could not be shown. Some retrospective studies show a
lesser incidence of parenteral nutrition-associated liver disease (PNALD:,
but large-scale RCTs are warranted. The use of SMOF in PNALD has been
shown to increase the resolution of abnormal liver function tests compared to
soyabean-based emulsions; however, its role in the prevention of PNALD is
yet uncertain (Cochrane 2019).
• Section 12
 Parenteral Nutrition 491

Amino Acids
PN should provide 3.0-3.5 g/kg/day of amino acids (AA). An
optimal amino acid solution should contain essential (valine,
leucine, isoleucine, methionine, phenylalanine, threonine, lysine,
and histidine) and conditionally essential (cysteine, tyrosine,
glutamine, arginine, proline, glycine and taurine) amino acids,
should not have an excess of glycine and methionine, and should
not contain sorbitol. Depending on practical feasibility, the amino
acid infusion should be started on the first day of birth, preferably
soon after birth. Providing adequate proteins since day one not only
contributes to fat-free mass but also helps in normalizing insulin
secretion in ELBW neonates, in whom insulin levels are low.?
Proteins in PN: Evidence
The amount started on day 1 of PN has varied from 0.5-3.0 g/kg/day in different
studies. A higher intake of 3-3.5 g/kg/day can be safely administered starting
from the first day of birth.? Early provision of protein is critical to attaining
positive nitrogen balance and accretion, as premature babies lose about 1%
of their protein stores daily.

MICRONUTRIENTS AND MINERALS

Sodium, potassium, chloride, calcium, magnesium, and phosphorus
must be provided in PN solution as their daily needs (Table 49.3). All
these minerals are readily available for administration in neonates
except for phosphate. Sodium, potassium, and chloride are essential
to life, and their requirements depend on obligatory losses, abnormal
losses, and amounts necessary for growth. Calcium, phosphorus,
and magnesium are the most abundant minerals in the body. They
are closely interrelated to each other in metabolism, the formation
of tissue structure, and function. Estimated and advisable intakes
(Table 49.3) are based on accretion studies and urinary and fecal
losses from balance studies."
Calcium and phosphate supplementation: The current
recommendation is to provide early and appropriate supplementation
of calcium gluconate and phosphate (on day 1) to prevent metabolic
bone disease. To promote the highest retention of these minerals,
the ideal ratio of calcium: phosphorus (mg: mg) for parenteral
nutrition should be 0.8-1.1 on Day 1 and 1.3-1.7:1, subsequently in
the neonatal period. 18
An ideal phosphate preparation (should not precipitate when
combined with intravenous calcium preparation) is difficult to
procure in India. Many units administer intravenous phosphorus
492 AIMS Protocols in Neonatology

Table 19.3: Daily requirement of mineral!

Mineral Requirement
Sodium 0-3 mEg/kg/day (1st week of life)
2-3 mEg/kg/day (beyond 1sf week in term neonates)
3-5 mEg/kg/day (beyond 1sf week in preterm neonates)
Potassium 0-2 miq/kg/day (1st week of life)
1-3 mEq/kg/day (beyond 1st week)
Chloride 2-3 mEq/kg/day
Calcium 2-4 mEg/kg
Magnesium 0.3-0.5 mEq/kg
Phosphorus 1-2 mEg/kg

(Injection Potphos; NEON Laboratories Ltd; 15 ml ampoule;

89 INR per ampoule) and intravenous calcium gluconate in separate
syringes in alternate 4-6 hours cycles to avoid precipitation.

VITAMINS

Vitamins are essential cofactors and coenzymes needed for

the metabolism of macronutrients and should be added to PN
solution to meet the daily requirement (Table 494). Preparations

Table 494: Recommended vitamin intake B

Term Preterm Available MVI
(daily dose)(dose/kg/day) (per 1 ml)
vitamin A (IU) 2300 1640 (700-1500) 1000
Vitamin D (U) 400 160 (80-400) 100
Vitamin E (IU) 2.8 (2.8-3.5) 0.50 mg
Vitamin K (pg) 200 10
Vitamin Be, (mg per kg) 1000 0.15-2 1500
Vitamin B,2 (rg) 1 0.3
Vitamin C (ig) 80 15-25 50 mg
Biotin (pg) 20 5-8
Folic acid (yg) 140 56
Niacin (mg) 17 4-6.8 10
Pantothenic acid (mg) 5 2.5 2.50
Ribo avin (mg) 1400 0.15-2 1400
fl
Thiamin (mg) 1200 0.35-0.5 5 mg
 Parenteral Nutrition 493

of fat-soluble and water-soluble vitamins suitable for neonates are

not available in India. Multivitamin injection (MVI), when added
in a dose of 1.5 ml/kg to lipid solution, meets the need for vitamin
A and most other vitamins. Intravenous vitamin delivery may be
less due to photodegradation of vitamins A, D, E, K, B2, B6, B12, C,
and folic acid and adsorption of vitamins A, D, and E into the viny!
delivery bags and tubing. Vitamin K needs to be given separately
as weekly intramuscular injections. Although vitamin B12 is absent
in MVI, its deficiency is not manifested unless the neonate is on
long-term PN. The total vitamin E dose from multivitamin infusion
should not exceed 11 mg/day.
TRACE ELEMENTS

Eight trace elements (zinc, copper, chromium, iron, manganese,

selenium, molybdenum, and iodine) should be part of PN solutions
in neonates.* Zinc is universally recommended from day one of TPN,
whereas the other trace minerals are generally provided after two
weeks of TPN without any appreciable enteral feeding. Copper,
selenium, molybdenum, and iron can be delivered separately also.
Zine is a critical micronutrient, and zinc deficiency is known if not
supplemented, especially in preterm neonates with excessive GI
and urinary losses. The dosage is 150-400 microgram/kg/day,
but a suitable preparation is difficult to find in the Indian market.
Enteral iron is the preferred mode, and the parenteral route for iron
is to be considered only in prolonged parenteral nutrition (beyond
three weeks). Manganese and chromium are usually present in many
parenteral nutrition solutions and need not be replaced. Selenium
and molybdenum are required only if prolonged PN beyond 3 weeks
is administered. Recommended daily doses of parenteral trace
elements are provided in Table 49.5.

WEANING AND DISCONTINUING TPN

There are no clear recommendations on when to start weaning
TPN-it depends on the underlying cause of initiating TPN and
the neonate's clinical condition. TPN can be gradually weaned off
once 50% of total daily needs are tolerated as enteral feeds. Sudden
stoppage of GIR may be associated with rebound hypoglycemia.
The other components of TPN can be stopped without tapering also.
Parenteral nutrition can be stopped once enteral feeds are tolerated
at 140-150 ml/kg/day in neonates less than 28 weeks of gestation
and 120-140 ml/kg/day in neonates born at or after 28 weeks of
gestation (NICE guidelines 2020).
 494 AIMS Protecols in Necrotor.By

Table 49.5: Recommended daily doses of parenteral trace d

Trace element Preterm Term
por tiny
Zine (pg per kg) 400-500 100-250 5 ing
Copper (ug per kg) 40 20 0.5 mg
Chromium (pg per kg) 0.05-0.3 0.2 5 р8
Iron (pg per kg) 200-250 50-100 5 mg
Manganese (pg per kg) <1 50 pg
Selenium (pg per kg) 7 2-3 100 pg
Molybdenum (ug per kg) 1 0.25 5 pg
lodine (pg per kg) 1-10 1
SUMMARY: RECOMMENDATIONS
Evidence-based recommendations for the use of PN constituents
are summarized in Table 49.6.

DISPENSING PN SOLUTION
In developed countries, the PN solution is prepared by a central
pharmacy and delivered ready for use. This facility is usually
unavailable in most Indian hospitals, and physicians and nurses
must chart and prepare PN. The steps for calculation and preparing
PN are as follows (a PN chart is provided in the appendix):
1. Determine the total fluid requirement for the day.
2. Subtract the amount of fluid used for medications (e.g. diluting
and infusing antibiotics) and enteral feeds.
3. Plan amino acids, intravenous lipids, and glucose to be given
over 24 hours.
4. Load intravenous lipid (IVL) suspension in one syringe and add
multivitamins (MVI).
5. Mix amino acids, dextrose, electrolytes, and trace elements in the
second syringe.
6. IV L+MVI suspension is infused separately from AA-glucose-
minerals solution, although they can be mixed using a three-way
adapter at the infusion site.
lon
Osmolarity of PN: Weak and conditional evidence recommends
that the osmolarity of PN should not exceed 900 mOsm/L to avoid
• | the potential risk of thrombophlebitis in neonates.
 Parenteral Nutrition 495

Table 49.6: Evidence-based recommendations for parenter. Knutrition

Component Recommendations

Fluids Day 1: 60-80 ml/kg/day (See the protocol on Fluid and

electrolyte management).
Postnatal weight loss up to 3% per day to a maximum of
10-15% is acceptable. This is achieved by progressively
increasing the uid intake to 150 ml/kg/d by the end of rst

fl
fi
week of life.
The goal is 100-120 kcal/kg/day (higher in infants with BPD).
Energy
An intake of 50 kcal/kg/day is sufficient to match ongoing
expenditure but it does not meet the additional requirements
of growth.
Protein The optimal parenteral amino acid intake is 3.5 g/kg/day.
Parenteral amino acids can begin from day 1 at 1.5-2 g/kg/day.
Carbohydrates From day one, 6 mg/kg/min can be infused, increased by
2 mg/kg/min every day to 12-14 mg/kg/min, and adjusted to
maintain euglycemia.
Insulin is only used in infants who continue to have
hyperglycemia associated with glycosuria and osmotic diuresis
even after the glucose intake has been reduced to 4-6mg/kg/
min. Insulin is given as a continuous infusion commencing at
a rate of 0.05 units/kg/h, increasing as required for persistent
hyperglycemia.
Fat Intravenous fat, 1.5 g/kg/d can be started from day 1, at the
same time as when intravenous amino acids are started. This
is increased to 2 g/kg/day and 3 g/kg/day over the next two
days, maximum of 3.5 g/kg/day.
It is delivered as a continuous infusion of 20% intravenous fat
via a syringe pump, separate from the infusate containing the
amino acids and glucose. The syringe and infusion line should
be shielded from ambient light.
Minerals Minerals should include sodium, chloride, potassium, calcium,
and trace phosphorus, magnesium.
elements Trace elements should include zinc, copper, selenium,
manganese, iodine, chromium, iron and molybdenum.
Vitamins Vitamins must be added to the fat emulsion to minimize
loss during administration due to adherence to tubing and
photodegradation.

ROUTE OF ADMINISTRATION

PN can be delivered through peripheral or central venous lines.

Short-term PN can be given through the peripheral venous line.
 496 AlIMS Protocols in Neonatology

Peripheral access offers the advantage of a lower risk of infection

due to the greater distance of the catheter from the central circulation
and fewer mechanical complications.
However, nutrition delivery is limited with peripheral lines dueto
constraints created by a solution's osmolarity. The limiting factor in
deciding the delivery route is the AA-glucose solution's osmolarity,
which depends on dextrose concentration. A dextrose concentration
greater than 12.5% has an acidic pH and causes irritation to the
peripheral veins. In addition to dextrose, electrolytes and minerals
added to the solution also increase the osmolarity. Hypertonic
solutions should ideally be administered through the central venous
line.
The use of peripherally inserted central catheters (PICC) has
facilitated the administration of PN while avoiding many potential
complications of surgically inserted central lines. Another attractive
option in neonates is a central line inserted through the umbilical
vein. An umbilical venous catheter can be used for up to 14 days,
after which the risk of complications increases. 15,16

MONITORING AND COMPLICATIONS

Meticulous monitoring is needed in a neonate receiving PN
(Table 49.7). Monitoring should be more frequent in the initial stages.
Once a steady metabolic stage has been achieved, monitoring can
be reduced to once a week.
Complications of PN can be nutrient-related or venous access-
related.
Nutrient-related complications include hypoglycemia (plasma
sugar <50 mg/dl) and hyperglycemia (plasma sugar >150
mg/dl), azotemia and metabolic acidosis (protein-related),
hypertriglyceridemia (triglyceride >200 mg/dl; lipid-related),
cholestasis, and trace element deficiency. Most of these complications
can be avoided by adequately monitoring and providing nutrients.
Parenteral nutrition-associated liver disease (PNALD) is a commonly
encountered complication of prolonged parenteral nutrition. The
most widely used definition of PNALD requires a direct bilirubin
(DIB) concentration of 2 mg/dl with no other cause of liver disease.
It presents initially with biochemical evidence of cholestasis, clinical
evidence of jaundice, and failure to thrive. The reported incidence of
PNALD varies from 25% to 60% in infants receiving long-term PN,
• Section 12
depending on the criteria used to diagnose PNALD.
 Parenteral Nutation 497

Table 49.7: Monltoring schedule for a neonate on parenteral nutrition

Parameter Frequency

Blood sugar 2-3 times a day while increasing glucose infusing rate
Once a day while on stable glucose infusion rate
Urine sugar
Once per nursing shift
Serum electrolytes
Twice a week initially, then weekly
Blood urea
Twice a week initially, then weekly
Calcium, magnesium Weekly
and phosphorous
Packed cell volume Weekly
Liver function tests Weekly
Serum triglycerides Weekly
Anthropometry
Weight Daily at the same time
Head circumference Weekly
Length Weekly
Nutrient intake Energy in kcal per kg day
calculation Proteins in grams per kg per day

Management strategies include two methods: Lipid replacement

and lipid restriction. Soyabean-based lipid composition (Intralipid)
contains phytosterols which are implicated in PNALD. Replacing
Intralipid with SMOFlipid has been shown to have liver-protecting
properties in older children receiving PN; however, lipid
restriction and lipid replacement in neonates with PNALD is still
controversial and requires further studies. 9,20 There are currently no
recommendations for restricting the amino acid component of the
TPN. The best protective strategy for PNALD would be to minimize
the duration of parenteral fluids and switch over to enteral feeds
as early as possible.
Intestinal failure-associated liver disease (IFALD):21 Preterm
neonates with gastrointestinal pathologies like necrotizing
enterocolitis (NEC) or surgical intestinal conditions and are on PN
are predisposed to develop IFALD. The clinical and pathological
features are similar to PNALD, with progressive cholestasis,
biliary brosis, and steatohepatitis. The etiology is multifactorial,
fi
with genetics, the role of soyabean oil in PN, and alteration of gut
microbiome being implicated to a certain extent in the development
498 AlIMS Protocols in Neonatology

of IFALD. Restriction of soyabean oil based PN and transition to

enteral feeds have been associated with a gradual reduction of
symptoms of IFALD in some reports.
Neonatal refeeding syndrome: Inappropriate rates of minerals,
electrolytes, and amino acids (low electrolytes and high amino
acids) can lead to increased uptake of phosphate, potassium, and
magnesium into cells for energy and protein synthesis, thus leading
to the neonatal refeeding syndrome characterized by low serum
phosphate, potassium, and magnesium and high serum calcium,
glucose, and sodium. This can trigger white matter injury and
chronic lung disease.
Venous access-related complications include occlusion,
dislodgement, and infection.
PREVENTION OF INFECTION22-24
Healthcare-associated infection (HAI) is a significant complication
of PN. All efforts should be made to avoid HAI:
• Aseptic precautions during the preparation of PN
• Use of laminar flow for preparation of parenteral fluid solutions
• No compromise on disposables
• Trained staff
• No reuse of the PN solutions
• No interruption of the venous line carrying PN
• Use of bacterial filter
APPENDIX
See Tables 49.8 and 49.9

Table 49.8: Sources of parenteral solutions

Component Commercial preparation Concentration

Proteins Aminoven 10% (0.1 g/ml)

Primene
Lipids Intralipid 10% (0.1 g/ml)
10% PLR (phospholipids reduced:
20% (0.2 g/ml)
Glucose Dextrose 5% (0.05 g/ml)
10% (0.1 g/ml)
25% (0.25 g/ml)
50% (0.5 g/ml)
(Contd)
 Patenteral Nutrition 499

Table 49.8 Source of parenteral volutlons (Coridi)

Component Commercial propaation Concentation

NuCI
NacI 0.9% (0.009 g/ml = 0.15 mf g/ml)
3% 60.03 g/ml = 0.5 ml g/ml)
15% (0.15 g/ml = 2 ml q/ml)
Cal ium Calcium gluconate 10% (9 mg/ml of elemental calcium)
Multivitamin Adult MVI
Trace Celcel 4 (Claris)
elements Celcel 5 (Claris)
Magnesium Magnesium sulfate 50% (0.5 g/ml = 4 mlq)
sulíate

Table 49.9: Cost and availability of common parenteral fluids

Name of the uid!
Concentration (%)Manufacturer Cost (INK)
fl
Aminoven 6 Fresenius Kabi 220(100 ml)
10 280(100 ml)
Primene (Amino acid) 10 Baxter
288 (100 ml)
Fresenius Kabi
Intralipid 10 255 (100 ml)
20 520 (250 ml)
SMOF lipid emulsion 20 Fresenius Kabi 690 (250 ml)
Calcium gluconate
10 Biostan 12 (10 ml)
Magnesium sulphate 50
Ravi Pharma 8(2 ml)
MVI Psychotropics 15 (10 ml)
India (Multizac)
NBZ Pharma
Infuvite Pediatric
(Baxter)

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CHAPTER

50
Peritoneal Dialysis

INDICATION
The indications for kidney replacement therapy in neonates include
hyperkalemia, hyponatremia with volume overload (pulmonary
edema, severe hypertension), metabolic acidosis (pH<7.20 despite
medical management), hypocalcemia, hyperphosphatemia
refractory to therapy, and uremic encephalopathy.
While anuria and the above are absolute indications for initiating
kidney replacement therapy, dialysis should begin early to prevent
catastrophic metabolic complications. In addition, dialysis is
indicated for removing dialyzable toxins, especially ammonia, in
the case of inborn errors of metabolism.
Fluid accumulation per se increases vulnerability for AKl and
often predates it. It can also worsen AKI by increasing venous
pressure and causing abdominal hypertension and interstitial
edema. Overall, evidence suggests >10-20% fluid overload may
represent a critical threshold at which outcomes are adversely
impacted, and targeted interventions should be considered.'
Therefore, additional indications for the initiation of kidney
replacement are the following:
• Fluid overload >10-20%.
• Inability to provide adequate nutrition due to fluid restriction.
Kidney replacement can be implemented by acute peritoneal
dialysis (PD), intermittent hemodialysis (IHD), or continuous
kidney replacement therapy (CKRT). Factors dictating the mode of
kidney replacement include the urgency of fluid and solute removal,
hemodynamic stability, the feasibility of vascular access, whether the
peritoneal membrane is intact for dialysis, and resources available
at a given institution.

MODE OF KIDNEY REPLACEMENT (PERITONEAL DIALYSIS)

Peritoneal dialysis is the preferred mode of kidney replacement in
neonates chiefly due to its technical simplicity, lack of hemodynamic
compromise, and requirement of vascular access.
502
 Peritoneal Dialysis 503

Trinciple: The two purposes of kidney replacement are dialysis

(removal of solutes) and ultrafiltration (removal of water),
Dialysis occurs by removing plasma solutes by diffusion
down their concentration gradient across the peritoneal lining.
Instilling hypertonic dialysate into the peritoneal cavity creates
a transmembrane osmotic gradient, allowing fluid removal by
ultrafiltration. Therefore, PD allows a slow continuous exchange of
luid and solutes.
Peritoneal dialysis catheters: Peritoneal access in most institutes
is achieved by a stiff catheter, but when used beyond 48-72 hours,
infection rates are high. The Acute Disease Quality Initiative
(ADQl) conference for neonatal AKI recommended cuffed catheters
(Tenckhoff catheters made of silicone polymer of methyl-silicate)
for prolonged PD due to its low risk of infection and visceral injury
(Fig.50.1).? Limitations of soft Tenckhoff catheter include its long
intraperitoneal length and relatively larger width for use in tiny
babies with sparse subcutaneous fat, with possible risks of catheter
migration and pressure skin necrosis.'
Procedure for peritoneal dialysis by stiff catheter:
• Empty the bladder by catheterization.
• Clean and drape the abdomen with the neonate supine.
• Create a fluid-filled reservoir by infusing 20-30 ml/kg of warmed
dialysate into the peritoneum using a 22G cannula in the midline
at the junction of the upper one-third and lower two-thirds of the
distance between the umbilicus and pubic symphysis.

• 31 cm

- 20 ст
3 cm 7.2 cm .75 cm

10.20 cm

b
Fig. 50.1: Peritoneal dialysis catheters: Soft Tenckhoff catheters (a and b) have single

or double cuffs and side holes (3 cm). Introducer set (items in b) is required for

insertion by the Seldinger technique. These catheters require approximately 10 cm

of the catheter to be inserted into the abdomen (a), limiting utility in very tiny
neonates, in which case a stiff 12 Fr single-lumen femoral catheter (c) may be used.
504 AlIMS Protocols in Neonatology

• Insert the PD catheter into the peritoneal cavity after placing a

small vertical nick using a 15 no. blade and connect it to a three.
way cannula. The common insertion sites are in the midline below
the umbilicus (midline approach) and the right or left lower
quadrant of the abdomen (paramedial approach). The exit site
should be out of the diaper region to prevent soiling and placed
on the side of the abdomen contralateral to any stoma. It is helpful
to place to grasp the catheter between the thumb and index finger
at a point just above the skin to control excessive penetration.
• The dialysate fluid is connected to a pediatric burette set, and
its terminal end is connected to one of the ports of the three-
way cannula. The remaining three-way port is connected to the
IV set, the end of which is let into a sterile container (emply IV
fluid bottle).
• The abdomen is filled with 20-30 ml/kg of dialysis fluid infused
over 10 min. A 15-30 min dwell time is used before draining the
fluid over 10 min. Peritoneal dialysis can be continued till the
desired effect is obtained.
• Hypothermia must be prevented by using pre-warmed dialysis
fluid.
PD fluid: The PD prescription includes dialysate type and
composition, number of exchanges, fill volume, inflow, dwell, and
outflow times, ultrafiltration volume and the number of exchanges,
or PD cycles, per day.

Composition of PD uid*
fl
Osmotic agent: Dextrose 1.4-3.9 g/cl
Base: Lactate 35-40 mEq/l. or bicarbonate 34 mEq/L
Sodium 132-134 mEq/L, calcium 1.25-1.75 mM/L,
Magnesium 0.25-0.75 mM/L, chloride 95-103.5 mEq/L

• The box above shows the composition of standard commercially

available PD fluids. The dialysate fluid contains 1.7% dextrose as
an osmotic agent with lactate/bicarbonate as a base. If a higher
gradient is required, as in the case of uid overload, a 3% dextrose
fl
solution can be used." This can be prepared by adding 25 ml of
50% dextrose to one liter of 1.7% PD fluid.
• Lactate-free, bicarbonate-based solutions are more biocompatible
and are available commercially or may be made in-house. Babies
with liver failure, as in asphyxia, may be unable to metabolize
lactate quickly and benefit from using such fluids."
 Penitoneal Dialysi 505

• The higher the fill volume, the greater is the ultrafiltration

and clearance. The initial fill volume recommended is 10-20
ml/kg (300-600 ml/m?), increased gradually up to 30 ml/
kg (800 ml/m?)'. Limited evidence shows that even low fill
volumes (10 ml/kg) with rapid exchanges can achieve adequate
ultrafiltration and clearance."
• Initial dwell times are 15-30 min, with 16-20 cycles daily being the
norm. The uid balance and biochemical abnormalities determine
fl
the dwell time; a shorter dwell time is used for rapid urea, uid,

fl
and potassium clearance.
• Dialysate inflow time should be restricted to 10-15 min for
efficient dialysis, with outflow times ranging from 20-30 min.
Complete drainage of effluent should be ensured to avoid
elevated intra-abdominal pressure.
• Ifbaby becomes hypokalemic during the procedure, add 3-4 mEq
of potassium to 1 L to dialysate fluid.
• Heparin 250-1000 U/L should be added if hemorrhagic effluent
is present to avoid catheter-related clotting.
• Prophylactic use of a single dose of IV vancomycin (10 mg per kg)
given 60 min before the procedure decreases the rate of peritonitis?
Monitoring: Neonates require careful clinical and biochemical
monitoring (Table 50.1).
Nutrition: Measures for the provision of adequate nutrition in
babies with PD include the following:
• Monitoring of serum sodium and supplementation to compensate
for PD losses(approximately 13 mEq for every 100 ml of
ultrafiltrate).*
• Total calorie intake should be calculated accounting for -10 kcal/
kg/day obtained from dextrose within the dialysate."
• Accounting for protein losses by PD by providing 1.8 g/kg/day
of dietary protein.5

Table 50.1: Monitoring of neonates on peritoneal dialysis

Parameter Frequency of monitoring
Clinical assessment of uid balance 6-12 hourly
fl
Blood sugar, sodium, potassium and bicarbonate 6 hourly
Serum creatinine
24-48 hourly
Peritoneal uid cell count 24-48 hourly
fl
End oi procedure
Therapeutic Modalities

Catheter hip and the uid culture

fl
506 AlIMS Protocols in Neonatology

Contraindications: Absolute contraindications include necrotizing;

enterocolitis, diaphragmatic hernia, recent intra-abdominal surgery,
and intra-abdominal malignancy. A relative contraindication is a severe
respiratory compromise, as it may worsen with abdominal distension.
The latter may be circumvented with smaller volume cycles.
Complications: PD is an invasive procedure, and the following
complications need to be remembered"-11
• Electrolyte imbalance is the commonest complication, including
hypokalemia (57-76%) and hyperglycemia (6-47%), especially
when a higher glucose concentration is used.
• Peritonitis is defined as the presence of > 100 cells/mm' or >50%
neutrophils in the PD fluid after a dwell time of 2 hours. It occurs
in 4-12.9% of cases with soft catheters. The common organisms
are 5. aurens and gram-negative bacteria. Peritoneal fluid cell
count should be monitored every 24-48 hours. If suggestive
of peritonitis, empirical intraperitoneal antibiotics (loading
doses of ceftazidime 500 mg/L and vancomycin1g/L) should
be initiated with a PD dwell time of 4-6 hours while awaiting
peritoneal fluid culture. Antibiotics should be modified based
on culture; recommended duration is 21 days for S. aurens and
14 days for other organisms. Removal of PD catheter should be
considered, based on the patient's overall condition, in case of
fungal peritonitis or failure of the PD fluid effluent to clear despite
5-7 days of appropriate antibiotics.
• Adhesion of catheter tip to omentum causing catheter malfunction
may occur. A systematic review showed catheter-related
complications, including catheter leakage and obstruction,
occurred in 21% of ELBW and VLBW infants."
• Bleeding due to catheter and perforation of abdominal viscera
are uncommon complications (2-6%).

HEMODIALYSIS

Challenges of hemodialysis in the neonatal age group include the

need for large extracorporeal volumes causing excessive uid shifts
fl
and impairing thermic control, technical difficulty in establishing
adequately sized vascular access, and calibration of machines not
designed for neonates.
Without access to neonatal blood tubings, the minimum
extracorporeal volume achieved at our center is approximately
80 mL with the smallest possible dialyzer (F×Paed, Fresenius) and
 Peritoncal Dialysis 507

pediatric bloodlines. Hence, hemodialysis in the Indian context is

currently possible only for neonates weighing at least 3 kg.

CONTINUOUS KIDNEY REPLACEMENT THERAPY (CKRT)

Continuous kidney replacement therapy (CKRT) helps manage

neonatal AKI in hemodynamically unstable patients, especially
if peritoneal dialysis is not feasible. The solutes are cleared by
hemofiltration and hemodiafiltration. Systemic anticoagulation and
placement of optimally sized vascular access are necessary. CRRT
machines are not designed to treat small infants requiring low and
accurate blood flow rates with minimal ultrafiltration error.

REFERENCES
1. Selewski DT, Gist KM, Nathan AT, et al. The impact of fluid balance on
outcomes in premature neonates: a report from the AWAKEN study group.
Pediatr Res. 2020;87:550-7.
2. Harer MW, Selewski DT, Kashani K, et al. Improving the quality of neonatal
acute kidney injury care: neonatal-speci c response to the 22nd Acute
fi
Disease Quality Initiative (ADQl) conference. J Perinatol. 2021;41:185-95.
Kaddourah A, Goldstein SL.
3. Spector BL, Misurac JM. Renal Replacement Therapy in Neonates.
Neoreviews. 2019;20:697-e710.
4. Kaddourah A, Goldstein SL. Renal replacement therapy in neonates. Clin Perina.
5. Fischbach M, Warady BA. Peritoneal dialysis prescription in children:
bedside principles for optimal practice. Pediatr Nephrol. 2009;24:1633-42;
quiz 1640,1642.
6. Golej I, Kitzmueller E, Hermon M, Boigner H, Burda G, Trittenwein G.
Low-volume peritoneal dialysis in 116 neonatal and paediatric critical care
patients. Eur / Pediatr. 2002;161:385-9.
7. Nourse P, Cullis B, Finkelstein F, et al. ISPD guidelines for peritoneal
dialysis in acute kidney injury: 2020 Update (paediatrics). Perit Dial Int.
2021;41:139-57.
8. Hölä THC RK. Peritoneal dialysis during infancy. Warady BA, Schaefer
F. Alexander SR, eds. Pediatric Dialysis. 2nd ed. New York, NY: Springer;
2012; chap 13.
9. Kara A, Gurgoze MK, Aydin M, Taskin E, Bakal U, Orman A. Acute peritoneal
dialysis in neonatal intensive care unit: An 8-year experience of a referral
hospital. Pediatr Neonatol. 2018;59:375-9.
10. Hakan N, Aydin M, Zenciroglu A, et al. Acute peritoneal dialysis in the
newborn period: a 7-year single-center experience at tertiary neonatal
intensive care unit in Turkey. Am ) Perinatol. 2014;31:335-8.
11. Bellos I, Karageorgiou V. Peritoneal dialysis in very low and extremely low
birhweight infants: A pooled analysis. Perit Dial Int. 2021:8968608211059888. • Therapeutic Modalities
CHAPTER

51
Blood Component Therapy

Blood component therapy is one of the common interventions in

NICUs. Approximately 40% of VLBW and 95% of ELBW neonates
would receive a packed red blood cells (PRBC) transfusion to correct
anemia during the NICU stay. The decision to transfuse needs
to be judicious because oxidative damage associated with blood
component transfusion has been implicated in the pathogenesis of

BLOOD COMPONENT SPECIFICATION AND PRETRANSFUSION

TESTING2-4

In contrast to adults and older children, neonates constitute a

vulnerable age group because of the small circulating blood volume
and neurological and immunological immaturity.
i. Donor specification: The donor should be negative for all
mandatory microbiological markers (HIV, Hepatitis Band C,
syphilis, and malaria) and preferably have had at least one
prior donation in the previous two years.
ii. Multiple donor exposure: Pedi packs/ satellite packs
(previously separated product units containing about one-
quarter of the typical unit volume in smaller storage bags)
should be considered for top-up transfusions to minimize
multiple donor exposure.
ili. CMV seronegativity: Recommended for intrauterine
transfusions (IUTs) and neonates up to 44 weeks postmenstrual
age.
iv. Use fresh blood (<5 days; collection day taken as day ''
and component to be transfused before midnight of day 5) to
minimize the risk of hyperkalemia. This is recommended for
red cell IUTs, neonatal exchange transfusion, and large volume
transfusion (equivalent to at least a single circulating blood
508
 Blood Component Therapy 509

volume-about 80 ml/kg for neonates over 24 hours or 50%

of the circulating volume within 3 hours). For routine top-up
transfusions, irradiated red cells may be used up to 14 days.
v: Pretransfusion testing: Antibody screening of a neonate
represents the maternal antibody status rather than the fetal/
neonatal antibody status because of the active transport of
maternal IgG antibodies across the placenta and poor red
cell antibody production within the first four months of life.
Both mother's (within 3 days predelivery or post-delivery)
and neonate's samples should be obtained for initial ABO and
D (Rhesus) group determination. If the maternal sample is
unavailable, details of the maternal group, antibody status,
and transfusion history of both mother and baby should be
obtained; antibody screening and crossmatch compatibility
with neonatal blood should be performed (Table 51.1).
vi. In neonates with a history of transfusion, there is no need to
repeat ABO typing or to perform crossmatch compatibility
testing if the antibody screen is negative and the neonate has
received either group O, ABO identical, or ABO compatible
RBCs as well as compatible D (Rh) type.
vii. In emergencies, when unable to meet all neonatal
specifications, the following hierarchy may be considered
for the issue of component:
1. ABO compatibility with mother and neonate.
2. Antigen-negative for maternal antibodies.
3. Age of unit.
4. Irradiation status.
5. CMV negativity or leukocyte reduction (LR).

Table 51-1: Investigations on the maternal and fetal/neonatal sample

Maternal/sample Fetal/neonatal sample
i. ABO and D group/lype i. ABO and D group/type
il. Antibody screening ii. Direct antiglobulin test (DAT) -10 be
performed when hemolysis/ hemolytic
disease of the newborn (HDN) is suspected
or when the mother has signi cant red cell
fi
antibodies
I. Identi cation of the ili. Antibody screening of plasma in the
fi
antibods tibodies if the absence of maternal sample
antibod icen (+)
510 AIMS Protocols in Neonatology

The preferred blood group component in different conditions

is shown in Tables 51.2 and 51.3.

Table 51.2: Blood component selection for transfusion

Component Preferred group Comment
Packed red cells (PRBC) Compatible with
maternal and neonatal
ABO group and Rh
type
Double volume
exchange transfusion
(DVET)
1. Rh isoimmunization • Rh-ve blood of • D (Rhesus) -ve and K
baby's ABO type (Kell) -ve
compatible with • Fresh blood (55 days)
maternal plasma • Irradiated blood it
(1st choice) prior IUT
2. ABO incompatibility • O-ve whole blood • CPD instead of SAGM
(2nd choice) to prevent mannitol
• Blood group 'O' toxicity
and Rh compatible
suspended in
AB plasma and
cross-matched
with baby's and
mother's blood

Platelets • ABO and D • Avoid use of group

identical or
compatible with Palaces nino
recipient possible.
• HPA compatible • Platelets should be
with maternal compatible for D.
platelet antibody • lí a patient requires
for neonates with HLA matched
NAIT (as for IUT platelets, HLA match
platelets) takes precedence over
ABO group.
FFP and cryoprecipitate • ABO compatible • Reserve AB plasma
for emergency
transfusions/patient's
possible. group is unknown.
• Group O plasma
must only be given
to O recipient.
 Blood Component Therapy 511

Table 51.3, Choice of ABO components in neonate ABO compatible with]

mother
Neonatal Group Choice Choice of ABO group for transfusion

RBC Platelet
FFP
0 1st
2nd - AB or A or B
AB or A or B
1st
2nd AB AB
1st
2nd AB AB
AB 1st AB AB
AB
2nd
Oor A or B Plasma free A or B -

Packed Red Blood Cells (PRBC)

PRBCs are prepared from the whole blood by centrifugation under
a closed system within 8 hours of collection. They must be stored
at 2-6°C irrespective of the preservative used. PRBCs are often
subjected to further modifications to make PRBC transfusion safer
in neonates (Table 51.4):

Indications of Blood Component Therapy2,3

a PRBC Transfusion
PRBC transfusion is mainly indicated for resolving symptomatic
anemia and to improve tissue oxygenation (which depends on
cardiac output, oxygen saturation, and hemoglobin concentration).
The thresholds for transfusion vary according to gestational age
(GA), postnatal age, respiratory support, and the presence of
congenital heart disease. Clinical factors like severity of illness,
symptoms of anemia (lethargy, difficulty in suckling, poor growth,
tachycardia, and tachypnea), rate of fall of Hb, anticipated blood
loss, and nutritional status also guide the decision to transfusion
(Tables 51.5 and 51.6). Evaluating the degree of reticulocyte response
is also essential: a reticulocyte count >100 x 103l indicates
adequate bone marrow compensation. Though there is a paucity
of evidence on transfusion thresholds in moderate to late preterm
and term infants, recent multicentric trials have tried to evaluate the
optimum transfusion threshold in very preterm neonates. Clinicians
may consider these thresholds used in preterm and term neonates
(Tables 51.5 and 51.6). • Therapeutic Modalities
512 AlIMS Protocols in Neonatology

HTLV-1) graft versus host disease (TA-GVHD) at or before 30 weeks of gestation (because they are at

(more than 20 ml/kg)

transmit CMV even if leukoreduced/ CMV negative donor

Preferred for
Comments • Only available method to prevent transfusion-associated
• IUTs, exchange transfusion, and large volume transfusions • IgA deficiency (five times washing advisable)

Table 51.4: Packed red blood cell modi cation

fi
depending on the method used, like buffy coat removal, red cell washing, and leukofiltration • Non-hemolytic febrile transfusion reactions (NHFTR)

or a combination of both
infection) anticoagulant preservative solution from
deficiency, transfusion from blood relations, • Risk of hyperkalemia

(preterm neonates <1200 g, cellular immune • Reduces shelf life of PRBCs to 28 days lesh coes er unit doesnid era sit CB • Vansit in the ventil latent had o infection admill

• Helps to reduce potassium in the RBC.

Method • Al least 3-log reduction in leukocytes • Transmission of leukotropic viruses (CMV, EBV, and
• Pre-storage LR preferred • Dose of 25-50 gray • Inactivates donor T cells • Recommended in susceptible patient groups • Irradiated blood to be used within 24 hours • A blood component containing <5 x 106 the greatest risk of CMV infection)
• Removes most of the plasma and

• Universal LR recommended before storage Prevents • By preselecting CMV negative donors or LR • Preferred in neonates weighing s1,500 g at birth or born

A comestonus tV Ipstm Bar vius HE / Human TAmphotose vi Recurent allergic reactions (wo times washing advisable)

Modi cation type Leucocyte reduction (LR) Irradiation

_MV reduced RBCs Washed RBCs
fi
(Gamma or X-rays)
 Bload Component Therapy 513

Table 51.5: Packed red blood cells transfusion thresholds in preterm morater
Postnatal age Suggested transtusion threshold: Hb in g/di (Het)
Ventilatedi On oxygen or No supplemental
CP'AP/ NIPPV oxygen
First 24 hours <12 (35) <12 (35) <10(30)
Davs 2-7 <12 (35) <10 (30) <10 (30)
Days 8-14 <10 (30) <9.5 (28) <7.5-8.5
(23-25)'
Day 15 onwards <10 (30) <8.5 (25) <7.5 (231*
•Le clinical judgment and consider transfusion at a higher threshold of <8.5

Table 51.6: Packed red blood cells transfusion thresholds in term neonates
Condition Suggested transfusion threshold:
Hb in g/dl (Hct)
severe pulmonary disease <10 (30)

Deinonsenion cant Mile

>14 and FIO, >0.4 on HFV)
Moderate pulmonary disease
<8 (24)
Detined as MAP 58 cm H,O and/or
FiO: 50.4 on a conventional ventilator,
0т MAP < 14 and/or FiO, <0.4 on HFV)
Severe cardiac disease <10 (30)
Major surgery <10 (30)
Symptomatic anemia <7 (21)
1. 224 hours of tachycardia (HR >180
bpm) or tachypnea (RR >60)
2. Doubling of the oxygen requirement
in the previous 48 hours
3. Serum lactate 22.5 mE/L or an acute
metabolic acidosis (pH <7.2)
4. Weight gain <10 g/kg/day over the
previous four days while receiving
≥120 kcal/kg/day
Hb: Hemoglobin; Hct: Hematocrit; HR: Heart rate; RR: Respiratory rate

For acute blood loss, transfusions should generally be considered

when there is blood volume loss of 10% with symptoms of decreased
oxygen delivery or when acute blood volume loss is >20%.
Theraneutic. Modalities
514 AIMS Protocols in Neonatology

Restrictive threshold for packed red blood cell transfusion. What is the
evidence?
Two recent multicentric trials- 'Effect of Transfusion Thresholds on
Neurocognitive Outcomes' of ELBW infants (ETTNO) and Transfusion of
Prematures' (TOP) trial—which randomized 2837 (1013 in ETTNO and 1824
in TOP) neonates of ‹30 weeks' gestation into liberal and restrictive thresholds
(28-41% vs. 21-34% in ETTNO and 32-38% vs. 21-32% in TOP) showed
no difference in mortality or neurodevelopmental impairment at 24 months
corrected age. A significant limitation of both trials is that neonates were
randomised to the most restrictive Hct levels only after 3 weeks of postnatal
age.

Practice tip: PRBC transfusion

1. What is the recommended rate and volume of PRBC transfusion?
Rate: 5 ml/kg/hour
Volume: Prefer smaller volume (10-15 ml/kg)—no benefit with higher
volumes.
DVET: The aliquot exchanged each time should be about 5 ml/kg. and the
rate should not exceed 2-3 ml/kg/min
2. Is it mandatory to use diuretics during blood transfusion?
The decision to use should consider known adverse effects with uncertain
benefits. Studies have found no difference in clinical respiratory, ventilatory,
or hemodynamic parameters with the use of furosemide compared to
placebo after elective RBC transfusion in preterm infants except for minimal
increase in post-transfusion FiO2.
3. What are the strategies to reduce or prevent PRBC transfusion in neonates?
• Limiting phlebotomy losses by using point-of-care devices, minimizing
unnecessary laboratory testing, in-line arterial testing, and optimizing
frequency and volume of blood draws; umbilical cord blood can also be
made use for sampling.
• Delayed cord clamping (≥ 30 seconds to 180 seconds)

Studies have also evaluated the role of recombinant human

erythropoietin (rh-EPO) in reducing the number of PRBC
transfusions in preterm neonates. EPO stimulates erythropoiesis
and reduces the number (early and late EPO) and volume (early
EPO) of RBC transfusions. However, a multicentric study (Preterm
Erythropoietin Neuroprotection Trial; PENUT) found no significant
impact of EPO on mortality or severe neurodevelopmental
impairment at two years of age and no effect on neonatal
morbidities, including ROP, IVH, sepsis, NEC, BPD. So, routine
use of rh-EPO is not recommended.
 Blood Component Therapy 515

b. Plotelet Transfusion
Platelet components used in neonates include random donor
platelets (RDP) and single donor platelets (SDP). The SDP unit
has a higher platelet concentration (3 x 10" per unit) than RDP
(0.5 x 101 per unit). SDP is not recommended for routine neonatal
transfusion except when prolonged and severe thrombocytopenia
is anticipated. Neonates, particularly high-risk neonates, have a
favorable outcome when a lower platelet count threshold is used
for transfusion (Table 51.7).
c. Fresh Frozen Plasma (FFP) and Cryoprecipitate Transfusion
Cryoprecipitate contains fibrinogen (150-250 mg), factor VIll
(80-120 IU), Factor XIII (40-60 IU), fibronectin (30-60 mg), and v WF
(100 IU). Given the paucity of evidence-based guidelines, plasma

Table 51.7: Suggested thresholds of platelet count for neonatal platelet

transfusion
Platelet CountCondition
<25,000/mm' Neonates with no bleeding (including neonates with NAIT
if no bleeding and no family history of ICH)
• Neonates with bleeding
<50,000/mm'
• Current coagulopathy
• Before surgery
• NAIT if previously affected sibling with ICH
<1.00,000/mm' Major bleeding c.g. significant IVH
Major surgery
NAIT: Neonatal alloimmune thrombocytopenia; ICH: Intracranial hemorrhage: IVH.
Intraventricular hemorrhage

Practice tip: Platelet therapy

1. Recommended volume and rate
Rate: 10-20 ml/kg/hour.
Start the infusion slowly; if there are no reactions, gradually increase the
rate to complete the transfusion within 1 hour.
Volume: 10-20 ml/kg
2. Whole blood derived platelets contain - 10 x 10" platelets in 10 ml; 10 ml/
kg, dose may increase platelet count by 100 x 10°/L or more. Studies have
shown that 15 ml/kg of platelets increase platelet count by - 30-90 x 10%1
in sick neonates with ongoing platelet consumption, e.g. NEC and sepsis
3. No role for routine use of platelet transfusion for PDA closure in
thrombocytopenic preterm neonates with hs-PDA.
Therapeutic Modalities
 516 AlIMS Protocols in Neonatolozy

Table 51.8: Indications for FFP and crypprecipitate transfusion

FFP Cryoprecipitate
1. Disseminated intravascular 1. Congenital factor VIII de ciency*

fi
coagulation (DIC)
2. Vitamin K deficiency 2. Congenital factor XIII deficiency*
associated bleeding
NKDB)
3. Neonates with ongoing 3. Afibrinogenemia and dysfibrinogenemia
bleeding and significant with active bleeding or while undergoing
coagulopathy° an invasive procedure
4. Neonates with significant 4. von Willebrand disease (vWD) with active
coagulopathy" who bleeding when
must undergo invasive a. Diamino-D-arginine vasopressin is
procedures with a risk of contraindicated, not available, or does
signi cant bleeding not elicit a response.
fi
b. Virus inactivated plasma-derived factor
VIll concentrate is not available.
•Signi cant coagulopathy (PT or aPTT signi cantly above the normal gestational and
fi
fi
postnatal age related reference ranges)
*In the absence of factor concentrate

Practice tip: FFP transfusion

1. Recommended rate: 10-20 ml/kg/hour; volume: 15-20 ml/kg.
2. No role of prophylactic FFP in non-bleeding neonates receiving therapeutic
hypothermia and having deranged coagulation parameters.

therapy is often misused in NICU. There is no role for routine

coagulation profile screening for neonates admitted to the NICU
(Table 51.8).
Cryoprecipitate may be used if there is persistent
hypofibrinogenemia (<1.0 g/L) despite FFP transfusion, rapidly
falling fibrinogen or significant hemorrhage in DIC.
Adverse Transfusion Reactions5-9
Transfusion of blood products is not without its inherent risks. The
adverse reactions associated with transfusions can be classified as
acute and delayed transfusion reactions (Table 51.9).
Acute
1. Allergic reactions: Caused by preformed immunoglobulin E
antibody against an allergen in the transfused plasma. It occurs
• Section 12
infrequently and responds to antihistamines.
 Blood Component Therapy 517

Table 51,9: Adverse transfusion reactions

Acute Delayed
Allergic transfusion reactions Transfusion transmitted infections
Febrile non-hemolytic transfusion Transfusion associated graft-versus-host
reaction (FNHTR) (rare in neonates) disease (TA-GVHD)
Pulmonary transfusion reaction Delayed serologic (DSTR) and delayed
• TAD hernolytic transfusion reaction (DHTR,
• TACO (rare in neonates)
• TRALI
Hypotensive transfusion reaction RBC alloimmunisation (rare in neonates)
Acute hemolytic transfusion reaction
(AHTR)

2. Pulmonary reactions: Range from transfusion-associated

dyspnea (TAD) to transfusion-associated circulatory overload
(TACO) and transfusion-related acute lung injury (TRALI). TACO
and TRALI are syndromes of acute respiratory distress that occur
within 6 hours of blood transfusion.
i. TRALI: Characterized by non-cardiogenic pulmonary edema.
Onset usually within 2 hours and presents with respiratory
distress, severe hypoxemia, and fever, with or without
hypotension. Examination findings include crackles or
diminished breath sounds without evidence of fluid overload.
X-ray chest might reveal bilateral alveolar and interstitial
infiltrates. TRALl is common with transfusion of plasma-rich
components like fresh frozen plasma, apheresis platelets,
and stored cellular blood components. Treatment includes
ventilatory and hemodynamic support. Diuretics are not
helpful. The prognosis is usually good, with the resolution
within 96 hours.
ii. TACO: TACO is characterized by pulmonary hydrostatic
(cardiogenic) edema. Clinical improvement after treatment
with a diuretic or an inotropic agent is characteristic of lities

TACO but not TRALI. Other findings suggestive of TACO

include persistent hypertension, a post-transfusion brain
natriuretic peptide (BNP) level of at least 100 pg/ml, and a
utic
post-transfusion:pre-transfusion BNP ratio of 1.5.
3. Hypotensive transfusion reaction: Not well defined in neonates.
4. AHTR: Rare in neonates and mainly occur following RBC
transfusion in 'mis-transfusion' situations: Either sample | •
518 AlIMS Protocols in Neonatology

misidenti cation ('wrong blood in tube') or patient

fi
misidentification. It presents as increased pallor, free hemoglobin
in the plasma, hemoglobinuria, increased serum potassium levels,
and acidosis.. Treatment is mainly supportive.
5. Metabolic complications: Include hypocalcemia, hyperkalemia,
hypomagnesemia, and hypo/hyperglycemia.

Delayed
1. TA-GVHD: Rare but fatal complication occurring 2 days to
6 weeks after a transfusion mediated by donor lymphocytes.
Fetuses requiring intrauterine transfusions, neonates receiving
exchange transfusions, and those with potentially undiagnosed
immunodeficiencies are at particular risk for TA-GVHD.
2. Transfusion-transmitted infections (TTI): It includes human
immunodeficiency virus (HIV), hepatitis B and C viruses,
cytomegalovirus (CMV), bacterial infections, parasites (malaria),
and prions. In India, it is mandatory to test every unit of blood
collected for hepatitis B, hepatitis C, HIV, syphilis, and malaria.
There still exists a risk of transmission of HBV, HCV, and HIV due
to the window period infections and mutant strains that evade
detection in testing.

Others
1. Iron overload: Occurs following repeated RBC transfusions. It can
lead to cardiac, hepatic, and endocrine complications.
2. Transfusion-associated acute gut injury (TRAGI)/Transfusion-
associated NEC (TANEC): Conflicting evidence with numerous
observational studies associating transfusion and NEC. TRAGI/
TANEC denotes a spectrum of severe gastrointestinal reactions
observed after a blood transfusion. Proposed etiological
mechanisms include inflammatory substances in PRBC units,
oxidative stress, gut immaturity, possible pre-transfusion
small bowel hypoxia, and mesenteric blood flow disturbances
secondary to transfusion. Reports also suggest that severe anemia
rather than transfusion leads to NEC. The precise etiology
remains unclear and is likely to be multifactorial.
3. Risk of ROP and BPD
• ROP: PRBC transfusion is an independent risk factor for ROT,
with an adjusted OR of 2.4 (95% CI: 1.4-4.) following two or
more transfusions compared to none. It is possibly related to
 Blood Component Therapy 519
adult hemoglobin (HbA) in the PRBCs with lower O, affinity
and a greater capacity to release 02
• BPD: The numerous pro- and anti-inflammatory mediators in
stored RBCs could play a role in the pathophysiology of BPD.

REFERENCES
1. Zerra PE, Josephson CD. Transfusion in Neonatal Patients: Review of
Evidence-Based Guidelines. Clin Lab Med. 2021;41:15-34.
2. New HV, Berryman J, Bolton-Maggs PH, Cantwell C, Chalmers EA, Davies T,
Gottstein R, Kelleher A, Kumar S, Morley SL, Stanworth S): British Committee
for Standards in 2016;175:784-828.
3. Tewari VV, Pandita A, Taligasalam V, Kumar A, Gupta G. Use of Blood
Components in newborns. In: Kumar P, Kabra NS, Gupta G, Chawla D,
Bhatia BD, Sankar MJ, Shah S, editors. In: Evidence-based clinical practice
guidelines. New Delhi: National Neonatology Forum of India: 2019.
p. 99-128.
4. Reece IT, Sesok-Pizzini D. Inventory Management and Product Selection in
Pediatric Blood Banking. Clin Lab Med. 2021;41:69-81.
5. Sostin N, Hendrickson JE. Pediatric Hemovigilance and Adverse Transtusion
Reactions. Clin Lab Med. 2021;41:51-67.
6. Girelli G, Antoncecchi S, Casadei AM, Del Vecchio A, Isernia P, Motta
M, Regoli D, Romagnoli C, Tripodi G, Velati C. Recommendations for
transfusion therapy in neonatology. Blood Transfus. 2015;13:484-97.
7. Mo YD, Delaney M. Transfusion in Pediatric Patients: Review of Evidence-
Based Guidelines. Clin Lab Med. 2021;41:1-14.
8. Jackson ME, Baker JM. Hemolytic Disease of the Fetus and Newborn:
Historical and Current State. Clin Lab Med. 2021;41:133-51.
9. Villeneuve A, Arsenault V, Lacroix J, Tucci M. Neonatal red blood cell
transfusion. Vox Sang. 2021;116:366-78.
 Kangaroo Mother Care

Kangaroo mother care (KMC) is a method of care for preterm or low

birth weight (LBW) infants by placing them in skin-to-skin (STS)
contact with the mother or other caregiver to ensure their optimum
growth and development.17 Initially devised as an alternative to
conventional technology-based care, KMC is now considered the
standard of care for LBW infants in all settings.
COMPONENTS?
The four components of KMC are
1. Kangaroo position (skin-to-skin contact) between the mother and
the infant in a vertical position, between the mother's breasts,
and under her clothes. The provider must keep herself in a semi-
reclining position to avoid gastric re ux in the infant. The mother
fl
can share this responsibility with the father and other relatives.
2. Exclusive or nearly exclusive breastfeeding.
3. Early discharge from health facilities.
4. Continued follow-up: Mothers at home require adequate
support and follow-up; hence, a follow-up program and access
to emergency services must be ensured.

BENEFITS

KMC is a simple, cost-effective intervention with numerous benefits

for the infant and the community.' A recent systematic review that
included studies done both in health facilities and in community
settings (27 studies and 12,000 neonates) shows that KMC when
compared with conventional neonatal care:
• Reduces the risk of death during birth hospitalization or 28 days
of age (RR 0.68; 95% Cl 0.53-0.86). This reduction in mortality is
noted irrespective of gestational age or weight at enrolment, time
of initiation, and setting (hospital or community).
• Reduces severe infection till the latest follow-up.
520
 Kangaroo Mother Care
521
• Reduces the risk of hypothermia by 68%.
• Results in better gain in anthropometric parameters, namely
weight gain per day and length and head circumference gains
per week.
• Results in higher exclusive breastfeeding rates at discharge and
28 days of life.
KMC of at least 8 hours per day was found to have greater
mortality benefits than shorter-duration of KMC. Long-term benefits
of KMC are difficult to ascertain due to additional influences from
parental nurturing, optimal home environment, and external factors
on development. Follow-up studies from a single RCT showed
that the risk of cerebral palsy, Griffith Quotients at 12 months of
corrected age, or IQ scores at 20 years of age were not different
between KMC and conventional care infants. The most vulnerable
infants (birth weight <1800 g) who received KMC demonstrated
significantly reduced school absenteeism and reduced hyperactivity,
aggressiveness, and externalization at 20 years of age.

WHEN TO INITIATE KMC?

Most units wait until infants become clinically stable and are weaned
from respiratory support and parenteral nutrition to initiate KMC.
Four recent studies explored the benefits of early initiation of KMC
before 24 hours of age compared to later initiation until neonates were
deemed hemodynamically stable. Three of these studies, including
the large immediate KMC (iKMC) multi-country study," were
conducted in low- and middle-income countries. In all the studies,
neonates in the early KMC group received KMC within 24 hours
of birth, even when on noninvasive respiratory support. The only
exclusions were inability to breathe at birth, invasive ventilation,
shock, seizures, severe jaundice, or major congenital malformations
requiring immediate management. The meta-analysis of these studies
showed that early-initiated KMC, compared to later initiation:
• Reduces neonatal mortality by 22% (RR 0.78, 95% C1 0.66-0.92).
• Reduces the incidence of hypothermia and clinical sepsis till
28-days of life.
• Results in higher rates of the exclusive breastfeeding at discharge.
Post-hoc analysis of the iKMC study data further showed that the
babies immediately initiated on KMC have no significant difference
in heart rate, respiratory rate, oxygen saturation as compared to
babies in control arm further demonstrating the safety of immediate
KMC initiation.?
 522 AIMS Prote 5 in Neon

Based on recent evidence, the WHO recommendations for the

care of preterm or low-birthweight infants advocate the following
• Kangaroo mother care (KMC) is recommended as routine care
for all preterm or LBW infants. KMC can be initiated in the
healthcare facility or at home and should be given 8-24 hours
per day (as many hours as possible). (Strong recommendation,
high-certainty evidence).
• KMC should be started as soon as possible after birth. (Strong
recommendation, high-certainty evidence).

REQUIREMENTS FOR KMC IMPLEMENTATION

KMC is feasible everywhere because it does not require any

equipment to implement. Also, it is advantageous for the
organization of health services provided the following requirements
are met:
1. Health facility or home setting.
a. The health facility should always allow entry of the parents
to the neonatal unit.
b. Mother-neonatal intensive care unit (Mother-NICUs),
wherein the bed of mother is beside the incubator / warmer of
preterm baby, wherever feasible can further help to promote
early KMC (as done in an Indian centre for iKMC study). Such
an undertaking will require interdepartmental coordination.
c. Reclining chairs in the nursery and postnatal wards and beds
with adjustable backrests (Fig. 52.1) help mothers to practice
KMC for long hours.
d. Mother can also provide KMC at home, sitting on an ordinary
chair or in a semi-reclining posture on a bed with the help of
pillows.

b
• Section 12
Fig. 52.1: Mother practicing KMC in reclining posture (a) and KMC chair (b)
 Kangeroo Mother Care
523
2. Supporting staff and family members.
a. In hospital settings, a trained nurse is indispensable in
assisting mothers with KMC.
b. Staff should receive adequate training on KMC, including
the nutrition of LBW infants. Additional training is needed
on the expression and storage of breast milk, using alternate
feeding methods, and daily monitoring of the growth of LBW
infants. The training could be done by exposing them to units
already practicing KMC.
c. Educational material such as information sheets, posters, and
video films on KMC in the local language should be available
to mothers, families, and the community.
d. At home, a supportive family who can also share the
responsibility of providing KMC is essential.
3. Follow-up.
a. Ensure continued KMC at home. Arrange follow-up to track
growth and development.
4. Institutional, social, and community support
a. The requirement for a successful KMC program can be
summarized in three words: Communication, sensitivity, and
education.
b. Apart from supporting the mother, family members should
also be encouraged to provide KMC when the mother wishes
to rest.
c. The mother would need her family's cooperation to handle
her conventional household chores and responsibilities until
the baby requires KMC.
d. Community awareness about the benefits should be created.
This is particularly important when there are social, economic,
or family constraints.
CRITERIA FOR ELIGIBILITY OF KMC
1. Neonate
• All preterm and LBW neonates are eligible for KMC.
• KMC can be initiated as soon after birth in spontaneously
breathing infants, even if they are on respiratory support (i.e.
non-invasive ventilation).
• KMC can be provided while the baby receives intravenous
fluids or is fed via an orogastric tube.
• Apnea is not a contraindication for KMC. On the contrary,
KMC helps decrease apneic episodes, probably related
524 AliMS Protocols in Neonatology

to the prone position of the infant that is associated with

better ventilatory mechanics and the rhythmic kinaesthetic
stimulation from the mother. A systematic review showed
that KMC resulted in a 60% reduction in apnoea episodes (RR
0.41; 95% Cl 0.22, 0.78).°
• Contraindications: hemodynamic instability (shock), severe
respiratory distress, seizures, asphyxia, or other medical
conditions that need priority management of airway, breathing,
or circulation.
2. Caregivers: Mothers and close family members can provide
KMC, irrespective of age, parity, education, culture, and religion.
The following points must be taken into consideration when
counseling for KMC:
a. Willingness: The mother must be willing to provide KMC.
Healthcare providers should counsel and motivate her. Once
the mother realizes the benefits of KMC for her baby, she will
learn and undertake KMC.
b. General health and nutrition: The mother should be free
from serious illness to be able to provide KMC. She should
receive an adequate diet and supplements recommended by
her physician.
c. Hygiene: The mother should maintain good hygiene: daily
bath/sponge, change of clothes, hand washing, and short
and clean fingernails.
INITIATION OF KMC

1. Counseling: When the neonate is ready for KMC, arrange a

convenient time for the mother and her baby. Demonstrate to
her the KMC procedure in a caring and gentle manner and with
patience. Answer her queries and allay her anxieties. Encourage
her to bring her mother/ mother-in-law, husband, or any other
family member. It helps build a positive attitude in the family
and ensures family support to the mother, which is particularly
crucial for post-discharge home-based KMC." It is helpful that the
mother starting KMC interacts with someone already practicing
KMC for her baby.
2. Mother's clothing: The mother can wear any front-open dress
per local culture. This may include a sari, a blouse, a front open
gown, a suit, or a simple shirt (Fig. 52.2). KMC can be done
 Kangaroo Mother Care 525

Fig. 52.2: Mother (a) and father (b)

practicing KMC in a front-open gown
and shawl. Mother performing KMC
using AlIMS KMC jacket (c). IIT-AIIMS
KMC Jacket (d) and mother performing
KMC using IIT-AlIMS KMC jacket (E).

with special apparel (such as the KEM bag or AIMS KMC

jacket) designed to suit the needs of mothers. Any other suitable
clothing that can retain the baby for an extended period can be
adapted locally.
3. Neonate's clothing: Neonate is dressed in a cap, socks, nappy,
and front-open sleeveless shirt.
526 AlIMS Protocols in Neonatology

KMC PROCEDURE
1. Kangaroo positioning
a. The neonate should be placed between the mother's breasts
in an upright position.
b. The head should be turned to one side and slightly extended.
This extended position keeps the airway open and allows
eye-to-eye contact between the mother and her baby.
c. The hips should be flexed and abducted in a "frog" position;
the arms should also be flexed. The baby's abdomen should
be at the level of the mother's epigastrium.
d. Support the baby's bottom with a sling/binder.
2. Monitoring
a. Neonates receiving KMC should be monitored carefully,
especially during the initial few days.
b. Nursing staff should make sure that the baby's neck position
is neither too flexed nor too extended, the airway is clear,
breathing is regular, the color is pink, and the baby is
maintaining temperature.
c. The mother should observe the baby during KMC so that she
can continue monitoring at home.
3. Feeding
a. The mother should be explained how to breastfeed while the
baby is in the KMC position.
b. Holding the baby near the breast stimulates milk production. 56
c. She may express milk while the baby is still in the KMC
position. Depending on the baby's condition, the baby could
be fed with a paladai, spoon, or orogastric tube.
4. Duration
a. Skin-to-skin contact should start gradually in the nursery.
b. The length of skin-to-skin contact should be gradually
increased up to 24 hours a day, interrupted only for changing
diapers.

Discharge Criteria
The unit's standard policy for hospital discharge should be
followed. Generally, the following criteria are accepted at most
centers:"
• The baby's general health is good.
 Kangaroo Mother Care 527

• Gaining weight (at least 15-20 g/kg/day for three consecutive

days).
• Able to maintain body temperature satisfactorily for at least three
consecutive days at room temperature.
• Feeding well and receiving exclusively or predominantly breast
milk.
• The mother and family members are confident in taking care of
the baby.

WHEN TO DISCONTINUE KMC?

If the mother and baby are comfortable, KMC is continued at the

hospital and at home for as long as possible. Often this is desirable
until the baby's gestation reaches term or the weight is around
2500 g. Once the neonate starts wriggling to show that she is
uncomfortable, pulls her limbs out, cries, and fusses whenever
put in skin-to-skin contact, the mother can wean the baby from
КМС.

POST-DISCHARGE FOLLOW-UP

Close follow-up is a fundamental prerequisite of KMC practice.

Baby is followed once or twice a week till 37-40 weeks of gestation
or until the baby reaches 2.5-3 kg. After that, a follow-up once in
2-4 weeks may be enough till 3 months of postmenstrual age. The
baby should gain adequate weight (15-20 g/kg/day up to 40 weeks
of postmenstrual age and 10 g/kg/ day subsequently). More
frequent visits should be made if the baby is not growing well or
his / her condition demands.

REFERENCES
1. Charpak N, Ruiz-Pelaez JG, Charpak Y. Rey-Martinez Kangaroo Mother
Program: an alternative way of caring for low birth weight infants? One year
mortality in a two cohort study. Pediatrics 1994; 94(6 Pt 1):804-10.
2. World Health Organization. Kangaroo mother care: a practical guide.
Department of Reproductive Health and Research, WHO, Geneva.2003.
3. Conde-Agudelo A, Belizán IM, Diaz-Rossello J, Jose L. Kangaroo mother
care to reduce morbidity and mortality in low birthweight infants. Cochrane
Database Syst Rev. 2016 August 16; (3):CD002771.
4. Sivanandan S, Sankar MJ. Kangaroo mother care for preterm or low birth
weight infants: A systematic review and meta-analysis. BM/ Global Health
2023;1-13. doi: bmjgh-2022-010728.
528 AlIMS Protocols in Neonatology

5. Charpak N, Tessier R, Ruiz IG, Hernandez IT, Uriza F. Villegas | et al.

Twenty-year Follow-up of Kangaroo Mother Care Versus Traditional Care
Pediatrics. 2017;139(1):e20162063.
6. Immediate "Kangaroo Mother Care" and Survival of Infants with Low Birth
Weight. N Engl | Med. 2021 May 27;384(21):2028-38.
7. Linnér A, Westrup B, Rettedal S, Kawaza K, Naburi H, Newton S, et al.
Immediate skin-to-skin contact for low birth weight infants is safe in terms
of cardiorespiratory stability in limited-resource settings. Global Pediatrics.
2023 Mar;3:100034.
8. Montealegre-Pomar A, Bohorquez A, Charpak N. Systematic review and
meta-analysis suggest that Kangaroo position protects against apnoea of
prematurity. Acta Paediatr. 2020 Jul; 109(7):1310-6.
9. Chan Gl, Labar AS, Wall S, Alun R. Kangaroo mother care: a systematic review
of barriers and enablers. Bull World Health Organ. 2016;94(2):130-141).
 CHAPTER

53
Pain Assessment and Management

Neonates admitted to NICU undergo several painful procedures per

day, and they communicate their pain and stress through various
autonomic, motor, and behavioral cues. The caregivers in NICU
must recognize these cues and modify the environment to reduce
stress and pain and facilitate self-regulatory mechanisms to promote
the infant's comfort.
Four subsystems need continuous positive environmental
influence and synchronized functioning to optimize well-being and
growth in neonates. Table 53.1a to d lists the subsystems and the
associated organized and disorganized behavior.
Pain prevention is essential from a humanitarian perspective
because pain is associated with long-term neurobehavioral
consequences. Every healthcare facility caring for neonates should
implement a comprehensive pain prevention program, including
routine assessment of pain, minimizing procedures that can cause
pain, effective use of nonpharmacological and pharmacological
techniques to prevent pain during common procedures, and
complete pain relief during major surgeries.'

Table 53.1a: Organized and disorganized behavior in autonomic and visceral

subsystem
Parameter Organized behavior Disorganized behavior
Respiratory rate Stable Very fast/very slow or with pauses
Heart rate Stable Very fast or very slow
Skin color Pink Blanching
Oxygen saturation Normal Gasping/ cyanosis
Other signs Absent Yawning, startles, tremors, twitches,
sneezing, coughing drooling.
spitting, vomiting, gagging, straining
as if passing bowel

529
530 AllMS Protocols in Neonatology

Table 53.1b: Organized and disorganized behavior in motor subryten

Parameter
Organized behavior Disorganized behavior
Tone Normal Flaccidity in trunk, extremities, stiffening or
arching and hyperextension
Posture Maintains flexed All limbs are extended
posture
MovementSlow regulated, Jerky movements/ very slow movements,
controlled smooth flailing movements of the arms and legs
movements
Other signs Nil Arching body, nger splay, foot splay,

fi
sting of hands, salute, high arm guard,

fi
sitting on air, tongue protrusion

Table 53.1c: Organized and disorganized behavior in attention and interactive

sub-system
Organized behavior Disorganized behavior
Neonate is in deep sleep or quiet and Neonate is in a diffused sleep
alert, maintains eye contact, mouthstate, twitching, fussy, frowning.
pursing, cooing, smiling, consolable grimacing, irritable, crying, eyes
rolling upwards, averting eye gaze,
gaping, sleepless

Table 53.1d: Behavior in self-regulatory subsystem

Organized behavior Disorganized behavior
This system helps the preterm infant to Neonate will be fussy, irritable,
calm and soothe themselves in stressful and unable to interact with the
situations. An infant who can self- environment positively.
regulate will have a longer duration of
undisturbed sleep; have better-organized
learning and coping mechanisms during
different painful experiences.
Self-regulatory signs are finger clasping.
clasping of blanket or sheet, fingers in
the mouth with or without sucking, foot
clasp, and ieet against the bassinet for
support.
*Observing an infant over a period is crucial. These cues indicate whether the
infant is ready for the activity, needs to be calmed before the activity is continued,
or is unprepared to engage.. The older the infant, the more they use self-calming
or self-regulatory techniques to organize themselves.
 Pain Assessment and Management 531
PAIN ASSESSMENT

• Use Premature Infant Pain Profile: Revised (PIPP-R; Table 53.2)

for assessment of acute pain.?
• ComfortNeo pain scale may be used to assess the degree of
prolonged pain and its response to analgesics.?

Table 53.2: Premature Infant Pain Profile: Revised (PIPP-R)

5.N. Parameters Score
+1 +2 +3
1. Change in 0-1 5-14 >24
heart rate
15-24
(bpm) from
baseline
Decrease
in oxygen
0-2 3-5 6-8 >8 ог
increase in
saturation
(%) from
02
baseline
Brow bulge None (<3) Minimal (3-10) Moderate Maximal
(sec) (11-20) (>20)
Eye None (<3) Minimal (3-10) Moderate Maximal
squeeze (11-20) (>20)
(sec)
Naso-labial None (<3) Minimal (3-10) Moderate Maximal
furrow (11-20) (>20)
(sec)
Subtotal score: (1 + 2 + 3 + 4 + 5)
6. Gestational >36 weeks 32 - 35 + 6
age (weeks) weeks
28 - 31 + 6 <28 weeks
weeks
7. Baseline Active and Quiet and
behavioral awake awake
Active and
asleep
Quiet and
asleep
state
Total score:
Instructions:
• Observe the infant for 15 sec at rest to determine baseline vital signs.
• Observe the infant for 30 sec after the procedure to assess changes in the vital parameters.
• If infants require an increase in FiO, during a procedure, give a score of 3 in the 0;
saturation score.
• If the subtotal score > 0, add gestational age and behavioral state scores.
• Total score = Sub-total score + GA score + BS score
• Maximum score = 21
• Score 7-12: non-pharmacological measures; score > 12: pharmacological analgesia
532 AIMS Protocols in Neonatology

PREVENTING OR REDUCING PAIN

General Measures
Pain is managed most effectively by preventing, limiting, or
avoiding noxious stimuli. The following measures in combination
are followed to minimize pain:
• Keep ambient light and sound levels minimum; avoid strong
perfumes and pungent odours.
• Close incubator doors gently and optimize alarm limits and
alarm sounds.
• Limit the number of painful procedures and handling by
clustering the care activities.
• Encourage parental involvement and interaction.
• 'Sensorial stimulation': gently stimulate audiovisual, gustatory,
and tactile systems simultaneously.
• Swaddling, facilitated tucking, distraction measures like talking,
music, etc.

Nonpharmacological Measures
The nonpharmacological measures include sucrose (24% solution),
dextrose (20-30% solution), breastfeeding or breastmilk through
pacifiers, skin-to-skin contact, and sensorial stimulation. These
measures have been best studied for acute mild-to-moderate
procedural pain, including pain during heel lance, venipuncture,
adhesive removal, intramuscular injections, etc. These measures are
more effective when used simultaneously. No significant adverse
effects have been described, though the long-term effects have yet
to be well-studied. Table 53.3 summarizes the evidence supporting
nonpharmacologic analgesics.
The sucrose/ dextrose solution is given orally by a syringe/
pacifier 2-3 min before the procedure and may be repeated
1-2 min afterward. The effect lasts around 4-6 minutes. Intragastric
administration has no analgesic effect. The usual dose is 0.1-0.5 ml
for preterm (<32 weeks neonates) and 0.2-1 ml for late preterm and
term neonates.

Pharmacological Measures
The pharmacological measures can be broadly divided into:
• Local anesthetic agents
• Systemic agents: opioids, paracetamol
 Pain Assessment and Management 533

Table 53.3: Evidence supporting nonpharmacological analgesic measures in

neonates
Agent Evidence Major ndings and conclusions

fi
Sucrose (24%) Cochrane mela- • Reduction in pain scores (PIPP)
analysis' (74 studies, during heel lance, venipuncture,
7049 infants) and intramuscular injections, in
both preterm and term infants.
• Inconclusive bene ts during other

fi
painful procedures.
• No major adverse effects.
• Combination of sucrose with other
nonpharmacological measures
may augment the analgesic effect.
Dextrose Systematic review • Reduction in pain scores during
and meta-analysis" heel lance and venipuncture.
(20-30%)
(38 studies, 3785
infants)
Breast milk and Cochrane meta- • Breastfeeding reduces pain during
breastfeeding analysis" (20 studies) heel lance and venipuncture.
• Supplemental breastmilk has
uncertain bene ts.
fi
• Glucose/sucrose have similar
effectiveness as breastfeeding.
Skin-to-skin Cochrane meta- • Reduction in composite pain
contact analysis' (25 studies, indicators (both physiological and
2001 infants) behavioral).
• Insufficient evidence regarding
additive effect with other
interventions.

Nonsteroidal anti-inflammatory agents (NSAIDs) are generally

not used as analgesics in newborns.

Local Anesthetics
Local anesthesia is helpful for the management of acute procedure-
related pain. It can be either topically applied on intact skin or
injected subcutaneously. The common preparations include EMLA
(eutectic mixture of local anesthetics), lidocaine (2%) injection,
and tetracaine (4%). Proparacaine eye drops are used for topical
anesthesia during ROP examination.
The dose of IMLA is 0.5-2 g with a contact period of 30 min to
1 hour. Apply the cream over a 2-3 cm? area with 1-2 mm thickness
534 AlIMS Protocols in Neonatology

and cover with transparent (Tegaderm) dressing. For maximal

analgesic effect, topical anesthetics should be combined with other
nonpharmacological measures like sucrose analgesia or breast
milk supplementation. The clinical effect of EMI.A is modest, with
good efficacy for lumbar puncture and no or minimal benefit for
heel lance and venipuncture. The major drawback is the delayed
onset of action and a contact period of at least 1 hour before the
procedure, making it unsuitable for emergent procedures. Though
EMLA is approved for use in only infants older than three months,
it has been used off-label in neonates." There is a possible risk of
methemoglobinemia with EMLA cream; it is recommended to test
for MetHb levels if multiple doses of EMLA are used.
For emergent procedures (e.g. chest drain insertion), subcutaneous
local anesthetic injection (2% lidocaine hydrochloride) is preferred
over topical creams.

Opioids
Opioid drugs are the mainstay in managing severe pain, including
mechanical ventilation, endotracheal intubation, and post-surgical
pain in neonates. The two most used agents are morphine and
fentanyl. The common adverse effects of opioids include respiratory
depression, hypotension, urinary retention, reduced intestinal
motility, bronchospasm, and chest wall rigidity (fentanyl). Also, their
pharmacokinetics have not been well-described in preterm neonates,
underscoring the need for cautious use. Tolerance and withdrawal
are common with prolonged use. Fentanyl is the preferred opioid
among neonates. Short-acting opioids like Sufentanil, Remifentanil,
etc. have been used for brief procedures like endotracheal intubation
and short surgeries.
Special considerations for fentanyl and morphine:
• Avoid morphine (and prefer fentanyl) in case of hypotension,
gestation <27 weeks, acute kidney injury, and reduced
gastrointestinal motility.'
• Avoid fentanyl in neonates who have undergone abdominal

suring RCMO (circuit sequestration of fentanyl, pressure and

Analgesia for Specific Procedures

Table 53.4 enumerates the recommended analgesia measures in
routine bedside procedures.
 Pain Assessment and Management 535

-Table 53.4: Analgesia measures for routine bedside procedures

Procedure Analgesia measure recommended
General Sucrose Breast milk* Skin-to-skin
measures analgesia contact/sensorial
stimulation
Venipuncture + + + +
Sampling'
Heel prick* + +
Subcutaneous/M
injection
+ + +
Adhesive tape
removals
+ ‡ ‡ +
IV cannulation + +
Urinary + + +
catheterization
Echocardiography + + +
*Either sucrose analgesia or breastfeeding can be adopted depending on the availability
and feasibility; for slightly longer procedures, sucrose analgesia is preferred over breast
milk breastieeding
*Venipuncture should be the preferred mode of blood sampling as heel lance is more
painful; automated lancets are superior to conventional lancets for the heel prick
'Use adhesive removal solution

NON-EMERGENCY INTUBATION
Endotracheal intubation is a stressful procedure and may be associated
with bradycardia, hypoxia, hypertension (both systemic and
pulmonary), and increased intracranial pressure. In all non-emergent
intubations, premedications are recommended to blunt the stress
response, decrease the risk of adverse events, and facilitate successful
intubation. These drug regimens generally consist of the following:
A. A sedative-analgesic (e.g. fentanyl, morphine) to decrease
pain and stress.
B. A vagolytic (e.g. atropine, glycopyrrolate) to counter
bradycardia and decrease secretions.
C. A muscle relaxant (e.g. vecuronium, rocuronium) to allow
adequate visualization (Table 53.5).
The AAP recommends the following for all non-emergency neonatal
intubations:12
• Analgesic agents or anesthetic doses of a hypnotic drug should
be given.
• Vagolytic agents and rapid-onset muscle relaxants should be
considered.
536 AlIMS Protocols in Neonatology

Table 53.5: Analgesia-sedation for non-emergency intubation

5.No. Drug Dose Timing
Inj Fentanyl 1-4 pg/kg IV Slowly over 3-5 minutes
Inj Atropine 0.02 mg/kgIV 1-2 min prior to
2
(minimum dose 0.1 mg) intubation
Inj Vecuronium' 0.1 mg/kgIV 2-3 minutes prior to
3
intubation
Preferred regimen includes the above three-drug combination.
*Avoid using paralytic agents (vecuronium) if an experienced person is unavailable for
intubation.

• Use of sedatives alone, such as benzodiazepines without analgesic

agents, should be avoided.
• A muscle relaxant without an analgesic agent should not be used.
Mechanical Ventilation
Mechanical ventilation is a painful and uncomfortable experience
that may adversely affect the course of acute illness and long-term
neurodevelopment.
• There is no role for routine opioids in mechanically ventilated
neonates. Consider opioids only in the following situations:
1. Chest tube insertion, post-surgery, planned intubation/
reintubation.
2. Significant ventilator dyssynchrony that is not attributable to
improper / inadequate ventilator settings or secretions. Note
that inadequate ventilatory setting is a more common cause
of ventilator dyssynchrony than lack of sedation-analgesia.
3. Documented pain (document PIPP-R pain score at baseline
and 30 minutes after dose)
4. PPHN requiring mechanical ventilation and not improving
with environmental measures alone.
• Assess the requirement of opioids daily and document the same
in case records.
• Consider early de-escalation.
• In neonates with expected short duration of mechanical
ventilation (e.g. preterm infants with respiratory distress
syndrome), use intermittent boluses of opioids only if required
to ensure lower cumulative doses:
- Fentanyl: 1-2 pg/kg IV slowly over 5 minutes.
- Morphine: 10-50 pg/kg IV over 15-30 minutes.
 Pain Assessment end Maregement 537

• Emergency intubation and resuscitation kit (including IV

naloxone: 0.1 mg/kg/dose) should be ready bedside while
administering a bolus dose of opioids.
• In neonates with an expected longer duration of ventilation.
continuous infusion of opioids is preferred over intermittent
boluses, but only in defined indications cited above.
• Avoid opioids in extremely preterm neonates due to uncertain
safety and pharmacokinetic pro le.

fi
Analgesia/sedation in ventilated neonates: what is the evidence?
A Cochrane review (2021), including 23 studies and 2023 neonates /both term
and preterm), examined the role of opioids during mechanical ventilation in
neonates. It found no signi cant bene t of using opioids over placebo in terms
of PIPP score 12-48 hours after starting the infusion, duration of mechanical
fi
fi
ventilation, IVH, BPD, neurodevelopmental impairment at 18-24 months and
5-6 years, and mortality. The authors recommended selective use of opioids
in neonates based on pain assessment using validated tools. '

Table 53.6 enlists the recommended analgesia measures for other

procedures in the NICU.

Table 53.6: Analgesic measures for specific procedure"

Procedure Measures
Arterial puncture/ • Sucrose/dextrose analgesia
cannulation • EMIA cream locally (esp for LP)
Lumbar puncture • General measures
PICC line placement
Chest tube placement • Inj Fentany!' 0.5-1 pg/kg 2-3 min prior
• Local infiltration with lignocaine 2%
• Sucrose/ dextrose analgesia
Chest drain removal • Sucrose/dextrose analgesia
• General measures
ROP screening • Local anesthetic eye drops
• Sucrose/dextrose analgesia
• General measures
Laser photocoagulation • Inj Fentanyl 2 pg#g bolus followed by 2-5 pg/
for ROP* kghr infusion till the procedure lasts
• Local anesthetic eye drops
• Sucrose analgesia
• General measures
• Post-procedure paracetamol 15 mg/kg q
6 hourly for 1-2 days
538 AlIMS Protocols in Necnatology

Table 53.6: Analgesic measures for speci c procedures" (Conti)

fi
Procedure Measures
CT/ MRI ior sedation Intubated:
• Inj Fentanyl 0.5-1 pg/kg IV 2-3 min prior
• Inj Midazolam 0.1-0.2 mg/kg IV
Non-intubated:
• Oral Trichlophos 20-30 mg/kg or chloral
hydrate 50-100 mg/kg, 20-30 min prior
• Inj Midazolam 0.1-0.2 mg/kg
In non-ventilated babies while using opioids, watch for apnea/respiratory depression;
IN Naloxone should be kept ready and used in case of respiratory depression or apnea
10.1 mg/kg or 0.25 ml/kg /V)
"Even ventilated patients on opioid infusion during procedures need additional analgesic
measures

Table 53.7 depicts the dosages and common adverse effects of

different analgesic agents used in the NICU.

Opioid Tolerance
• Tolerance leads to reduced ef cacy of the drug and may require
fi
dose escalation. Tolerance is rare, with a duration of therapy
of less than 4 days. Other causes of increased pain, such as
worsening primary disease, opioid-related hyperalgesia, and
ventilator asynchrony, must be considered and ruled out.
• Consider escalating the dose after about 4 days of fentany!
infusion or 14 days of morphine infusion, based on pain scores.
• Opioid rotation, i.e. switching to an equianalgesic dose of a
different opioid, may help counter tolerance and decrease the
need for dose escalation.
• While switching from one opioid to another, reduce the
equianalgesic dose of the new opioid by 20-30% to adjust for a
probable lack of cross-tolerance.
• To convert intravenous fentanyl to an equivalent intravenous
morphine dose, multiply the fentanyl dose (in pg/kg/hour)by
10-20, reduce it by 25%, and continue that dose as morphine
infusion (in pg/kg/hour).
• When very high doses of opioid analgesics are required or
sedation is desirable, adding agents like midazolam (to be used
cautiously in preterm infants), dexmedetomidine, or ketamine
may help decrease the opioid doses.
 Pain Assessment and Management

(Contd.)

Respiratory depression,
ileus, urinary retention;
naloxone can reverse effects with rapid push), urinary
chest wall rigidity (esp naloxone can reverse effects
Adverse effects retention, hypotension;
myoclonic jerks,
hypotension; flumazenil can
Apnea, CNS depression, reverse effects

Pharmacology Narcotic analgesic 3-5 hoursNot recommended in neonates <28 weeks 50-100 times more
potent than morphineOnset: immediate Duration of action 30-60 min
Short acting
benzodiazepine preterm
Not recommended in neonates

Preparation/administration 1 ml = 15 mg Dilute in NS/10D/5D to make a Onset: 5-15 min

phenobarbitone
Incompatible with phenytoin,
phenobarbitone
Incompatible with phenytoin,
1ml = 1 mg Dilute in NS/ 5D/10D emulsion
Incompatible with NaHCO,, fat

mg/kg slow IV rg/kg/min

used
mg/kg may also be

Modolities
Dose Bolus: 25-100 pg/kg
hour IV
slow IVInfusion: 7-50 pg/kg/ Bolus 1-4 pg/kg IV 1 ml = 50 over
;low pg 3-5 minutes Dilute in NS/5D/10D
tour (232 weeks);
nfusion: 1-4 pg/kg/ tour in neonates
itart at 0.5 pg/kg/
veek of life
<32 weeks during 1st • Bolus: 0.05-0.1 • IV Infusion: 0.25-1 • Intranasal: 0.2-0.3
 AlIMS Protocols in Neonatology

Methemoglobinemia
Adverse effects Avoid in hepaticdysfunction

Rectal route has an

Onset: 30-60 min Duration of action: 2-4 hours
Pharmacology erratic absorption

Lidocaine (2.5%) and prilocaine

Preparation/administration Syrup 5 ml = 125 mg Drops 1 ml = 100 mg available in India) 5 g/30 g with
(2.5%) in 1:1 ratio (e.g. Oint Prilox
Suppositories 80 mg transparent dressing

Table 53.7: Drugs and dosages of analgesic/sedative medications commonly used in NICU

Dose 10-15 mg/kg/dose PO 6-8 hourly30 mg/kg/ dose per rectal minutes

Drug Paracetamol EMLA cream 0.5-2 g for 30-60

 Pain Assessment and Management 541

Withdrawal and Oplold Tapering

• Withdrawal symptoms may be seen with rapid tapering of
opioids and present with features similar to those seen in
neonatal abstinence syndrome, such as irritability, poor sleep,
diarrhea, vomiting, jitteriness, tremors, tachycardia, sweating,
fever, mottling, seizures, excessive sucking. Certain factors like
prematurity, male gender; longer duration of therapy, lower initial
dose of opioids, use for post-operative pain, and concomitant use
of sedatives have been associated with a higher risk of opioid
withdrawal."
• Assess the need for opioids daily, and start de-escalating the dose
as carly as possible.
• If the neonate has received opioids for less than 5 days, initially
decrease the original dose by 30-50% and then by 20-30% every
6-S hours.
• lí the neonate has received opioids for 5 or more days, decrease
the original dose by 20% and then by 10% every 12 hours.!
• Document modified Finnegan score before starting tapering and
then every 4 hours subsequently.
If the score is 8 or more, pause the tapering. Increase the dose to
the previous higher dose if the score is 12 or more.
In case of a prolonged tapering regimen, switching from IV
fentanyl or morphine to oral morphine may help obviate the need
for IV access (Table 53.8).

Table 53.8: Algorithm for converting IV dose of opioid to equianalgesic oral

dose of opioids

Current Equivalent oral opioid dose

Usual maintenance
intravenous agent infusion rate
IN fentanv 1-5 pg/kg/hour Multiply hourly fentany/ dose (in
pg/kg/hour) by 0.1; Administer
as oral morphine (in mg/kg/dose)
q 4 hours
IN fentany! 1-5 pg/kg/hour Multiply hourly fentanyl dose
(in pg/kg/hour) by 0.05-0.1;
Administer as oral methadone
(mg/kg/dose) q 6 hours
IN morphine 7-50 pg/kg/hour Multiply hourly morphine
dose (in pg/kg/hour) by 0.01;
Administer as oral morphine (in
mg/kg/dose) q hours
 542 AIMS Protocols in Neonatology

REFERENCES
1. Committee On Fetus And Newborn And Section On Anesthesiology And Pain
Medicine. Prevention and Management of Procedural Pain in the Neonate:
An Update. Pediatrics. 2016;137:20154271.
2. Stevens BI, Gibbins S, Yamada J, Dionne K, Lee G, Johnston C, et al.
The premature infant pain profile-revised (PIPP-R): initial validation and
feasibility. Clin | Pain. 2014;30:238-43.
3. van Dijk M, Roofthooft DWE, Anand KIS, Guldemond F, de Graaf J.
Simons S, et al. Taking up the challenge of measuring prolonged pain in
(premature) neonates: the COMFORTneo scale seems promising. Clin | Pain.
2009;25:607-16.
4. Stevens B, Yamada J, Ohlsson A, Haliburton S, Shorkey A. Sucrose for
analgesia in newborn infants undergoing painful procedures. Cochrane
Database Syst Rev. 2016;7:CD001069.
5. Bueno M, Yamada J, Harrison D, Khan S, Ohlsson A, Adams-Webber T, et
al. A systematic review and meta-analyses of nonsucrose sweet solutions
for pain relief in neonates. Pain Res Manag. 2013;18:153-61.
6. Shah PS, Herbozo C, Aliwalas LL, Shah VS. Breastfeeding or breast
milk for procedural pain in neonates. Cochrane Database Syst Rev.
2012;12:CD004950.
7. Johnston C, Campbell-Yeo M, Disher T, Benoit B, Fernandes A, Streiner D,
et al. Skin-to-skin care for procedural pain in neonates. Cochrane Database
Syst Rev. 2017;2:CD008435.
8. Weise KL, Nahata MC. EMLA for painful procedures in infants. J Pediatr
Health Care Off Publ Natl Assoc Pediatr Nurse Assoc Pract. 2005;19:42-7.
9. Hall RW. Kronsberg SS, Barton BA, Kaiser JR, Anand KJS, NEOPAIN Trial
Investigators Group. Morphine, hypotension, and adverse outcomes among
preterm neonates: who's to blame? Secondary results from the NEOPAIN
trial. Pediatrics. 2005;115:1351-9.
10. Koehntop DE, Rodman JH, Brundage DM, Hegland MG, Buckley II.
Pharmacokinetics of fentanyl in neonates. Anesth Analg. 1986;65:227-32.
11. Shekar K, Roberts JA, Mcdonald CI, Fisquet S, Barnett AG, Mullany DV, el
al. Sequestration of drugs in the circuit may lead to therapeutic failure during
extracorporeal membrane oxygenation. Crit Care. 2012;16:R194.
12. Kumar P, Denson SE, Mancuso T); Committee on Fetus and Newborn, Section
on Anesthesiology and Pain Medicine. Premedication for nonemergency
endotracheal intubation in the neonate. Pediatrics. 2010;125:608-15.
13. Hall RW, Shbarou RM. Drugs of choice for sedation and analgesia in the
neonatal ICU. Clin Perinatol. 2009;36:15-26.
14. Ancora G, Lago P, Garetti E, Merazzi D, Savant Levet P, Bellieni CV, et al.
Evidence-based clinical guidelines on analgesia and sedation in newborn
infants undergoing assisted ventilation and endotracheal intubation. Acta
Paediatr Oslo Nor 1992. 2019;108:208-17.
Section 12
 CHAPTER

54
Donor Human Milk

INTRODUCTION
Preterm neonates are vulnerable and have feeding issues due to
immature gut. They are more at risk of developing necrotizing
enterocolitis (NEC) and sepsis. Direct breastfeeding may not be
possible in such neonates. Expressed breast milk (EBM) from their
own mothers is provided to them. In case of absence of mother's
own milk (MOM), donor human milk is the second-best option for
a preterm neonate.

DONOR HUMAN MILK

Donar human milk (DHM) is the milk expressed and voluntarily

donated by lactating women other than the biological mother of
the recipient baby. This donor human milk is pasteurized using
the Holder pasteurization method (pasteurized donor human milk;
PDHM) and dispensed for use of the recipient.
Donation should be free and without any monetary benefit. The
recipient should also be provided the DHM free of cost.

Advantages
World Health Organization (WHO)' and National Neonatology
Forum (NNF)?, India recommends DHM as the preferred choice if
mother's own milk is not available for feeding of preterm or low-
birthweight (LBW) infants, including very preterm (<32 weeks'
gestation) or very LBW (<1.5 kg) infants. The acceptance of PDHM
among preterm neonates is increasing globally. DHM is species-
specific and contains various bioactive and immunomodulatory
factors that has a beneficial and protective effect.? However,
pasteurization affects the nutritive content of DHM. Hence, PDHM
does not provide nutritional and non-nutritional benefits equivalent
to mother's own milk. In addition, the nutritive content of DHM is
variable and may be affected by the duration of lactation.

543
 544 AIMS Protocols in Neonatology

Studies have shown the protective effect of DHM against NEC

(particularly severe NEC with ≥Bell's stage 2), late-onset sepsis,
BPD.' Systematic review with meta-analysis published in 2018
examined and compared the effect of human milk vs preterm
formula on NEC, late-onset sepsis, retinopathy of prematurity
(ROP), bronchopulmonary dysplasia (BPD) and neurodevelopment
among preterm neonates with gestation ≤28 weeks and/or birth
weight ≤1500 grams. The results showed clear protective effect of
human milk against NEC, and a possible reduction in LOS, severe
ROP and severe NEC." Another systematic review was conducted to
investigate the role of DHM in duration of hospital stay, and it was
seen that DHM and preterm infant formula had comparable duration
of hospital stay. The incidence of NEC was however reduced, further
validating the protective role of DHM among VLBW neonates."
Nevertheless, more studies need to be conducted to understand
the long-term and neurodevelopment outcomes among neonates,
also how the nutritive value of DHM is affected on pooling,
pasteurization and storage.
Comprehensive Lactation Management Centre (CLMC)
Many lactating mothers have surplus breastmilk left even after
feeding their own baby. In such cases, mothers can donate the
extra milk for other neonates who do not have access to their own
mother's milk due to various reasons.
In CLMC, lactation counseling and support is provided regarding
early initiation of breastfeeding, proper positioning, and attachment
of the baby to the breast, and also helps in resolving breastfeeding
issues like engorgement, cracked nipple, flat or inverted nipple.
CLMC also provides facilities for collection, screening, processing,
storage and dispensing of DHM to babies who do not have access
to their own mother's milk.
First human milk bank was opened in Vienna, Austria in 1909. In
India, Sneha, founded by Dr Armida Fernandez, was the first milk
bank started at SION, Mumbai in 1989.
In 2017, the Ministry of Health and Family Welfare, Government
of India issued 'National guidelines on lactation management
centres in public health facilities'?

Process of Screening the Donor Mothers and Consent

Who can donate milk: Donor mothers are healthy lactating mothers,
voluntarily willing to give their extra breastmilk for other babies,
• Section 12
without compromising the needs of their own baby.
 Donor Human Milk 545

Mothers of the babies who are admitted in NICU, attend OP'D or

immunization clinic, lactating staff working in the hospital, mothers
who have lost their babies or cannot give milk to their own babies
and lactating mothers motivated by community and other awareness
means can donatemilk. Mothers should be tested negative (within
6 months prior to donating milk) for HIV, VDRL, hepatitis B and
hepatitis C. If tests were done earlier, fresh blood tests will be
required to be done before the mother can be accepted as a donor.
For eligible mothers it is essential to obtain a written informed
consent before milk donation.
Milk Expression, Storage and Processing
Breastfeeding is when the baby is latched and fed directly from
the breast. But in preterm babies, direct breastfeeding may not
be possible. In such babies, mothers may express the milk either
manually or through breast pumps, and then feed their babies using
palade or katori and spoon.
Expression protocol: Mother should wash their hands properly
using soap and water. Breast should be wiped with a swab moist
with water. Place a clean container below the breast to collect the
milk. The breast should be massaged gently towards the nipple. The
mother should place the thumb and index finger opposite each other
outside the areola, and squeeze to express the milk. Breast pumps
may also be used for expression.
Storage and processing of DHM: The collected milk is first properly
labelled with mother's details and date of collection, and then stored
in -80 deep freezer. Pasteurization needs to be done within 3 months
of collection of milk. Batches are prepared, milk thawed and pooled
before pasteurization. Prepasteurization, culture testing is done
from each batch and counts should be <105 CFU / ml for total viable
organisms. Pasteurization is done using Holder method, i.e. milk
is gently heated at 62.5°C in a shaking water bath for 30 minutes.
It virtually eliminates HIV, HTLV, CMV and mycobacteria. Post-
pasteurization, again the microbiology culture testing from each
batch needs to be done and it should not show any growth. PDHM
is then stored in the freezer in clean, dry, and sterilized bottles that
are properly labeled.
A unit can have its own PDHM dispersal policy. PDHM should be
preferably dispersed to the preterm neonates of less than 32 weeks
or < 1500 g at least for a span of first 14 days of life, after taking Therapeutic Modalities

consent from the parents.

546 AlIMS Protocols in Neonatology

Comprehensive Lactation Managment Centre (CLMC):

Process and Activities (Fig. 54.1)
Milk collection
No growth
LMU 1 found in post-
Storage al Processing of milk pasteurization Storage al
-80°C deep • Thawing and pooling culture result -80°C
freezer (max • Pre-pasteurization deep freezer
LMU 2} of 3 months) microbiology testing (max of
• Pasteurization 6 months)
• Post-pasteurization
[MU 3 microbiology testing
Dispensing of milk
• Lactation management • Thawing as per
• Counseling of eligible mothers
• Screening of donor mothers Dispersing ont
• Consent
criteria and
parent(s) give
consent

Fig 54.1: Comprehensive lactation management centre

REFERENCES
1. WHO recommendations for care of the preterm or low birth weight infant.
Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.
2. Clinical Practice Guidelines. Feeding of low-birth weight neonates: National
Neonatology Forum, India 2020.
3. Bertino E, Giuliani F, Baricco M, Nicola PD, Peila C, Vassia C, Chiale F,
Pirra A, Cresi F, Martano C, Coscia A. Bene ts of donor milk in the feeding
fi
of preterm infants. Early human development 2013; 89 (2): 53-56.
4. Villamor-Martínez E, Pierro M, Cavallaro G, Mosca F, Kramer BW, Villamor
E. Donor Human Milk Protects against Bronchopulmonary Dysplasia: A
Systematic Review and Meta-Analysis. Nutrients 2018, 10, 238:2-16.
5. Miller J, Tonkin E, Damarell RA, McPhee Al, Suganuma M, Suganuma H,
Middleton PF, Makrides M, Collins CT. A Systematic Review and Meta-
Analysis of Human Milk Feeding and Morbidity in Very Low Birth Weight
Infants. Nutrients 2018, 10: 707. doi:10.3390/nu10060707.
6. Yang R, Chen D, Deng O, Xu X. The effect of donor human milk on the
length of hospital stay in very low birthweight infants: a systematic review
and meta-analysis. International Breastfeeding Journal 2020; 15, 89 https://
doi.org/10.1186/s13006-020-00332-6.
7. National guidelines on lactation management centres in public health
facilities 2017. National Health Mission, Child health division, Ministry of
Health and Family welfare, Government of India.
 55
Developmentally Supportive Care

The period of maximum cognitive development of an extremely

in an environment that is not conducive to optimal growth

and development. The constant exposure to the harmful and
overstimulating environment of the NICU leaves these infants fussy,
irritable, and exhausted.
Developmentally supportive care (DSC) is a systematic,
structured process that begins when an infant is brought into NICU
and continues until discharge and beyond that. Though guided
by a protocol, the DSC activities may not strictly conform to a set
routine. All members of the NICU family-healthcare providers,
parents, therapists, and support staff—must consciously provide a
structured healing environment to every infant that is customized
for her needs. Table 55.1 lists the standard terms used in DSC.
Developmentally supportive care has seven components'
(Fig. 55.1).

A. Safeguarding Sleep
Kangaroo mother care, containment, nesting, swaddling, non-
nutritive sucking, placing the infant in the lateral position, and
cluster care aid undisturbed sleep. Each infant deserves adequate
'quiet time' when no medical intervention or routine caregiving
activities are provided. Dimming the lights, reducing noise, and
appropriately handling the baby during feeding would help the
infant sleep without disturbances.

B. Partnering with Families

Partnering with families involves the family and the parents in
the decision-making and caregiving of the infants. The family
communicates its concerns and fears with the treatment team if

547
548 AIMS Protocols in Neonatology

Table 55.1: Definitions of terms used in DSC

• Containment: Holding and calming a baby during a painful procedure. One
hand of the caregiver is placed firmly yet gently on the head of the baby,
while the other hand can be placed on the lower back, buttocks, or soles.
• Swaddling: Wrapping the baby in a sheet around in such a way that the
infant feels safe, secure, and contained.
• Nesting/creating a boundary: Creating a nest-like oval boundary around
the infant using sheets.
• Healing environment: An environment that supports the infant's appropriate
growth and development while minimizing the pain and stress caused by
continuous exposure to unwanted and harsh stimuli during their NICU stay.
• Protected sleep: Modifying the environment and infant's cue-based care to
ensure undisturbed sleep.
• Family-centered care: Family works together closely, making informed
decisions regarding their infant's medical and developmental well-being.
• Activities of daily living: Caregiving activities that are important for the
infant's growth, development, hygiene, and general well-being, e.g. dressing
and undressing, diaper change, sponging, massage, skincare, and feeding.
• Non-nutritive sucking (NNS): Sucking opportunities provided to the infants
in the form of sucking their own fingers, the mother's fingers, a gauze lollipop
dipped in mother's milk or even mother's breast. NNS helps the infant to
self-regulate, stay calm and organize self during painful medical and other
stressful situations in the NICU.

Healing Optimizing
environment nutrition

Minimizing Positioning
stress and pain and handling

Protecting
Safeguarding
skin
sleep

Partnering
with families

Fig. 55.1: Seven core components of developmentally supportive carel.3

approached with respect and a non-judgmental attitude. This

empowers the family members to participate in the activities of
daily living actively.
 Developmentally Supportive Care 549
C. Minimizing Stress and Pain
Infants communicate their pain and stress through several cues
that caregivers can observe and measure. Care during the medical
intervention and activities of daily living should respect these cues
and adjust and modify the environment to reduce stress and pain
and facilitate self-regulatory mechanisms to promote the optimal
organization of the infant.

D. Healing Environment
Simple modi cations in the NICU enhance the quality of care and
fi
development of preterm and sick infants. These modifications are
listed below:

1. Spacing
• The distance between the bassinettes should be adequate to
allow caregiving and medical interventions without disturbing
the other infants.

2. Visual Stimulation
• Minimise light unless required for a procedure.
• Cover the incubator with a thick cloth to prevent daylight from
directly reaching the infant's eyes.
• Cover and shield the eyes of the infant during phototherapy.
• Limited visual stimulation, e.g. only a brief exposure of the
mother's face, is what the infant will tolerate. The mother's face
should be 20-25 cm from the infant's face.
• Avoid talking while encouraging eye contact.
• Ensure the infants do not arch and extend their heads upwards
to look at the overhead light.

3. Auditory Stimulation
• Sound intensity of up to 45 dB is considered safe for neonates.
• Healthcare providers and caregivers should talk softly near
the infant's bassinet or move slightly away while medical
intervention is being discussed.

• Mother's speaking or singing comforts the infant.

• Attend to telephone rings and alarms of the monitor quickly.

Reduce the volume of alarms/keep only visual alarms, if
appropriate.
550 AlIMS Protocols in Neonatolesy

• Refrain from speaking loudly from across the room.

• Do not drag chairs or close the incubator doors loudly.
• Avoid musical toys over the bassinettes.

4. Olfactory and Gustatory Sensation

• Avoid opening pungent-smelling alcoholic wipes, perfumes, or
oils near the infant.

5. Vestibular Sensation
• Gently roll the infant from one position to another during routine
postural change.
• Swaddle the baby during transfers and transportation.
• Providers should bend forward while lifting or placing the infant
on the mother's lap or bassinet.

6. Tactile Sensation
• Club medical interventions together with caregiving activities to
reduce the frequency of contact with the infant.
• Use gentle yet firm touch (not feathery or tickling) to calm the
infant.
• Do cleaning, sponging, massaging, dressing, and undressing or
removal of adhesives with care and caution.

7. Positioning a Preterm Infant in NICU

• The position of the neonate should be changed regularly.
• The prone position facilitates flexion and the development of
early head control. The baby is positioned with some pelvic
elevation so that the legs are weight-bearing through the anterior
knee and lower legs, and the hips are not flexed more than 90°.
• Supine position promotes the development of visual skills,
and appropriate and adequate support would allow the knees
and elbows to be supported off the cot surface to reduce hip
and shoulder abduction. Potential disadvantages include neck
extensor muscle tightness and arching.
• Side-lying/lateral position is the closest to the fetal position
maintained in the womb, with minimized hip abduction and
retraction of shoulders. Side-lying position encourages flexion
and symmetry. The hands can be placed near the mouth for
self-regulation.
 Developmentally Supportre Care. 551

E. Optimising Nutrition
Human milk is the ideal source of nutrition for a preterm neonate
but may not be able to meet their complex nutrition requirements
and hence the need of optimising feeding practices.
• While feeding with paladai or spoon infant must be awake and
not asleep.
• Swaddle the infant and support the 'head, neck, and trunk with
the caregiver's arm or body.
• Do not wake infants by pinching, tickling, pulling, or flicking
their ears or soles.
• Do not sing or talk to the infant while feeding.
F. Positioning and Handling
Activities of daily living should be carried out according to the
baby's readiness and not be protocol driven. During these activities,
care should be taken to position the preterm infant to ensure that it
supports symmetric development.
Sponging
• Lukewarm water should be used for sponging the infant. Check
the temperature of the water before sponging.
• Start from the head and sponge down to the legs (clean to
unclean).
• Stop sponging and calm the newborn if stress signs are seen.
• Do not leave the infant in the middle of sponging to get cloth for
drying, clean diapers, and clothes.
Massaging
• Apply oil for very preterm and extremely low birth weight
infants.
• In supine, prone and side-lying positions, start massaging from the
head and move to the face, the chest, the abdomen, and the limbs.
• Fingers should be placed flat on the infant's body, and the
massage should be done with moderate pressure using long,
firm, yet gentle strokes.
• Gentle extending and flexing of limbs can be done during the
massage.
Diaper Change
• Make sure clean diapers and wet cotton swabs are ready and
near the infant.
 552 AlIMS Protocols in Neonatology

• Open the dirty nappy and pick up both the legs of the infant,
flexing them towards the abdomen, clean from front to back in
gentle strokes.
• Make sure all the folds are cleaned and dried thoroughly. The
touch should be firm and gentle. Stretch the infant's lower limbs
one at a time and beyond their flexibility.
Changing Clothes
Some important points to remember during changing clothes:
• Gently change clothes taking care of wires and tubes attached
to the infant.
• Cover the head and hands of preterm and extremely low birth
weight infants with caps and mittens.
Transfers and Transportation
• Care should be taken when transporting premature, sick, and
fragile infants to prevent exposure to sudden movements or
change in position and temperature.
G. Profecting Skin
• Avoid using lotions and soap.
• Protect the skin surface during the removal or application of
adhesive products.
• Care is to be taken to avoid pressure and device-related sores.

REFERENCES
1. Altimier L, Phillips R. The Neonatal Integrative Developmental Care
Model: Advanced Clinical Applications of the Seven Core Measures for
Neuroprotective Family-centered Developmental Care. Newborn and Infant
Nursing Reviews. 2016;16:230-44.
2. Lubbe W, Van der Walt CS, Klopper HC. Integrative literature review de ning
fi
evidence-based neurodevelopmental supportive care of the preterm infant.
| Perinat Neonatal Nurs. 2012;26:251-9.
3. Bruton C, Meckley I, Nelson L. NICU Nurses and Families Partnering to
Provide Neuroprotective, Family-Centered, Developmental Care. Neonatal
Netw. 2018 Nov;37(6):351-7. doi: 10.1891/0730-0832.37.6.351. PMID:
30567884.

Section 12
 Annexures

1. Drug Dosages
2. Medication Use in G6PD De ciency
fi
3. Drug Dose Modi cation in Acute Kidney Injury
fi
4. Immunization Schedule
 Drug Dosages

1. Adrenaline
Resuscitation, and bradycardia:
• Intravenous/Intraosseous: 0.01-0.03 mg/kg with 0.1 mg/ml
solution.
• Endotracheal: 0.05-0.1 mg/kg via endotracheal tube with
0.1 mg/ml solution.
• Continuous IV infusion: 0.1-1 pg/kg/min.
Septic shock, and fluid refractory shock: 0.05-0.3 pg/kg/minute.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Ampicillin, aminophylline, and
sodium bicarbonate.
2. Amikacin
Dose: IV infusion in syringe pump over 30-60 minutes.
• Dose interval
PMA: 29 weeks or lesser
- 0-7 days: 14 mg/kg/dose every 48 hours
- 8-28 days: 12 mg/kg/dose every 36 hours
- 29 days or older: 12 mg/kg/dose every 24 hours
PMA: 30-34 weeks
- 12 mg/kg/dose every 36 hours for 0-7 postnatal days.
- 12 mg/kg/dose every 24 hours for 8 postnatal days.
PMA: ≥35 weeks
- 12 mg/kg/dose every 24 hours for all postnatal days.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Ampicillin, amphotericin B, heparin
(>1 unit/L), azithromycin, imipenem/ cilastatin, oxacillin, and
phenytoin.
555
556 AlIMS Protocols in Neonatology

3. Aminophylline
Dose, and administration:
• Loading: 8 mg/kg over 30-60 min IV or can be given orally.

• Minous minan kids ally art no plin dose.

• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• but, crimp bia cop, led pencil amine, adrenaline,
4. Ampicillin
Dose: Slow IV push or IM
• Dose interval
PMA <29 weeks
- 0-28 days: 25-50 mg/kg/dose every 12 hours.
- 29 days or more: 25-50 mg/kg/ dose every 8 hours.
PMA: 30-36 weeks
- 0-14 days: 25-50 mg/kg/ dose every 12 hours.
- 15 days or older: 25-50 mg/kg/dose every 8 hours.
PMA: 37-44 weeks
- 0-7 days: 25-50 mg/kg/dose every 12 hours.
- 8 days or more: 25-50 mg/kg/ dose every 8 hours.
PMA: ≥45 weeks
- 25-50 mg/kg/dose every 6 hours.
• Solution compatibility: 5% dextrose, normal saline, and sterile
water.
• Solution incompatibility: Amikacin, dopamine, adrenaline,
gentamicin, midazolam, sodium carbonate, and tobramicin.

5. Amphotericin B
Dose: 1-1.5 mg/kg every 24 hours IV infusion over 2-6 hours.
• Solution compatibility: 5% dextrose, and 10% dextrose.
• Solution incompatibility: Normal saline, Lipid emulsion,
amikacin, calcium gluconate, ciprofloxacin, dopamine,
fluconazole, gentamicin, meropenem, penicillin G, piperacillin-
tazobactam, and tobramycin.

6. Liposomal Amphotericin B
Dose: 2.5-7 mg/kg per dose every 24 hours iv infusion by syringe
pump over 2 hours.

T.ME/NEONATOLOGY
 T.ME/NEONATOLOGY

Daug Dosages 557

• Solution compatibility: 5%, 10%, and 20% dextrose.
• Solution incompatibility: Amino acid, and normal saline.

7. Acyclovir
Dose: IV infusions by syringe pump over 1 hour.
• Dose interval
PMA: <30 weeks; 20 mg/kg/dose every 12 hours.
PMA: 30 weeks; 20 mg/kg/dose every 8 hours.
• Duration:
- Localized HSV infection: 14 days.
- Disseminated HSV infection OR CNS disease: 21 days.
(Continue IV therapy for seven more days if repeat DNA PCR
done between 19-21 days after treatment is positive).
• Solution compatibility: 5% dextrose, and normal saline
• Solution incompatibility: Amino acid, fat emulsion, caffeine
citrate, dobutamine, dopamine.
• Monitoring: RFT at baseline, and at least once weekly in patients
with renal dysfunction on prolonged therapy.

8. Caffeine Citrate
Dose: Loading of 20-25 mg/kg of caffeine citrate IV (over 30 min)
or oral.
• Maintenance: 5-10 mg/kg of caffeine (slow IV or oral), to be
started 24 hours after loading dose.
• Mechanism of action: CNS stimulant (stimulates central
inspiratory drive).
• Solution compatibility: 5% dextrose.
• Solution incompatibility: Furosemide, acyclovir, lorazepam,
oxacillin, and ibuprofen.

9. Cefoperazone Sulbactam
Dose: 30-40 mg/kg/dose of cefoperazone (not combined
cefoperazone-sulbactam). Infuse over 30-60 minutes every 8 hours.
• Solution compatibility: Normal saline, 5% dextrose, and 10%
dextrose.

10. Cefotaxime
Dose: IM injection, IV push, or Intermittent IV infusion over
10-30 minutes.
558 AlIMS Protocols in Neonatology

• Sepsis:
PNA: Less than 7 days: 50mg/kg/dose IV every 12 hours.
PMA: < 32 weeks.
- 7 days or older: 50 mg/kg/dose IV every 8 hours.
PMA: ≥32 weeks.
- 7 days or older: 50 mg/kg/dose IV every 6 hours.
• Meningitis:
PNA: 7 days: 100-150 mg/kg/day IV every 8-12 hours, 8 days:
150-200 mg/kg/day IV every 6-8 hours.
• Disseminated gonococcal infection: 25 mg/kg/ dose IV or IM
every 12 hours for 7 days, for meningitis 10-14 days.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Sodium bicarbonate, vancomycin,
fluconazole, and azithromycin.
11. Ceftazidime
Dose: IV infusion over 30 min.
PMA: 29 weeks or lesser
- 0-28 days: 30 mg/kg/ dose every 12 hours.
- 29 days or older: 30 mg/kg/dose every 8 hours.
PMA: 30-36 weeks
- 0-14 days: 30 mg/kg/dose every 12 hours.
- 15 days or older: 30 mg/kg/dose every 8 hours.
PMA: 37-44 weeks
- 0-7 days: 30 mg/kg/ dose every 12 hours.
- 8 days or older: 30 mg/kg/dose every 8 hours.
PMA: 45 weeks or greater
- 30 mg/kg/dose every 8 hours.
• Meningitis:
0-7 days: 100-150 mg/kg/day IV every 8-12 hours.
8-28 days: 150 mg/kg/day IV every 8 hours.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Erythromycin, phenytoin, midazolam,
fluconazole, and Vancomycin.
12. Ceftriaxone
Dose: IV infusion over 60 minutes
 Drug Dosages 559

Sepsis: 50 mg/kg every 24 hours; meningitis: 100 tng/kg

loading dose followed by 80mg/kgevery 24 hours.
Gonococcal infection prophylaxis, and Uncomplicated
Gonococcal Ophthalmia: 25-50 mg/kg/dose as a single dose
Disseminated Gonococcal infection: 25-50mg/kg/dose IV/
IM single dose for seven days, for meningitis 10-14 days
• Contraindications: Premature infants, Neonatal Hyper-
bilirubinemia (Increased risk of Kernicterus), along with calcium-
containing solution.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Aminophylline, calcium chloride,
calcium gluconate, azithromycin, fluconazole, and vancomycin.

13. Cipro oxacin

fl
Dose: IV infusion over 30-60 minutes
PMA:
- 32-37 weeks:10 mg/kg/ dose every 12 hours.
- 38 weeks or more: 15 mg/kg/dose every 12 hours.
• Solution compatibility: 5% dextrose.
• Solution incompatibility: Antacids, and divalent salts.

14. Calcium Gluconate

Dose
- Acute symptomatic hypocalcemia: 100-200 mg/kg/dose
10% calcium gluconate to be diluted and infused IV over
10-30 minutes.
- Maintenance dose: 200-800 mg/kg/day for 3-5 days.
Oral and IV to be given in the same dose (2-8 ml/kg/day,
equivalent to 20-80 mg/kg elemental calcium).
• Solution compatibility: Normal saline, 5% dextrose, and 10%
dextrose.
• Solution incompatibility: Amphotericin B, ceftriaxone,
fluconazole, indomethacin, meropenem, metoclopramide, sodium
bicarbonate, lipid emulsions, phosphate, and magnesium salts.

15. Cloxacillin
Dose: 25-30 mg/kg/dose IV or orally every 6-8 hours.
• Solution compatibility: 5% dextrose and normal saline.
• Annexure 1
560 AlIMS Protocols in Neonatology

• Solution incompatibility: Aminoglycosides, letracycline, and

erythromycin.

16. Colistin
Dose as per renal function:
GFR (ml/min/ 1.73 m%) Amount (Colistin-based activity)
280 ml/min 5 mg/kg/day in 2-3 divided doses
50-79 ml/min 2.5-3.8 mg/kg 12 hourly
30-49 ml/min 2.5mg/kg/q24 hourly/1.25mg/kg 12 hourly

10-29 ml/min 1.5 mg/kg q 36 hourly

Hemodialysis 1.5 mg/kg 24-48 hourly
Continuous renal replacement 2.5 mg/kg 12-24 hourly
therapy
1 mg of colistin base activity = 30,000 I colistin

• Solution compatibility: 5% dextrose, 10% dextrose, 0.9% normal

saline, and ringer lactate
• Solution incompatibility: Incompatible with erythromycin and
hydrocortisone sodium succinate.

17. Dexamethasone
Dose
- For extubation and airway edema: 0.25-0.5 mg/kg/dose;
may repeat eight hourly, max of 4 doses IV.
- For prevention of BPD: 0.15 mg/kg per day for three days,
0.10 mg/kg per day for three days, 0.05 mg/kg per day for
two days, and 0.02 mg/kg per day for two days; a total of 0.89
mg/kg over 10 days (DART regimen)
- Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Midazolam, glycopyrrolate, and
Vancomycin.
• Monitoring: Blood sugar, Blood pressure, and intraocular
pressure.
18. Digoxin
Dose: Loading dose given for treating arrhythmias and acute
congestive heart failure IV slowly over 15-30 min, administered as
three divided doses eight hourly. It is not to be administered as an
IM injection.
 Drug Dosages 501
• Loading dose
PMA 29 weeks: IV-15 pg/kg: oral-20pg/kg.
PMA 30-36 wceks: IV-20 pg/kg; oral-25 pg/kg
PMA 37-48 weeks: IV-30 pg/kg; oral-40 pg/kg
- PMA 49 weeks: IV-40 pg/kg; oral-50 pg/kg
• Maintenance dose
- PMA 29 weeks: IV-4 pg/kg; oral-5 pg/kg every 24 hours.
- PMA 30-36 weeks: IV-5 pg/kg; oral-6 pg/kg every 24 hours.
- PMA 37-48 weeks: IV-4 pg/kg: oral-5 pg/kg every 12 hours.
- PMA 49 weeks: IV-5 pg/kg; oral-6 pg/kg every 12 hours.
• Solution compatibility: 5% dextrose, 10% dextrose, normal
saline, and sterile water.
• Solution incompatibility: Dobutamine, furosemide, meropenem,
midazolam, milrinone, and propranolol.
19. Dopamine
Dose: 2-20 pg/kg/minute as continuous infusion. Start at less than
10 pg/kg/minute for fluid refractory shock. Use a large vein for IV.
• Solution compatibility: 5% dextrose, 10% dextrose, normal
saline, and ringer lactate.
• Solution incompatibility: Ampicillin, furosemide, indomethacin,
penicillin G, insulin, and sodium bicarbonate.

20. Dobutamine
Dose: 2-25 pg/kg/minute as a continuous infusion.
• Solution compatibility: 5% dextrose, 10% dextrose, normal
saline, and ringer lactate.
• Solution incompatibility: Aminophylline, cefepime, digoxin,
ibuprofen, indomethacin, phenytoin, piperacillin-tazobactam,
and sodium bicarbonate.
21. Domperidone
Dose: 0.2-0.4 mg/kg per dose, 8 hourly orally
22. Furosemide
Dose: 1 mg/kg/dose IV, IM, or can be given orally. Maximum of
2mg/kg/dose IV or 6 mg/kg/dose orally.
• Dose interval: Preterm infants-24 hourly. Term infants-12 hourly.
Term infant older than one month 6-8 hourly. Consider alternate-
day therapy for long-term use.
• Contraindications: Anuria and hypersensitivity to furosemide.
562 AIMS Protoco's in Neonatology

• Monitoring: Serum, and urine electrolytes, RFT periodically

during therapy.
• Solution compatibility: 5% dextrose, 10% dextrose, normal
saline, and sterile water.
• Solution incompatibility: Ciprofloxacin, dopamine, dobutamine,
erythromycin, gentamycin, midazolam, and netilmicin.
23. Fluconazole
Dose: Invasive candidiasis 12-25 mg/kg as a loading dose, then

seal: Thrus om/gen day, hens my/s per dost every

24 hours orally. Prophylaxis 3-6 mg/kg per dose via IV infusion
twice weekly or orally for 6 weeks (considered in VLBW infants at
high risk of fungal disease).
• Dosing interval for invasive candidiasis:
PMA: 29 weeks or lesser
- 0-14 days: every 48 hours
- 15 days or older: every 24 hours
PMA: 30 weeks or older
- 0-7 days: every 48 hours
- 8 days or older: every 24 hours
• Solution compatibility: 5% dextrose, 10% dextrose.
• Solution incompatibility: Amphotericin B, ampicillin, calcium
gluconate, cefotaxime, ceftazidime, ceftriaxone, chloramphenicol,
piperacillin, clindamycin, digoxin, erythromycin, furosemide,
and imipenem.
24. Fentanyl
Dose:
- Sedation - 0.5-4 pg/kg per dose IV slow push. Infusion rate-
1-5pg/kg/hour.
- Analgesia - 0.5-3 pg/kg per dose IV slow push. Infusion rat-
0.5-2 pg/kg/hour.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Drug incompatibility: Azithromycin, phenobarbitone, and
phenytoin.
25. Fosphenytoin
Dose:
- Loading dose: 15-20 mg PE/kg IM or IV over at least 10 min
(IV route is preferred).
 Ory Prosages 613

Maintenance dose 4-8 mg PI. /kgevery 24 hours, PE- Phenyton:

equivalents.
Fosphenytoin 1 mg P'F= phenytoin 1 my
• Monitoring: ECG, blood pressure, and respiratory function
during infusion and 10-20 min after infusion.
• Solution compatibility: Normal saline, 5% dextrose, and 10%
dextrose.
• Solution incompatibility: Midazolam.
26. Gentamicin
Dosage and route of administration: Slow IV infusion over 30
minutes
• Prolonged serum half-life in neonates undergoing hypothermia
for HIE.
PMA: 29 wecks or lesser
- 0-7 days: 5 mg/kg/dose every 48 hours.
- 8-28 days: 4 mg/kg/dose every 36 hours.
29 days or older: 4 mg/kg/dose every 24 hours.
PMA: 30-34 weeks
- 0-7 days: 4.5 mg/kg/dose every 36 hours.
- Eight days or older: 4 mg/kg/dose every 24 hours.
PMA: 35 weeks or older
- 4 mg/kg/dose every 24 hours.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Ampicillin, furosemide, heparin, and
indomethacin.
27. Ganciclovir
Dose: 6 mg/kg per dose every 12 hours IV infusion over 1 hour.
Treatment for a minimum of 6 weeks if possible.

Meripy, neckly ater that i sabe during the first there wecks of
• Solution compatibility: 5% dextrose, normal saline, and Ringer's
lactate.
• Incompatibility: Lipid emulsions, aztreonam, cefepime, and
piperacillin/ tazobactam.

28. Hydrocortisone
Dose:
- Hypoglycemia: 10 mg/kg/day IV or PO in 2 divided doses.
Taper after a few days once the blood glucose levels stabilize.
564 AIMS Protocols in Neonatology

- Physiologic replacement: 7-9 mg/m? per day IV or orally

every 8-12 hours.
- Shock:
Day Dose (mg/kg) Interval (hes)
Day 1 8 hours x3 doses'
Day 2 12 hours x2 doses
0.5 12 hours x2 doses
Day 3 0.25
Day 4 24 hours xl dose
0.125
*The BP response is evident as early as 2 hours alter hydrocortisone treatment. If efficacy is
noted, the dose can be repeated every 8 hours for 2-3 days. Slow dosage weaning after that

• Chorioamnionitis-exposed ELBW infants to decrease the risk

of CLD: 0.5 mg/kg/dose IV every 12 hours for 12 days, followed
by 0.25 mg/kg IV every 12 hours for 3 days.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Midazolam, phenobarbitone, and
phenytoin.
29. Intravenous Immunoglobulin
Dose:
- Usual Dosage: 500-1000 mg/kg per dose over 2-6 hours; may
repeat in 12 hours if necessary.
- For neonatal alloimmune thrombocytopenia: 1g/kg/ dose IV
every day for two doses.
- Most studies have used a single dose, although additional
doses have been given at 24-hour intervals.
• The rate of administration varies by product
30. Ibruprofen
Dose: 1st dose 10 mg/kg, 2nd dose, and 3rd dose is 5 mg/kg 24 hourly.
• Contraindications: In patients who have experienced asthma,
urticaria, and allergic-type reactions after aspirin or other NSAIDs.
• Solution compatibility: Normal saline, and 5% dextrose.
• Solution incompatibility: Caffeine citrate, and dobutamine
31. Indomethacin
Dose: 3 doses per course maximum 2 courses. 12-24 hourly intervals.
- Age <48 hours: 0.2 mg/kg on day 1; 0.1 mg/kg on day 2, and
day 3.
 Drug Dosages 565
Age 2-7 days: 0.2 mg/kg once a day for 3 days.
Age 8 days or more: 0.2 mg/kg on day 1, 0.25 mg/kg on days
2 and 3.
• Contraindications: Active bleeding, significant thrombocytopenia
or coagulation defects, NEC, impaired renal function.
• Monitoring: Urine output, serum electrolytes, glucose, and
platelet count.
• Solution compatibility: 5% dextrose, and normal saline.
• Solution incompatibility: Calcium gluconate, dobutamine,
dopamine, and gentamicin.
32. Insulin
Dose: 0.1-0.2 unit/kg subcutaneously every 6-12 hours.
• Continuous infusion: 0.01-0.1 unit/kg/hour.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Aminophylline, dopamine,
phenobarbitone, and phenytoin.
33. Lorazepam
Dose: 0.05-0.1 mg/kg per dose IV slow push. Avoid intra-arterial
administration and Perivascular extravasation.
• Solution compatibility: Normal saline, 5% dextrose, and sterile
water.
• Solution incompatibility: Lipid emulsion, caffeine, micafungin,
nafcillin, and imipenem.

34. Levetiracetam
Dose: Loading 20-150 mg/kg/day IV every 24 hours, maintenance
dose: 41.7-65 mg/kg/day IV every 12 hours.
• Solution compatibility: 5% dextrose, 10% dextrose, normal
saline, Ringer lactate.

35. Metronidazole
Dose
- Loading dose: 15 mg/kg/dose orally or IV infusion over 30
to 60 minutes.
- Maintenance dose: Orally or IV infusions over 30-60 minutes.
• PMA: 24-25 weeks - 7.5 mg/kg/dose every 24 hours.
a PMA: 26-27 weeks - 10 mg/kg/dose every 24 hours.
• PMA: 28-33 weeks - 7.5 mg/kg/dose every 12 hours.
566 AlIMS Protocols in Neonatology

• PMA: 34-40 weeks - 7.5 mg/kg/dose every 8 hours.

• PMA>40 weeks - 7.5 mg/kg/dose every 6 hours.
• Solution compatibility: 5% dextrose, and normal saline.
• Solution incompatibility: Aztreonam, and meropenem.

36. Midazolam
Dose: 0.05-0.15 mg/kg over 5 min every 2-4 hours IV. Decreased
dose requirement with concurrent use of narcotics. Can be used
intranasally, sublingual, and orally.
• Continuous infusion: 10-60 pg/kg/hour.
• Anticonvulsant:
• Loading dose: 0.15 mg/kg IV followed by maintenance dose.
• Maintenance infusion: 0.06-0.4 mg/kg/hour (1-7 pg/kg/min).
• Solution compatibility: 5% dextrose, sterile water, and normal
saline.
• Solution incompatibility: Ceftazidime, dexamethasone,
furosemide, hydrocortisone, and sodium bicarbonate.

37. Morphine
Dose: 0.05-0.2 mg/kg per dose IV, IM or subcutaneous over
5 min repeat every 4 hours.
• Continuous infusion: Loading dose 0.1 mg/kg over 1 hour
followed by 0.01-0.02 mg/kg/hour. Dose reduction required in
neonates undergoing Therapeutic hypothermia for HIE.
• Neonatal abstinence syndrome: 0.03-0.1 mg/kg per dose orally
every 3-4 hours. Maximum dose 0.2 mg/kg. Wean dose by
10-20% every 2-3 days based on abstinence scoring.

•Contri dialia, sused Grosion in cine paralie

ileus.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Phenytoin, azithromycin, and
cefepime.

38. Meropenem
Dose:
- Sepsis: 20 mg/kg/dose IV infusion over 30 minutes.
PMA: Less than 32 weeks; 0-14 days: every 12 hours, and
15 days or older: every 8 hours.
 Dnig Dosages 567

PMA: 32 wecks; 0-7 days: every 12 hours, and 8 days: 30 mg/

kg, IV every 8 hours.
Meningitis, and infections caused by Pseudomonas species
40 mg/kg per dose.
I'MA: <32 arcks; 0-14 days: every 12 hours 15 days: every S hours.
PMA: 32 weeks- every 8 hours.
• Solution compatibility:5% dextrose, 10% dextrose, and normal saline.
• Solution incompatibility: Acyclovir, amphotericin-B, calcium
gluconate, metronidazole, and zidovudine.
39. Magneslum Sulfate
Dose:
• Resuscitation (pulseless torsades) 25-50 mg/kg IV/rapid
intraosseous infusion.

magnesenic S) insing N minutes

• Antidote: Calcium chloride.
• Solution compatibility: 5% dextrose, sterile water, and normal
saline.
• Solution incompatibility: Pat emulsion, amiodarone,
amphotericin B, cefepime, and sodium bicarbonate.
40. Milrinone

infusion: 0.3-0.75pg/kg/minute.
• Premature infants less than 30 weeks GA: Loading dose:
1.35 pg/kg intravenous over 3 hours, immediately followed by
maintenance infusion 0.2 pg/kg/minute.
• Solution compatibility: 5% dextrose, 10% dextrose, normal
saline, ringer lactate.
• Solution incompatibility: Furosemide, imipenam, cilastin, and
procainamide.
41. Noradrenaline
Dose: Septic shock 0.2-0.5 pg/kg/minute of nor-adrenaline base

• Solution compatibility: 5% dextrose, 10% dextrose, normal

saline, and half normal saline.
• Solution incompatibility: Aminophylline, phenobarbitone,
phenyloin, and sodium bicarbonate.
568 AlIMS Protocols in Neonatolosy

42. Naloxone
Dose: 0.1 mg/kg IV push, the amount needed to reverse narcotic-
induced depression may be as low as 0.01 mg/kg.
• Monitoring: Respiratory effort, and neurologic status. Monitor
24 hours for relapse.

• Solution compbibig easin and side and nialine

43. Netilmycin
Dose: IV infusion over 30 minutes
PMA <29 weeks
- 0-7 days: 5mg/kg/ dose every 48 hours
- 8-28 days: 4 mg/kg/dose every 36 hours
- 29 days or older: 4 mg/kg/dose every 24 hours
PMA 30-34 weeks
- 0-7 days: 4.5 mg/kg/dose every 36 hours
- 8 days or more: 4 mg/kg/ dose every 24 hours
PMA ≥35 weeks
- 4 mg/kg/ dose every 24 hours
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Ampicillin, furosemide, heparin, and
penicillin G.
44. Paracetamol (Acetaminophen)
Dose:
- For PDA: 15 mg/kg/ dose 6 hourly for 12 doses
- For pain, and fever:
Oral loading dose 20-25 mg/kg followed by maintenance
12-15 mg/kg per dose.
Maintenance intervals: Term infants- every 6 hours, preterm
infants greater than or equal to 32 weeks PMA- every 8 hours,
and preterm infants less than 32 weeks PMA- every 12 hours.
• Solution compatibility: 5% dextrose, Normal saline.
• Solution incompatibility: Diazepam.

45. Phenobarbitone
Dose:
- Loading dose of 20 mg/kg IV slowly over 10-15 minutes.
 Refractory seizures: Additional 10 mg,/kg, / dose, up to a total
of 40 mg/kg.
Maintenance dose: 3-5 mg/kg/day beginning, 12-24 hours
after the loading dose q 24 hours.
VIBW, preterm neonates: Lower loading doses of less than 15
mg/kg IV Followed by a single injection of less than 3 mg/
kg/day 24 hours later.
• Contraindications: Patients with manifest or latent porphyria,
marked liver function impairment, or respiratory depression.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Lipid emulsion, hydrocortisone,
insulin, and Vancomycin.

46. Phenytoin
Dose:
- Loading: 15-20 mg/kg IV infusion over at least 30 minutes.
Maintenance: 4-8 mg/kg every 24 hours IV slow push or
orally.
• Monitoring: ECG, blood pressure, and respiratory function
during infusion, and 15 minutes to 1 hour after infusion.
• Solution compatibility: Normal saline only.
• Solution incompatibility: 5% dextrose, 10% dextrose, amino acid
solutions, amikacin, ceftazidime, dobutamine, heparin, insulin,
morphine, dobutamine, sodium bicarbonate, hydrocortisone,
and sodium bicarbonate.

47. Piperacillin Tazobactum

Dose: 50-100 mg/kg/dose of piperacillin IV infusion over
30 minutes.
PMA <29 weeks
0-28 days: every 12 hours
- 29 days or more: every 8 hours
PMA: 30-36 weeks
- 0-14 days: every 12 hours
15 days or older: every 8 hours
PMA: 37-44 weeks
0-7 days: every 12 hours
8 days or more: every 8 hours
P.MA ≥45 works every 8 hours
570 AIMS Protocols in Neonatology

• Solution compatibility: 5% dextrose, 10% dextrose, and normal

saline.
• Solution incompatibility: Amikacin, dobutamine, gentamicin,

neim in ontomicin, tobramycin, azithromycin, amphotericn

48. Prostaglandin E1
Dose:
- Initial: 0.05-0.1 pg/kg/min by continuous IV infusions,
titrate to infants response.
- Maintenance: may be as low as 0.01 pg/kg/min.
- The initial dose depends on duct size. If PDA is significant,
therapy can be started at a low dose of 0.01 pg/kg/min. If the
duct is restrictive, the initial dose can be started at 0.05 pg/
kg/min.
• Solution compatibility: 5% dextrose, and normal saline.
• Solution incompatibility: Aminophylline, ampicillin, caffeine
citrate, calcium chloride, cefotaxime, dopamine, dobutamine,
furosemide, gentamicin, metronidazole, penicillin G, tobramycin,
and vancomycin.
49. Sildenafil
Dose:
- Loading: 0.4 mg/kg IV infusion over 3 hours.
- Maintenance: 1.6mg/kg every 24 hours (0.067mg/kg/hour).
- Oral: 0.5-1mg/kg/dose orally three times daily.
• Monitoring: Blood pressure, and oxygenation.
• Solution compatibility: Dextrose, and sterile water.
50. Vancomycin
Dose: 10-15 mg/kg/dose every 6-18 hours IV infusion over
30 minutes. Meningitis: 15mg/kg/dose, bacteremia: 10mg/kg/dose.
PMA ≤29 weeks PMA
- 0-14 days: every 18 hours
- 15 days or older: every 12 hours
PMA: 30-36 weeks
- 0-14 days: every 12 hours
- 15 days or older: every 8 hours
PMA: 37-44 weeks
- 0-7 days: every 12 hours
- 8 days or more: every 8 hours
 PMA 245 ae%s
every o hours
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline
• Solution incompatibility: Cefepime, cefotaxime, ceftriaxone,
ceftazidime, dexamethasone, heparin, phenobarbitone,
pipcracillin-lazobactam, and ticarcillin.
51. Vitamin K
Dose: At birth: < 1.5 kg-0.5 mg IM, > 1.5 kg 1 mg IM
b. Hemorrhagic discase: 1-10 mg slow IV push
• Monitoring: Check prothrombin time when treating clotting
abnormalities.
• Solution compatibility: 5% destrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Dobutamine, and phenytoin.
52. Vecuronium
Dose: 0.1 mg/kg (0.03-0.15 mg/kg) 1V push. The usual dosing
interval is 1-2 hours.
• Solution compatibility: 5% dextrose, Kinger lactate, and normal
saline.
• Solution incompatibility: Diazepam, furosemide, ibuprofen,
and micafungin.

53. Albumin
Dose:
Hypotension, and septic shock: 0.5 g/kg of 5% albumin IV
over 30 min. may repeat up to a maximum of 3 doses.
• Contraindications: Severe anemia or cardiac failure with normal
or increased intravascular volume.
• Solution compatibility: 5% dextrose, 10% dextrose, and dextrose
normal saline.
• Solution incompatibility: Amino acid mixtures, protein
hydrolysates, alcohol-containing solutions.

54. Heparin
Dose:
- Maintaining patency of central, and peripheral vascular
catheters: 0.5 units/kg/hour
572 AlIMS Protocols in Neonatology

- Thrombosis: Loading dose: 75 units/kg IV over 10 min (Avoid

IM injection as there is a risk of hematoma formation)
- Continuous infusion: 28 units/kg/hour
• Contraindications: Intracranial or GI bleed, thrombocytopenia.
• Specific monitoring: aPTT measured 4 hours after initiating
therapy, and the dose adjusted to achieve a PTT of 60-85 sec.
• Solution compatibility: 5% dextrose, 10% dextrose, and normal
saline.
• Solution incompatibility: Amikacin, amiodarone, phenytoin,
diazepam, Vancomycin.

55 Nevirapine
Dose: Perinatal HIV transmission:
- For prophylaxis - 3 doses; the first dose within 48 hours
of birth, the second dose 48 hours after the first dose, and
the third dose 96 hours after the second dose. It must be
administered with Zidovudine.
- Birth weight: 1.5-2 kg - 8 mg/dose, > 2 kg - 12 mg/dose
HIV treatment:
- PMA: 34-37 weeks
• 0-7 days - 4 mg/kg/ dose orally twice daily.
• Older than 7 days - 6 mg/kg/dose orally twice daily.
• Older than 4 weeks - 200 mg/m? orally twice daily.
- PMA: 38 weeks or greater
• Younger than one month - 6 mg/kg/ dose orally twice daily.
• Older than four weeks - 200 mg/m? orally twice daily.
• Contraindication: Moderate-to-severe hepatic impairment.

56. Potassium Chloride

Dose: IV infusion over 1 hour or orally. Maximum concentration
for peripheral infusion 60-80 mEq/L.
• Contraindications: Renal failure.
• Adverse effects: GI irritation-diarrhea, vomiting, and bleeding.
• Specific monitoring: Continuous ECG monitoring during
infusion.
• Solution incompatibility: Amphotericin B, diazepam, and
Phenytoin.
 ANNEXURE

2
Medication Use in
GoPD Deficiency

AVOID
1. Anti-malarial, e.g. primaquine, pamaquine, lafenoquine.
2. Anti-bacterials, c.g. fluroquinolones, nitrofurantoin, nalidixic
acid, dapsone, mafenide cream.
3. Analgesics, e.g. phenacetin, acetanilid, phenazopyridine
(pyridium).
4. Sulfonylureas, e.g. chlorpropamide, glipizide, glyburide,
glibenclamide.
5. Miscellaneous, e.g. flutamide (eulexin), methylene blue, rasburicase.
6. Chemical exposures: Fava beans, henna compounds, naphthalene,
phenylhydrazine, RUSH (isobutyl nitrite).
SAFE'

1. Anti-malarial, e.g. quinine, chloroquine and hydroxychloroquine.

2. Anti-bacterials, e.g. chloramphenicol, streptomycin, sulfa-
containing drugs (sulfacetamide, sulfadiazine, sulfamethoxazole,
trimethoprim-sulfamethoxazole, sulfanilamide, sulfisoxazole),
pyrimethamine, trimethoprim.
3. Antifungals, e.g. clotrimazole.
4. Analgesics, e.g. acetaminophen, aspirin (acetylsalicylic acid).
5. Miscellaneous, e.g. antazoline (antihistamine), ascorbic acid
(vitamin C), colchicine,diphenhydramine (Benadryl), isoniazid,
levodopa (L-dopa), para-aminosalicylic acid, para-aminobenzoic
acid (PABA),phenylbutazone, phenytoin, probenecid,
procainamide, vitamin K.

REFERENCE
Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Popliski H, Shimonov I,
Beig S, Berkovitch M. Medications and glucose-6-phosphate dehydrogenase
de ciency: an evidence-based review. Drug Saf. 2010 Sep 1;33(9):713-26.
fi
573
ANNEXURE

3 Drug Dose Modi cation

fi
in Acute Kidney Injury

EXAMPLE
A preterm (32 weeks; 1600 g; length 45 cm) neonate develops
lethargy and poor feeding on day 5 of life. Due to clinical sepsis,
the treating team initiates antibiotics (piperacillin-lazobactam and
amikacin). On postnatal day seven, the infant develops oligo-anuria
and deranged renal function (serum creatinine 1.5 mg/ di; baseline
of 0.3 mg/di). How will you make renal dose adjustments for this
baby?
Answer (Table A3.1)
1. Calculate the eGFR to define the category K (0.33) Length (45)/
S Creatinine (1.5 mg/dl).*
2. eGFR - 10 ml/1.73 m?/ min.
a. Inj piperacillin-tazobactam (70% of recommended dose) - 110
mg/kg/ dose q 8 hourly.
b. Inj amikacin (5-7.5 mg/kg/day)—12 mg in 10 ml NS over
30 mins to 1 hour as an infusion
*K is 0.45 for term infants

Table A3.1: Dose modification of common neonatal drugs in renal failure -5

Medication Dose in Dose with impaired renal Supple-
normal function (GFR mL/min/1.73 m?) mental
renal 30-50 10-29 dose with
function <10 peritoneal
(in neonates dialysis
>35 weeks,
per dose)
Amikacin 15 mg/kg q 5-7.5 5-7.5 5-7.5 Yes
24 hours mg/kg q mg/kg q mg/kgq
12-18 24 hours 48-72
hours hours
(Contd.)

574
 Drug Pose Modi cation in Acute Kidney Injury 575

fi
Table A3.1: Dose modi cation of common neonatal drugs In renal tillure (Cond)

fi
Medication Dose in Dose with impaired renal Supple-
normal mental
function (61 K ml/min/1.73 m')
renal 30-50 10-24 • 10 dose with
function peritoneal
(in neonates dialyst.
> 35 weeks,
per closel
Amphotericin 1-1.5 mg/ No No No No
kg q 24 change change change
hours
Ampic illin 25-50 mg/ No Reduce Reduce No
kg 48-12 change dose to close to
hours 25% of 15% of
normal normal
50 mg/kgq 50 mg/kg 50 mg/ 50 mg/ No
Celotaxime kg q 24
8-12 hours 48-12 kg q 12
hours hours hours
Ceftazidime 30 mg/kgq30 mg/ 30 mg/ 30 mg/ No
8-12 hours kg q 12 kg q 24 kg q 48
hours hours hours
Cettriaxone 50-80 mg/ No No Reduce No
change dose by
kg q 24 change 25-50%
hours
Cefoperazone 30-40 mg/ No 50% of 25% of No
kg q8 dose of dose of
+ sulbactam change sulbactam sulbactam
hours
Cipro oxacin 10 mg/kg q No Reduce Reduce No
dose to
fl
12 hours change dose to
50% of 25% of
normal normal
6-12 mg/kgReduce Reduce Reduce No
Fluconazole
424 hours dose to dose to dose to
50% of 50% of 25% of
normal normal normal
Meropenem 30-40 mg/ 10-20 10-20 10-20 NA
kg q 8 mg/kg q mg/kgq mg/kgq
hours 12 hours 12 hours 24 hours
Piperacillin- 50-100 Reduce Reduce Reduce No
tazobactam dose by dose by dose by
mg/kg of
piperacillin 30%; q 8 30%; q 830%; q8
98-12 hours hours hours
hours
(Contd.)
576 AlIMS Protocols in Neonatology

Table A3.1: Dose modi cation of common neonatal drugs in renal failure (Contd.)

fi
Medication Dose in Dose with impaired renal Supple-
normal function (GFR mL/min/1.73 m?) mental
renal 30-50 10-29 <10 dose with
function peritoneal
(in neonates dialysis
>35 weeks,
per dose)
Phenobarbitone1.5-2 mg/ No No Reduce Yes
kg q 12 change change the dose
hours to 50%
of normal
Footnote: Dose modi cations given above are approximate and guided by features of drug
fi
toxicity and, if feasible, drug levels; Loading dose, wherever applicable, remains the same
as for neonates with normal renal function. GFR Glomerular ltration rate.

fi
REFERENCES
1. Stoops C, Stone S, Evans E, Dill L, Henderson T, Griffin R, et al. Baby
NINJA (Nephrotoxic Injury Negated by Just-in-Time Action): Reduction of
Nephrotoxic Medication-Associated Acute Kidney Injury in the Neonatal
Intensive Care Unit. J Pediatr. 2019 Dec;215:223-8.e6.
2. Girardi A, Raschi E, Galletti S, Allegaert K, Poluzzi E, De Ponti F. Drug-
induced renal injury in neonates: challenges in clinical practice and
perspectives in drug development. Expert Opin Drug MetabToxicol. 2017
May; 13(5):555-65.
3. Hanna MH, Askenazi D), Selewski DT. Drug-induced acute kidney injury
in neonates. CurrOpinPediatr. 2016 Apr;28(2):180-7.
 ANNEXURE

4
Immunization Schedule

Age
Schedul munizaion APSchedule
Birth BCG, OPV, Hepatitis B BCG, OPV, Hepatitis- B1
6 weeks DTwP/DTaP-1, Hib-1, Hepatitis
B-2(Pentavalent), Rotavirus-1,
PCV-1, IPV-1 (No OPV)
10 weeks Pentavalent-2, Rota-2, DTwP/DTaP-2, Hib-2, Hepatitis
OPV-2 B-3 (Pentavalent), Rotavirus-2,
PCV-2, IPV-2 (No OPV)
14 weeks Pentavalent-3, Rota-3, DTwP/DTaP-3, Hib-3, Hepatitis
B-4 (Petavalent), Rotavirus-3, PCV-
PCV-2, OPV-2, PV-2
3, IPV-3 (No OPV)
fi
6 months In uenza vaccine (IIV)-1
fl
7 months In uenza vaccine (IIV)-2
fl
6-9 months Typhoid conjugate vaccine (TCV)
9 months 9-12 months MMR-1
MR-1, JE-1 (Endemic No PCV booster
districts), PCV- Booster
(selected states) fIPV-3
12 months - Hepatitis A-1
15 months - MMR-2, Varicella-1,
PCV- Booster
16-24 months MR-2, JE-2 (Endemic 16-18 months
districts), DPT
DTWP/DTaP-B1,
Bouster-1, OPV Booster Hib-B1, IPV-B1(No OPV)
18-19 months - Hepatitis A-2, Varicella-2
5-6 years DPT Booster 4-6 years
DTwP/DTaP-B2, IPV-B2,MMR-3

19 years Td 10-12 years

Tdap,HPV

577
578 AlIMS Protocols in Neonatology

(Conta.)

Yes Yes NA
LBW (<2500 g)

Yes Yes Yes

Safety Preterm (<37 weeks)

Yes NA
LBW (<2,500 g) Yes

Immunogenicity/ Preterm (<37 weeks)* Yes Yes Yes

Age age) recomm-endation in

(chronological Eifectiveness
India At birth or as early as one year of
possible till age hours
possiblewithin 24
First doseat birth oras early as within therst 15 days
At birth oras early possible
as fi
in National Immunization Program Yes Yes Yes
Included

India (IAP)
Yes Yes Yes

Recommended by WHO Yes Yes

mmendations and overview of availability of immunogenicity and safety of recommended vaccinations for preterm and LBW

ts 512 months of age,

ine Ititis B Yes -0
 Immunization Schedule
579

(Conta.)

LBW NA NA

Safety
Preterm Yes Yes

LBW NA .NA.

Yes Yes
Immunogenicity/Effectiveness
Preterm 37 weeks" (<2,500 g) («37 weeks) 1<2500 g)

NA

Age (chronologicalage) recomm- endation in India At 6, 10 and 14 weeks

(OPV can be
given till 5
years of age) Two fractionaldoses at a of age
6nd 14 weeks
At 6 weeks, weeks and14 weeks(can
10
be given of age)
till one year

in National Immunization
Program Yes Yes Yes

Yes, at6 and 14weeks, incase IPV NA Yes Yes

India (AP) Included

Recommended
by WHO
Yes Yes
NA

Vaccine Hep B)
Irenest months cage: (Confda OPV - 1.
2, 3 Fractional
IPV Pentavalent (DPT-Hib.
combination
580 AIMS Protocols in Neonatology

LBW(«2500 g) Yes NA Yes NA

Preterm
Yes Yes Yes NA
Safety (<37 weeks)

LBW (<2,500 g) Yes Yes(PCV7,PCV10) NA Yes NA

Effectiveness Preterm (<37 weeks)* Yes

PCV10,PCV13)
Yes (PCV7,
Yes Yes
Immunogenicity/

At 6 and14 weeks.Booster doseat 9-15 of age) 6 months-5 years

Yes 14 weeks 9-12 months NA
months of age. At 6, 10 and
Age (chronological age) recomm-
endation in India (can be giventill one year

in National Immunization Program No Yes Yes No Yes

India (IAP) Included

Yes Yes Yes Yes

Recommended by WHO Yes Yes No NA

infants ≤12 months of age. (Contd.)

Recommendations and overview of availability of immunogenicity and safety of recommended vaccinations for preterm and LBW Vaccine Hexavalent No combination (DTaP- Hib-
IPV-Hep B) PCV Rotavirus
In uenza MMR,Varicella
fl
 limmunization 5c hertule: 501

Vaccine reactions and onset Interval

vaccine Reaction Onset interval
BCC Fatal dissemination of BCG 1-12 months
OlV Vaccine associated paralytic poliomyelitis (VAI'') 4-30 days
DTWP Prolonged crying and seizute 0-24 hours
Hypotonic-hyporesponsive episodes 0-24 hours
Aleasles Febrile seizure 6-12 days
Thrombocytopenia
15-35 days
Anaphylaxis 1 hour
Rotavirus Intussusception 3-14 days
 Index

Cefoperazone sullactam 557

ACE inhibitors 334 Cefotaxime 557
Activated partial thromboplastin time Ceftazidime 555
(alTT) 320 Ceftriaxone 558
Central vascular access 435
Acute
Acute kidney
tubularinjury
injury333,574
330
Control pity i (Sn
Acyclovir 557 examination 428
Adductor angle 368
Adrenaline 555 Cipro oxacin 559
fl
Aggressive ROP (A-ROP) 378 CKD 344
Albumin 571 Cloxacillin 559
Alveolar arterial oxygen tension Congulation factors 320
difference (AnDO:) 421 Cochlear implant 398, 395
Amiel-Tison 368 Colistin 560
Amikacin 555 Complementary feeding 361
Amino acids 491 Complete blood count 322
Aminoglycosides 333 Comprehensive Lactation
Aminophylline 556 Managment Centre
Amphotericin B 556 (CLMC) 546
Ampicillin 556 Conductive hearing loss 393
Antenatal steroids 388 Congenital cytomegalovirus
Anthropometry 359 infection 397
Anti-VEGF 381,386 Congenital diaphragmatic
Apt-Downey test 321 hernia 413
Continuous kidney replacement
aTT 322
Arterial blood gas 417
Auditory neuropathy 393, 395 Conin unes positive irvay pressure 469
Automated auditory brainstem Continuous renal replacement 344
response 394 Convulsions 302
Cord blood bank 401
Cranial ultrasound 372
Bevacizumab 387 Cryoprecipitate 328
Bleeding diathesis 320 Crystalloids 316
Blood component therapy 508 Cystatin C 336
Blood culture 425
Brainstem auditory evoked
responses 370
D
Danger signs 358
Bronchopulmonary dysplasia DASIl 364
(BPD) 412 D-dimer 322
Buffers 418 Delayed cord clamping 312
Developmental assessment 362

Caffeine citrate 557 Developmensily supportive

Calcitonin 291 Developmental screening 362, 364
Development Assessment Scale for Indi-
Calcium carbonate 342
Calcium gluconate 294,341, 559 an Infants (DASIl) 366
 AIMS Protocols in Neonatology

Dexamethasone 560 Hearing screening 394

Dextrose gel 303 Heated, humidi ed high- ow nasal

fi
fl
Diazoxide 305 cannula 477
DiGeorge's syndrome 296 Hematocrit 311
Digoxin 560
Disseminated intravascular
coagulation 324 Hemoglobin F 322
Dobutamine 561
Hemphin plies 101
Domeridone silk 503 Heparin 571
Dopamine 561 High-risk clinic 355

E
Early stimulation 372
Human platelet antigen 322
Hydrocortisone 563
Hydronephrosis 348
Hyperinsulinemic hypoglycemia 305
Endotracheal tube tip 415 Hyperinsulinism 299, 305
End-stage kidney disease 351
Hyperkalemia 310
Hyperphosphatemia 291, 343
F Hypertension 343
Factor replacement therapy 327
Family-centered care 518 hypertonic saline 340
Fentanyl 386, 562 Hypocalcemia 291,342
Fenton's charts 363 Hypoglycemia 299
Fibrinogen 321 Hypomagnesemia 297
Fluconazole 562 Hyponatremia 340
Fluid and electrolyte status 465 Hypoparathyroidism 295
Fluid overload 343
percentage 335
Fosphenytoin 562 Ibruprofen 564
Fractional excretion of sodium
Immune thrombocytopenia 320,326
(FENa)% 337 Immunization 362,363
Fresh frozen plasma (FFP) 324 Immunization schedule 577
Indications for CPAl' 470
and cryoprecipitate transfusion 515
Furosemide 339, 561 Indomethacin 564
Infants of diabetic mothers 314
Insensible water loss 339
G Insulin 565
Ganciclovir 563 International classification of ROP 378
Gentamicin 563 Intracranial hemorrhage 320
Gestational hypertension 312
Glomerular filtration rate 338 Intravenous immunoglobulin
(IVIG) 327,561
Glucose infusion rate 304 lonized calcium 291
Glucose oxidase 302
Graft-vs-host disease 401
Gross Motor Functional Jitteriness 293,302
Classification System 369 seizures 313

K
Growth monitoring 362, 363

Kangaroo mother care 520

Hammersmith Neonatal Ketogenesis 303
Neurological Examination
(HNNE) 368 L
Labetalol 300 343
Hearing aids 398
hearing impairment 355, 393
Laser treatment 386
Hearing loss 393 Leveliracetam 565
 Index
Lipid infusions 490 Otoacoustic emissions (OAE) 391
Liposomal amphotericin B 556 Oxygenation index 423
Lorazepam 565 Oxygen saturation 449
Lumbar puncture 428 targeting 149
Lung hypoplasia 348

Packed cell volume 314

Magnesium sulfate 567 Packed red blood cell 324, 511
Massaging 551
Meconium aspiration syndrome Pain 529
(MAS) 411 Paracetari mone 291
Meropenem 566
Metabolic acidosis 343
Parenteral nutrition 487
Metronidazole 565
Partial exchange transfusion 317
Micro-capillaries 314 Partial exchange transfusion 315
Micturating cystourethrogram 347 PDA 333
Midazolam 566 Percutaneous arterial
Milk expression, storage and catheterization 144
processing 545 Percutaneous central line 415
Milrinone 567
Mixed acid-base disorder 418 Percutaneste inserted central
Mixed hearing loss 394 Perinatal asphyxia 333
Morphine 566 Peritoneal dialysis 341, 341, 502
Muscle tone 356 Persistent avascular retina 381
Phenobarbitone 568
Phenylephrine 383
NAIT 323 326
Naloxone 568 Piperacillin tazobactum 569
Nasal intermittent positive pressure
ventilation 481 Placental insufficiency 312
Near-infrared spectroscopy 336 Plasma glucose 299
NEC 544
Netilmycin 568 Platelet disordro n 315
Neurodevelopment 308 Pleural effusion 412
Neurodevelopmental screening 356 Plus disease 380
Neutropenia 401 Pneumomediastinum 411
Nevirapine 572 Pneumonia 412
Newborn Individualized Pneumothorax 411
Developmental Care and Polycystic kidney disease 334
Assessment Program Polycythemia 311
(NIDCAP) 372
Non-nutritive sucking 548
Potest angli al valive 35, 245
Nonoliguric AKI 336
Potassium chloride 572
Noradrenaline 567
Pre-plus disease 380

0
OAEs 370
Prostaglandin 570
Prothrombin time (PT) 320, 322
Oligohydramnios 348
Oligohydramnios 334
Oliguria 333 (PIE) 411
Optimality score 369
Oral sucrose solution 389
Oro-motor coordination 356 QoTc 294
Otacoustic emissions 394 QT interval 293
I Iv AlIMS Protocols in Neonatology

R Teller acuity cards 371

The partial pressure of oxygen 421
Random donor platelets 327
Ranibizumab 387 Tracheoesophageal tistula 413
Rehabilitation 356 TRALI 517
Renal failure index 337 Trivandrum Developmental Screening
Renal replacement therapy 338, 343 Chart 364
Renal tubular disorders 334 Trivandrum Development Screening
Resistant hypoglycemia 307 Test 365
Respiratory distress syndrome 410 Tropicamide 383
Retinal detachment 380,388 Two-step screening programme 395
Retinopathy of prematurity (ROP) 378, 449
U
Umbilical arterial line 415
type 2 ROP 385 Umbilical cord blood (UCB) 400
banking 400
S sampling 432
Umbilical venous catheter 316
Scarf sign 368
Schwartz formula 338 Umbilical venous line 415
Seizures 293 Urinay NGAL 336

V
Sensorineural hearing loss 393
Serum creatinine 333
Serum creatinine 335 Vancomycin 570
Sildenafil 570 Vecuronium 571
Simple acid-base disorder 418 Vesicoureteric reflux 347-349
Small for gestational age infants 300,311 Viscosity 311
Society of Fetal Urology (SFU) Vision assessment 371
grading 347 Visual acuity 371
Sodium 461 Vitamin K 571
Surfactant replacement therapy 452 Vitamin K deficiency bleeding (VKDB)
Symptomatic hypocalcemia 294 323
Symptomatic hypoglycemia 303 Voiding cystourethrogram
Syndrome of inappropriate ADH 336 (VCUG) 349

T
TACO 517
W
WHO-MGRS 363