Perinatal/Neonatal

Casebook
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Neonatal Transport: A 3-Day-Old Neonate With Hypothermia,

Respiratory Distress, Lethargy and Poor Feeding
Monica Joseph, MD lungs sounded ‘‘wet’’ at that time. A chest radiograph showed
Joseph R. Hageman, MD borderline normal-sized heart and bilateral fluffy infiltrates in the
lungs. He was also noted to have significant abdominal distention.
Journal of Perinatology ( 2002 ) 22, 506 – 509 doi:10.1038/sj.jp.7210755 An orogastric tube was placed and 5 ml of fresh blood was
suctioned from the stomach. The baby was transported without
difficulty. Upon arrival to the Neonatal Intensive Care Unit, an
CASE PRESENTATION
arterial blood gas was obtained and results included: pH 7.17,
The neonatal transport team was called to transport a 3-day-old p aCO2 55 mm Hg, p aO2 of 147 mm Hg and a base deficit of 10.
male infant who had stopped nursing and became jittery and He was then intubated and was placed on a ventilator. It became
hypothermic. He was born at 37 weeks’ gestation to a 34-year-old evident that he had suffered a severe pulmonary hemorrhage. A
gravida 3, para 2 mother; his birth weight was 2694 g. Mother’s plasma ammonia level of >2000 M/l directed the diagnosis.
prenatal laboratory studies were blood type B + , VDRL-negative,
Hepatitis B surface antigen–negative, rubella-immune and HIV-
negative. Her pregnancy was uncomplicated. The presentation was DENOUEMENT AND DISCUSSION
vertex and the route of delivery was by Cesarean section with labor. Hyperammonemia is often the sign of an underlying metabolic
APGAR scores were 9 at 1 minute and 9 at 5 minutes; he did not disturbance. Normally, excess dietary and waste nitrogen, which
require cardiopulmonary resuscitation. remain after protein synthesis, are converted to urea through the urea
The patient did well until early on day of life 3 when he stopped cycle. Urea is produced in the liver where the urea cycle converts 80%
nursing. He was supposed to be discharged to home later that day, of excreted nitrogen. The five enzymes that make up the urea cycle
but his father noted noisy breathing and grunting. Neonatology was (Figure 1) are regulated long term by the quantity of protein in the
consulted at this point in time. His physical examination was diet.1 Disorders of any of the urea cycle enzymes lead to
remarkable for hypertonia and jitteriness involving all four accumulation of ammonia and its precursors. This can lead to
extremities. These movements could be stopped but would restart encephalopathy and death or devastating neurologic sequelae if not
again. His rectal temperature was 36.5 8C. He had also lost 270 g treated promptly.1
since birth. His oxygen saturation was 96% while breathing room
air. An arterial blood was obtained: pH 7.41, p aCO2 26 mm Hg,
p aO2 95 mm Hg and a base excess of 6 (in room air). The CLINICAL MANIFESTATIONS
blood pressure was noted to be elevated. Additional laboratory Most infants with severe deficiency of urea cycle enzymes present
studies included: total bilirubin of 9 mg%, electrolytes including similarly to our patient: a full-term infant who was normal at birth
Na + of 149 mEq/l, K + of 6.9 mEq/l, Cl of 111 mEq/l, total Ca of but then developed progressive signs and symptoms of encephalo-
8.6 mg% and a glucose screen of >80 mg%. White blood cell count pathy.1 – 3 Elevated plasma ammonia levels that exceed three times
was 16,800, and hematocrit and platelet counts were 48% and the normal (normal levels are <50 M/l) are considered toxic. The
484,000, respectively. SGPT was 34 and a blood culture was drawn. clinical manifestations are poor feeding, anorexia, behavioral
A peripheral venous line was placed and the infant was started on changes, irritability, vomiting, lethargy, ataxia and seizures. The
10% dextrose with electrolyte solution and, because of a low urine earliest symptoms are poor feeding and lethargy. Other important
output, he was also given a bolus of 10 ml/kg 5% albumin. early warning signs may also include tachypnea or respiratory distress.
Ampicillin and gentamicin were started as well. By the time the Hyperammonemia may cause central hyperventilation resulting
neonatal transport team arrived, he required supplemental oxygen in a respiratory alkalosis. This can also be an early warning sign of
of 35% to 40%. His heart rate was 170 to 180 beats/min and his a urea cycle disorder.1,4 Hyperammonemia and/or other inborn
errors of metabolism should be high in the differential diagnosis
Department of Pediatrics, Evanston Hospital, 2650 Ridge Avenue, Evanston, IL, USA. (Table 1), especially when a full-term infant presents in respiratory
Address correspondence and reprint requests to Joseph R. Hageman, MD, Department of
distress in the first few days of life. Inborn errors of metabolism
Pediatrics, Evanston Hospital, 2650 Ridge Avenue, Evanston, IL 60201 - 1493, USA. may mimic sepsis and respiratory disorders that are common.
Journal of Perinatology 2002; 22:506 – 509
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506 www.nature.com / jp
Neonatal Transport Joseph and Hageman

sufficient; capillary blood is not suitable. Barsotti discusses the steps

in order to get an accurate level; these include the following.
o Ideally, the patient should fast for at least 6 hours before
drawing the sample;
o Ammonia-free heparin should be used (heparin is the choice
because it has been shown to reduce red blood cell ammonia
production;5
o A chilled heparinized vacuum tube that is immediately placed
in ice;
o The plasma should be separated within 15 minutes. If allowed
Figure 1. The urea cycle. to sit, the blood and plasma ammonia concentration will
spontaneously increase secondary to ongoing production of
Physicians should add a plasma ammonia level to the initial ammonia from the red blood cells and the deamination of amino
bloodwork, especially when there is no obvious source of infection. acids, especially glutamine.5 Standing at room temperature, red
If it progresses, the infant may fall into a coma and require blood cell hemolysis and delay in sample processing are also
endotracheal intubation and assisted ventilation. Circulatory important to avoid since one or all may factitiously increase the
collapse and cerebral edema may occur.1 plasma ammonia level. Proper processing is felt to be more
Transient hyperammonemia is seen more commonly in important than whether the sample is drawn from an artery or vein
premature infants. Transient hyperammonemia in the newborn may according to the Consensus Statement from the Conference for the
be mild [ammonia (NH3 )=40–50 M/l] or severe (NH3 near Management of Patients with Urea Cycle Disorders.6
4000 M/l). The mild form may last for 6 to 8 weeks without Serum electrolytes and arterial blood gases initially will help with
symptoms. These infants do not have any neurologic sequelae.2 The immediate management. Liver function tests including partial
severe form of transient hyperammonemia in the newborn occurs thrombin time, partial tissue thromboplastin time, transaminases,
most commonly in premature infants, often in conjunction with bilirubin and albumin aid in determining the possibility of liver
respiratory distress. In reported cases, the plasma ammonia level rose insufficiency as the cause of hyperammonemia.4 The specific
quickly during the first few days of life leading to central nervous diagnosis for many of these disorders can be established with
system depression and coma.3 The cause remains unknown; though quantitative plasma amino acids. Urinary amino acids will rule out
it is apparently not genetic. Therapy is focused on reducing plasma disorders such as: hyperornithinemia, hyperammonemia, homoci-
ammonia levels, and dialysis, preferably hemodialysis, may be trullinemia and lysinuric protein intolerance. Other tests may be
necessary. The prognosis for aggressively treated infants appears good necessary, such as: skin fibroblasts for citrullinemia and a liver biopsy
and transient hyperammonemia in the newborn does not recur in which may be significant for evidence of portal fibrosis in
these infants. argininosuccinic aciduria.1

EPIDEMIOLOGY TREATMENT DURING INITIAL PRESENTATION

The overall incidence of the five urea cycle enzyme deficiencies is Hyperammonemia is a medical emergency. The longer the patient
1/10,000 live births.1 All disorders of ammonia metabolism are remains in a coma due to hyperammonemia, the worse the
inherited as autosomal recessive defects except for ornithine
transcarbamylase deficiency that has an X-linked inheritance
pattern. Ornithine transcarbamylase is the most common defect. Table 1 Differential Diagnosis
Genetic analysis of the present case demonstrated arginosuccinic Mild increase in plasma ammonia ( NH3 < 500 M )
aciduria (Table 2). Sepsis
Perinatal asphyxia with hepatic necrosis or failure
Generalized herpes simplex infection
DIAGNOSTIC TESTS Moderate increase ( NH3>500 M )
Once hyperammonemia is established, then further laboratory testing Deficiencies of urea cycle enzymes
is required to determine the specific diagnosis. Repeat plasma Organic acidemias
ammonia levels should be obtained frequently during the acute Lysinuric protein intolerance
Hyperammonemia – hyperornithinemia – homocitrullinemia syndrome
stage. A reminder is that proper processing of the blood is of utmost
Transient hyperammonemia of the newborn
importance so that levels are truly reflective. The choice of drawing
Congenital hyperinsulinism with hyperammonemia
arterial blood is well known; however, venous blood may be

Journal of Perinatology 2002; 22:506 – 509 507

 Joseph and Hageman Neonatal Transport

Table 2 Urea Cycle Disorders

Disorder Deficient enzyme Inheritance pattern

Carbamyl phosphate synthetase deficiency Carbamyl phosphate synthetase Autosomal recessive

Ornithine transcarbamylase deficiency Ornithine transcarbamylase X - linked
Citrullinemia Arginosuccinate synthetase Autosomal recessive
Argininosuccinic aciduria Arginosuccinate lyase Autosomal recessive
Argininemia Arginase Autosomal recessive

prognosis.1 Prior to transport to a tertiary care center, endotracheal along with L -citrulline or L -arginine to ‘‘prime’’ the urea cycle.
intubation to support or assist ventilation and prevent hypoxemia Protein should only be withheld for a short period of time. Without
may be necessary; the placement of a central line such as an protein, the body goes into negative nitrogen balance, which
umbilical arterial and/or an umbilical venous catheter may be increases the need for nitrogen excretion and worsens the
helpful in management of fluids, acidosis and supporting blood hyperammonemia.
pressure. The next goal is to remove exogenous protein. Hemodialysis
is the only means of rapidly removing ammonia from the body.6,8
Peritoneal dialysis does not remove ammonia quickly enough to MAINTENANCE THERAPY
minimize brain injury.1,7,8 While preparing for hemodialysis or There are three parts to maintenance therapy: protein-restricted diet,
extracorporeal membrane oxygenation, ammonia scavenging supplementation with citrulline or arginine, and medication which
therapy should be initiated, even prior to the diagnosis of a specific provides an alternate pathway for waste nitrogen excretion (sodium
metabolic etiology, if it is felt that alteration of the central nervous phenylbutyrate and/or sodium benzoate).1 The specifics of treatment
system status is secondary to the high ammonia level. Loading doses depend on which enzyme is deficient. A plasma glutamine level is
of L -arginine–HCl (600 mg/kg per dose), sodium benzoate (250 useful as a marker of effective therapy and should be maintained at
mg/kg per dose) and sodium phenylacetate (250 mg/kg per dose) levels <1000 M/l.4 Growth, especially length (or height), and
all in 25 to 35 mg/kg 10% dextrose solution given over 90 minutes development should be monitored closely. Poor growth is a sign of
have been recommended for emergency treatment of newborn infants inadequate dietary protein intake. Other services should also be
with hyperammonemia.1,4 Sustained infusion of these three involved: physical, occupational and speech therapy, psychology and
medications is recommended over the next 24 hours (Table 3). The genetic counseling.
doses depend on enzyme deficiency. The mechanism of action of Intermittent episodes of hyperammonemia can occur despite
these medications is as follows: benzoate binds glycine to form maintenance therapy. Potential causes include illness or drugs such
hippurate, and phenylacetate combines with glutamine, and are then as valproic acid, haloperidol and anesthetic agents. These episodes
excreted rapidly by the kidney. can also end in death or severe neurological sequelae. Once again,
Parenteral nutrition is needed to prevent protein catabolism. Use aggressive treatment is required.
glucose and intravenous fat emulsion, without protein, to maximize Whenever a patient with a urea cycle defect has symptoms of
calories. Once the ammonia level is <100 M/l and the patient is emesis, lethargy, agitation, disorientation or emotional lability, a
stable, oral or nasogastric feeds may be initiated using a protein- plasma ammonia level should be checked. If the ammonia is three
free powder. Essential amino acid supplementation may be needed, times the normal, the child should be hospitalized and treated.

Table 3 Treatment of Intercurrent Episodes of Hyperammonemia in Patients With Urea Cycle Disorders
Disorder Initial infusion Maintenance infusion
Administer over 90 min Daily dose given as
24 - hr infusion

Carbamyl phosphate Sodium benzoate, 250 mg / kg Sodium phenylacetate, 250 mg / kg

synthetase deficiency or Sodium phenylacetate, 250 mg / kg Sodium benzoate, 250 mg / kg
ornithine transcarbamylase 10% arginine HCl, 2 ml / kg 10% arginine HCl, 2 ml / kg
deficiency
Citrullinemia Sodium benzoate, 250 mg / kg Sodium benzoate, 250 mg / kg
Sodium phenylacetate, 250 mg / kg Sodium phenylacetate, 250 mg / kg
10% arginine HCl, 6 ml / kg 10% arginine HCl, 6 ml / kg
Arginosuccinic aciduria 10% arginine HCl, 6 ml / kg 10% arginine HCl, 6 ml / kg

508 Journal of Perinatology 2002; 22:506 – 509

Neonatal Transport Joseph and Hageman

Currently, the only way to correct the enzyme deficiency as the patient presented in this transport casebook who proved to have
permanently is liver transplant. Gene therapy is the hope of the argininosuccinic aciduria.
future. Specifically, the genes for argininosuccinic synthetase and Finally, when a term newborn infant presents with signs of mental
argininosuccinate lyase have been mapped to chromosomes 9 and 7, status changes, emesis, seizures and/or poor feeding, seriously con-
respectively.1 sider adding a plasma ammonia level to the diagnostic work-up.

SURVIVAL References
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chance for minimal sequelae, but neurologic deficits usually occur Lippincott; 1994. p. 88 – 91, 1922 – 3.
when the coma is longer than 2 days. Since the onset of ‘‘rational 3. Nelson W. Textbook of Pediatrics, 15th ed. Philadelphia: WB Saunders; 1996;
treatment,’’ the 1-year survival rate for infants ahs been 92%.1,7 p. 350 – 5.
Many who survive may have neurologic sequelae: mental retardation, 4. Burton B. Inborn errors of metabolism in infancy: a guide to diagnosis.
seizures, cortical atrophy and spastic quadriparesis. Later acute Pediatrics 1998;102:E69.
episodes from protein intake or infection can result in further 5. Barsotti R. Measurement of ammonia in the blood. J Pediatr 2001;138:S11 – 20.
morbidity and death. Few patients with urea cycle defects live into 6. Summar M. Urea cycle disorders: proceedings of a consensus conference for the
adulthood.1 management of patients with urea cycle disorders, Washington, DC, April 27 –
29, 2000. J Pediatr 2001;138:S1 – 80.
7. Msall M, Batshaw M, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in
CONCLUSION children with inborn errors of urea synthesis. Outcome of urea - cycle
enzymopathies. N Engl J Med 1984;310:1500 – 5.
Early diagnosis and management are the key to minimizing 8. Summar M, Pietsch J, Deshpande J, Schulman G. Effective hemodialysis and
neurologic sequelae in infants presenting with hyperammonemia in hemofiltration driven by extracorporeal membrane oxygenator pump in
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