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Approach to the child with metabolic

acidosis

Authors: Peter Yorgin, MD, Robert Mak, MD, PhD

Section Editor: Tej K Mattoo, MD, DCH, FRCP
Deputy Editor: Laurie Wilkie, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes

available and our peer review process is complete.

Literature review current through: Mar 2022. | This

topic last updated: Sep 21, 2020.

INTRODUCTION

Metabolic acidosis is a biochemical

abnormality defined by an increase in blood
hydrogen ion concentration or a reduction in
serum bicarbonate (HCO3) concentration. It is
either an acute or chronic process and is
secondary to a wide range of underlying
disorders.

The etiology, clinical impact, and diagnostic

evaluation of children with metabolic acidosis
will be reviewed. Metabolic acidosis in adults
is discussed separately. (See "Approach to the
adult with metabolic acidosis".)

DEFINITIONS

● Metabolic acidosis is defined as a

pathologic process that increases the
concentration of hydrogen ions (H+) and
reduces blood bicarbonate (HCO3)
concentration (<22 mmol/L). It can be
acute (minutes to days) or chronic
(weeks to months).

● Respiratory acidosis is defined as an

elevation in arterial partial pressure of
carbon dioxide (PaCO2) concentration
that reduces arterial pH.

● Acidemia (as opposed to acidosis) is

defined as a low arterial pH (<7.35),
which can result from a metabolic
acidosis, respiratory acidosis, or a
combination of both.

● Total CO2 measured in the electrolyte

panel includes measurements of serum
bicarbonate (95 percent of total CO2),
dissolved CO2, and carbonic acid.

ETIOLOGY BASED ON
PATHOGENESIS

Pathogenesis — The etiology of metabolic

acidosis in children can be separated into
three pathogenetic mechanisms ( table 1).

● Increase in acid concentration either

due to increased acid generation
(endogenous production or exogenous
ingestion/infusions) or decreased renal
acid excretion.

● Loss of bicarbonate via the intestine or

kidneys.

● Dilution of serum bicarbonate

concentrations by
nonbicarbonate/acetate/lactate-
containing solutions with a resultant
rise in blood H+ concentrations.

Increased acid concentration: High anion

gap metabolic acidosis — A high anion gap
metabolic acidosis is due to the
overproduction of endogenous acids,
excessive intake of exogenous acids, or
accumulation of acids due to the kidney's
inability to excrete acid in sufficient
quantities to maintain normal serum
bicarbonate concentrations.

A frequently used mnemonic to identify the

more common causes of anion gap
metabolic acidosis in children is MUDPILES,
where M= methanol; U = uremia; D = diabetic
ketoacidosis; P = paraldehyde; I = iron,
isoniazid, and inborn metabolic errors; L =
lactic acid; E= ethylene glycol; and S =
salicylates.

● Methanol, or wood alcohol, when

ingested in excessive quantities, causes
an increase in serum formaldehyde,
which is converted to formate and
formic acid. These metabolites inhibit
cytochrome oxidation, leading to
progressive acidosis due to the rise of
blood lactic acid and ketoacid
concentrations [1]. The osmolal gap is
useful in detecting the ingestion of
methanol. (See "Methanol and ethylene
glycol poisoning: Pharmacology, clinical
manifestations, and diagnosis" and
"Serum osmolal gap".)

● Uremia in patients with acute or chronic

kidney failure is associated with
reduced renal acid excretion resulting in
an accumulation of lactic acid, hippuric
acid, amino acids [2], pyroglutamic acid
[2], guanidinosuccinic acid [3], short
chain fatty acids [3], and sulfuric acid.

● Diabetic ketoacidosis (hyperglycemia

due to insulin deficiency) results in
excess serum levels of acetoacetate
(acetoacetic acid), L-lactate/D-lactate,
and beta-hydroxybutyrate [4].

● Paraldehyde administration is reported

to increase serum concentrations of
lactic acid [5]. The inclusion of
paraldehyde is more historical as it is no
longer available in the United States.

● Inborn errors of metabolism [IEM] can

present with metabolic acidosis due to
accumulation of lactic acid, ketoacids,
and methylmalonic acid depending on
the underlying etiology ( table 2). In
particular, metabolic acidosis is a
predominant finding of organic
acidemias (methylmalonic, propionic,
and isovaleric acidemia, glutaric
acidemia type 1, 3-methylglutaconic
aciduria ( table 3)) and also observed
in children with maple syrup urine
disease and disorders of carbohydrate
production (eg, pyruvate carboxylase,
pyruvate dehydrogenase, and
phosphoenolpyruvate carboxykinase
deficiency) ( table 4). (See "Metabolic
emergencies in suspected inborn errors
of metabolism: Presentation,
evaluation, and management", section
on 'Metabolic acidosis' and "Inborn
errors of metabolism: Classification".)

● Iron overdose can cause a high anion

gap metabolic acidosis from
accumulation of lactic acid due to the
complications of dissociated ferrous or
ferric molecules, including intestinal
ulceration, fulminant liver failure, and
decreased cardiac output [6]. "I" also
may refer to other possible ingestions
that are associated with metabolic
acidosis ( table 5). (See "Approach to
the child with occult toxic exposure".)

● Isoniazid overdose is characterized by

seizures, coma, and metabolic acidosis
due to elevated levels of ketoacids [7-9].

● Lactic acidosis occurs when lactate is

overproduced or underutilized. In
children, causes of lactic acidosis
include:

• Conditions associated with shock

resulting in increased lactate acid
due to impaired tissue oxygenation,
such as sepsis, cardiac failure, and
severe hypoxia. Elevated lactate
levels >36 mg/dL measured in
children with sepsis have been
correlated with a high mortality [10]
(See "Causes of lactic acidosis",
section on 'Type A lactic acidosis'.)

• Underlying mitochondrial
dysfunction, either congenital (
table 6) or acquired due to fasting
[11]. (See "Inborn errors of
metabolism: Classification", section
on 'Mitochondrial disorders' and
"Causes of lactic acidosis", section on
'Mitochondrial dysfunction'.)

• Severe crush injury resulting in

rhabdomyolysis resulting in lactic
acidosis due to muscle ischemia.
(See "Clinical manifestations and
diagnosis of rhabdomyolysis",
section on 'Fluid and electrolyte
abnormalities'.)

● Ethylene glycol poisoning causes

increased levels of lactic acid and
ketoacids [12]. The osmolal gap is useful
in detecting ingestion of ethylene glycol
as well as methanol and ethanol. (See
"Serum osmolal gap" and "Methanol
and ethylene glycol poisoning:
Pharmacology, clinical manifestations,
and diagnosis".)

● Salicylate toxicity in children produce

elevated levels of salicylic acid,
ketoacids, and lactic acid [13]. (See
"Salicylate poisoning in children and
adolescents".)

● Ketosis due to either starvation or

ketogenic diet is another cause of anion
gap metabolic. Ketosis results in
increased serum levels of acetoacetate
(acetoacetic acid) and beta-
hydroxybutyrate and ketones in the
urine [14-16].

Loss of bicarbonate: Normal anion gap

metabolic acidosis — Normal anion (also
referred to as nonanion) gap metabolic
acidosis occurs with a loss of serum
bicarbonate, which is matched with a
concomitant rise in serum chloride
(hyperchloremic metabolic acidosis).

The following causes should be considered in

a child who presents with normal anion gap
metabolic acidosis:

● Gastrointestinal losses of
bicarbonate due to diarrhea, small
bowel, or pancreatic drainage cause a
significant reduction in serum
bicarbonate concentrations.

● Kidney losses of bicarbonate or the

inability to acidify the urine, as is seen
with renal tubular acidosis (RTA), leads
to a hyperchloremic metabolic acidosis.
(See "Etiology and clinical
manifestations of renal tubular acidosis
in infants and children".)

Carbonic anhydrase inhibitors like

acetazolamide decrease conversion of
carbonic acid to water and carbon
dioxide at the renal tubule brush border
resulting in bicarbonate loss and
subsequently metabolic acidosis. (See
"Mechanism of action of diuretics",
section on 'Carbonic anhydrase
inhibitors (acetazolamide)'.)

Mixed high anion and normal gap

acidosis — Occasionally, there are pediatric
patients who have mixed causes of metabolic
acidosis, where both high and normal anion
gap causes coexist. (See 'Mixed anion gap'
below.)

● In certain situations, children with

chronic kidney disease can have both
accumulated acids (high anion gap
acidosis due to uremia) and RTA (normal
gap acidosis with the inability to excrete
adequate H+ and/or the loss of
bicarbonate) occur at the same time.

● Children recovering from ketoacidosis

may still have elevated serum ketoacids
that are converted back to bicarbonate.
However, if ketoacid anions are lost in
urine before they can be metabolized
(as sodium or potassium salts), they
represent lost potential bicarbonate.
The effect of these urinary losses is that
most patients with diabetic ketoacidosis
with initial high anion gap acidosis
develop a normal anion gap metabolic
acidosis during their recovery phase.

● Children with severe diarrhea have a

normal anion gap due to loss of HCO3,
and if severe hypovolemia develops,
high anion gap metabolic acidosis may
develop due to increased lactic acid
production (poor tissue perfusion) and
impaired acid excretion by the kidney.
These patients with hypovolemic shock
require fluid resuscitation to restore
tissue perfusion. (See "Initial
management of shock in children",
section on 'Volume and rate'.)

Dilutional metabolic acidosis — Dilutional

acidosis refers to a fall in serum bicarbonate
concentration that is due to expansion of the
intravascular fluid volume with large volumes
of intravenous fluids containing neither
bicarbonate nor the sodium salts of organic
anions that can be metabolized to
bicarbonate (such as lactate or acetate).
Dilutional metabolic acidosis has been
reported in children who receive parenteral
fluids following trauma or those undergoing
surgery [17-20]. Dilution-induced metabolic
acidosis is usually mild and often associated
with clinical signs of fluid overload
(periorbital or pretibial edema, pleural
effusions, ascites), fluid intake greatly in
excess of urine output, and increases in
patient weight. Laboratory studies that
support a diagnosis of dilutional-induced
acidosis include a low serum chloride, low
serum uric acid, low blood urea nitrogen
(BUN), low serum osmolality, and a high beta-
type natriuretic peptide (BNP).

The underlying mechanism of dilutional

acidosis remains unknown, as the dilution of
both serum bicarbonate and H+ ion with
normal saline is proportional. Proposed
mechanisms include [21,22]:

● Carbon dioxide (CO2) from the lungs

equilibrates with lower CO2 in the
diluted blood and becomes hydrated to
carbonic acid.

● Normal cellular metabolism contributes

the H+ ions.

CLINICAL MANIFESTATIONS

There are no distinguishing clinical features

of pediatric metabolic acidosis. Findings are
nonspecific and vary between the acute and
chronic disorders.

Acute metabolic acidosis — Children with

acute metabolic acidosis typically present
with symptoms related to the underlying
condition and may also have signs/symptoms
of compensatory respiratory alkalosis.

● Tachypnea and hypernea – The most

common manifestations of acute
metabolic acidosis in children are
tachypnea and/or hyperpnea due to
compensatory respiratory
compensation. Older children can
exhibit an increase in respiratory rate
(tachypnea) and depth of respiration
(eg, Kussmaul respirations). In young
children and infants, the increase in
depth of respiration, as observed in
classic Kussmaul breathing, may not be
as apparent and the only response to
metabolic acidosis maybe tachypnea.
An inability to generate an appropriate
hyperventilatory response may be
indicative of significant underlying
neurologic and/or respiratory disorder.

● Laboratory findings

• Partial pressure of carbon dioxide –

The respiratory alkalotic
compensation results in a decreased
in the partial pressure of carbon
dioxide (PCO2) concentrations, which
raises the blood pH towards normal,
although usually never complete,
and never overcompensated. The
respiratory compensation for
metabolic acidosis generates a
reproducible and relatively linear
relationship between the arterial
PCO2 and bicarbonate concentration
with a decreased of PCO2 of 1.2
mmHg for every 1 mmol/L decrease
in serum bicarbonate. This
respiratory response to metabolic
acidosis begins within 30 minutes
and is complete by 12 to 24 hours.
(See "Approach to the adult with
metabolic acidosis", section on
'Determination of whether
respiratory compensation is
appropriate'.)

• Hyperkalemia – Acute metabolic

acidosis can precipitate
hyperkalemia, which, if severe, is
associated with life-threatening
cardiac conduction abnormalities.
(See 'Effect of acidemia on
potassium and ionized calcium and
magnesium levels' below and
"Causes, clinical manifestations,
diagnosis, and evaluation of
hyperkalemia in children", section on
'Cardiac conduction abnormalities'.)

● Neurologic findings – Mental

confusion and lethargy have been
observed in patients with severe acute
metabolic acidosis, despite minor
changes in cerebrospinal and brain pH
[23]. As an example, children with
severe metabolic acidosis due to DKA
generally present with lethargy, altered
mental status, seizures, ataxia,
hypotonia, muscle weakness, and
developmental delay, as well as vision
and hearing impairments [24].

● Unknown cardiac effects – The impact

of acute acidemia on cardiac function
remains unclear. Data from animal and
tissue studies have shown myocardial
depression and arrhythmias when the
pH falls below 7.1 [25,26]. However,
clinical studies in humans have not
reported the same effect on cardiac
function, as observed transient
decreases in pH to 6.8 in individuals
with diabetic ketoacidosis were not
associated with depressed cardiac
function [27].

Chronic metabolic acidosis — Children with

chronic metabolic acidosis can be
asymptomatic or present with multiple-
system manifestations depending on the
duration and severity of the underlying
disorder. For children with long-standing
uncorrected metabolic acidosis (eg, renal
tubular acidosis), findings include:

● Poor growth and skeletal muscle

wasting ‒ Poor growth and skeletal
muscle wasting are attributed to
aberrant growth hormone secretion
and resistance to insulin-like growth
factors as well as rickets due to bone
abnormalities [28]. Growth impairment
is commonly seen in children with
uncorrected acidosis due to renal
tubular acidosis; however, adequate
treatment can prevent poor growth and
in some young children can result in
catch-up growth [29]. (See "Etiology and
clinical manifestations of renal tubular
acidosis in infants and children" and
"Pathogenesis, evaluation and
diagnosis of growth impairment in
children with chronic kidney disease",
section on 'Metabolic acidosis'.)

● Rickets ‒ Rickets is observed in children

with chronic acidosis due to bone
biochemistry abnormalities. Bone
buffering of some of the excess
hydrogen ions is associated with the
release of calcium and phosphate from
bone resulting in a decrease in bone
mineral content. Treatment of chronic
metabolic acidosis improves bone
mineral density and rickets, as well as
linear growth in these children [29,30].
(See "Pathogenesis, consequences, and
treatment of metabolic acidosis in
chronic kidney disease", section on
'Prevention of bone buffering'.)

● Nephrolithiasis and nephrocalcinosis

‒ Hypercalciuria in children with chronic
metabolic acidosis increases the risk of
nephrolithiasis and nephrocalcinosis. In
these patients, there is mobilization of
calcium out of the bone resulting in an
increased renal load of calcium [31]. In
addition, hypocitraturia occurs in
response to metabolic acidosis with
enhanced proximal tubular citrate
reabsorption, which limits the ability to
reabsorb tubular calcium leading to
stone formation [32]. Distal (type 1)
renal tubular acidosis is also associated
with an increased risk of nephrolithiasis
and nephrocalcinosis. (See "Kidney
stones in children: Epidemiology and
risk factors", section on 'Hypocitraturia'
and "Nephrocalcinosis in neonates",
section on 'Hypocitraturia' and "Etiology
and clinical manifestations of renal
tubular acidosis in infants and children",
section on 'Clinical manifestations'.)

Neonates — Newborns and infants are more

vulnerable to developing metabolic acidosis
than older children and adults as they have a
lower renal capacity for net acid excretion
[33].

Infants with perinatal asphyxia are at-risk for

metabolic acidosis due to increased blood
lactic acid concentrations, which can be
detected in umbilical cord samples [34,35].
(See "Perinatal asphyxia in term and late
preterm infants", section on 'Basic laboratory
tests'.)

Neonates who require parenteral fluids are

at-risk for dilutional metabolic acidosis due to
the infusion of normal saline. The use of
(serum) chloride-sodium ratio (<0.75) has
been reported to be useful in identifying
these infants as they have hypochloremic
metabolic acidosis [36]. (See 'Dilutional
metabolic acidosis' above.)

LABORATORY TESTS

Detection: Electrolyte panel and blood gas

measurements — Metabolic acidosis is
typically detected by a low serum total CO2 in
an electrolyte panel and less commonly by a
low bicarbonate level within a blood gas
sample. The total serum CO2, which is
routinely reported in serum electrolyte
panels, includes measurements of serum
bicarbonate (95 percent of total CO2),
dissolved CO2, and carbonic acid. In contrast,
arterial and venous blood gas measurements
separately report total bicarbonate values
and the partial pressure of carbon dioxide
(PCO2). In some clinical settings, the
diagnosis may be apparent without a blood
gas measurement of pH (eg, diabetic
ketoacidosis). As a rule of thumb, serum total
CO2 concentrations lower than 14 mmol/L
are due to metabolic acidosis, not as
compensation for a respiratory alkalosis. (See
'Confirmation of primary metabolic acidosis'
below.)

Normative total CO2 and bicarbonate

levels by age — Serum total CO2 and
bicarbonate concentrations vary with age
[37].

● 18 to 40 years of age – 23 to 30 mmol/L

[38]
● >2 to 18 years – 22 to 26 mmol/L [39,40]
● Infants to 2 years – 16 to 24 mmol/L

Newborn infants normally have lower serum

bicarbonate concentrations compared with
older infants and children. The lower normal
values are due to a lower capacity to excrete
an acid load during the neonatal period,
resulting in a greater risk to develop
metabolic acidosis, and a reduced
regeneration and reabsorption of
bicarbonate in the proximal renal tubule.
Both bicarbonate reabsorption and renal acid
excretion improve rapidly during the first few
days to weeks of life, resulting in higher
levels of bicarbonate [33,41]. (See "Neonatal
acute kidney injury: Evaluation, management,
and prognosis", section on 'Metabolic
acidosis'.)

Effect of acidemia on potassium and

ionized calcium and magnesium
levels — Metabolic acidosis can affect the
following:

● Serum/plasma potassium –
Serum/plasma potassium (K+) increases
with increasing acidemia (decreasing
pH). For every decrease in the blood pH
by 0.1, the serum potassium increases
by 0.6 mEq/L.

There is a diffusion-based equilibration

of H+ ions between extracellular and
intracellular spaces so that when serum
H+ concentrations are high, there is a
net influx of H+ into the cells.
Serum/plasma K+ concentrations rise
due to the exchange of intracellular K+
for extracellular H+ ions. Sodium is
incapable of moving intracellularly in
response to the H+ diffusion due to the
presence of the sodium-potassium
ATPase (Na+/K+-ATPase). (See "Causes,
clinical manifestations, diagnosis, and
evaluation of hyperkalemia in children",
section on 'Metabolic acidosis'.)

● Ionized calcium and magnesium –

Ionized calcium and magnesium
increase with increasing acidemia [42].
When H+ ions compete with calcium
and magnesium for binding sites on
albumin and other serum proteins,
calcium and magnesium are displaced
from their protein binding sites,
resulting in an increase in ionized (free)
calcium and magnesium ions in the
serum/plasma. Ionized magnesium
changes 0.12 mmol/L per pH unit and
ionized calcium changes 0.36 mmol/L
per pH unit [42]. Of note, when acidosis
is corrected (eg, bicarbonate therapy),
ionized calcium and magnesium levels
will fall and may have clinical
application. (See "Relation between
total and ionized serum calcium
concentrations", section on 'Acid-base
disorders'.)

DIAGNOSTIC EVALUATION

A diagnostic evaluation that includes serum

or plasma electrolytes, calculation of the
anion gap, and elements from the history
and physical examination are usually
sufficient to determine the cause of the
metabolic acidosis and guide therapy (
algorithm 1). In some cases, a blood gas
measurement is needed to confirm primary
metabolic acidosis from compensated
respiratory alkalosis.

Confirmation of primary metabolic

acidosis — If metabolic acidosis is tentatively
identified by a low total CO2 on an electrolyte
panel measurement, an arterial or venous
blood gas sample may be needed to
differentiate metabolic acidosis from
compensated respiratory alkalosis, as a low
bicarbonate level may be observed in both
conditions. If the patient has a simple
metabolic acidosis, then the patient will be
acidemic with a pH <7.35, and if the patient
has respiratory alkalosis with compensated
metabolic acidosis, the patient is alkalemic
with a pH >7.42. (See 'Detection: Electrolyte
panel and blood gas measurements' above
and "Simple and mixed acid-base disorders".)

In the following two examples, the

bicarbonate level is 18 mmol/L and the pH
from a blood gas example differentiates
between the two processes.

● Primary metabolic acidosis (with

incomplete compensatory respiratory
alkalosis) will have a pH: 7.34, PCO2: 35
mmHg, HCO3: 18 mmol/L.

● Primary acute respiratory alkalosis with

incomplete compensatory metabolic
acidosis: pH: 7.46, PCO2: 29 mmHg,
HCO3: 18 mmol/L.

Blood gas PCO2 values can assist in

determining the primary acid-base
derangement:

● If the primary acid-base perturbation is

metabolic acidosis, then the PCO2
should drop by 1.2 mmHg for every 1
mmol/L drop in serum total CO2
concentration.

● If the primary acid-base perturbation is

respiratory alkalosis, then the serum
total CO2 concentration should
decrease by 5 mmol/L for every 10
mmHg decrease in PCO2.

Anion gap — Once the diagnosis of a

metabolic acidosis has been confirmed,
serum electrolyte values are used to
determinate the serum anion gap (
algorithm 1). The serum AG is defined as
the difference between measured cations
and measured anions. (See "Approach to the
adult with metabolic acidosis", section on
'Assessment of the serum anion gap'.)

Since sodium (Na) is the primary measured

cation and chloride (Cl) and bicarbonate
(HCO3) are the primary measured anions,
most institutions, including our center, use
the following formula to determine the anion
gap (calculator 1).

Serum AG = Na – (Cl + HCO3)

The normal value of the serum anion gap is

dependent on the specific chemical analyzers
used to measure each analyte and therefore
will vary from laboratory to laboratory and
over time. In general the normal range is
approximately 4 to 12 mEq/L. However, it is
best for each laboratory to determine its own
local normal range.

Other centers, particularly outside the United

States, will also use the potassium (K) as a
measured cation and the following formula.

Serum AG = (Na + K) – (Cl + HCO3)

The normal range for this formula will

be 4 mEq/L higher than above as the
normal value of K used in this formula is
4 mEq/L.

Interpretation of the serum anion gap is

most helpful when an individual's usual, or
baseline, anion gap is known and serial
measurements are available from the same
laboratory. As an example, if a patient's
baseline anion gap is 4 mEq/L and is found to
be 12 mEq/L, then this 8 mEq/L increase in
the anion gap is probably clinically significant
despite the fact that the anion gap is still
within the "normal" range. Unfortunately,
baseline data are often unavailable.

The anion gap can be underestimated in

children with hypoalbuminemia. To adjust for
hypoalbuminemia the following equation is
used:

Corrected anion gap = Anion gap + (0.25

x (4 – albumin in g/dL))

High anion gap — For patients with a high

anion gap, the etiology of their metabolic
acidosis is caused by an increased acid
concentration due to the presence of
unmeasured anions. (See 'Increased acid
concentration: High anion gap metabolic
acidosis' above.)

Results from the initial basic metabolic tests

and the history and physical examination are
typically helpful in determining the
underlying cause and in some circumstances,
guide further diagnostic evaluation:

● Elevated blood glucose and a history of

polyuria with or without weight loss,
abdominal pain, and vomiting is
suggestive of diabetic ketoacidosis.
Patients with diabetic ketoacidosis will
also have elevated urine ketones. (See
"Diabetic ketoacidosis in children:
Clinical features and diagnosis", section
on 'Diagnosis'.)

● Elevated blood urea nitrogen (BUN)

and serum creatinine are observed in
children with uremia and impaired renal
acid excretion. (See "Acute kidney injury
in children: Clinical features, etiology,
evaluation, and diagnosis", section on
'Other laboratory findings' and "Chronic
kidney disease in children:
Complications", section on 'Metabolic
acidosis'.)

● History of accidental or intentional

ingestion ( table 5):

• Ethylene glycol, ethanol, or

methanol ingestion results in both
a serum high anion gap and an
osmolal gap ( table 7). (See
"Methanol and ethylene glycol
poisoning: Pharmacology, clinical
manifestations, and diagnosis".)

• Elevated levels of iron, cyanide,

carboxyhemoglobin, salicylates,
cocaine, or amphetamines are
associated with high anion gap
metabolic acidosis but with a normal
osmolal gap. They can be confirmed
by laboratory testing and in some
cases, rapid drug screening. (See
"Acute iron poisoning" and
"Salicylate poisoning in children and
adolescents" and "Approach to the
child with occult toxic exposure",
section on 'Diagnosis of poisoning'.)

Serum osmolal gap greater than 10 to

15 mOsm/L is consistent with the
presence of ethylene glycol, ethanol, or
methanol. The serum osmolal gap is the
difference between measured serum
osmolalities and is calculated using the
following formula based on the normal
solutes (urea, sodium, and glucose)
(calculator 2 and calculator 3).

Calculated serum osmolality = (2 x

Na) + (BUN in mg/dL/2.8) + serum
glucose in mg/dL/18.

● Evidence of poor tissue perfusion

(shock) ‒ Blood lactic acid is elevated in
patients with poor tissue perfusion
(eg, sepsis, cardiac failure, and severe
hypoxia) and severe crush injuries. (See
"Septic shock in children: Rapid
recognition and initial resuscitation
(first hour)" and "Clinical manifestations
and diagnosis of rhabdomyolysis",
section on 'Clinical manifestations'.)

● Neurologic signs and symptoms ‒ A

history of severe hypotonia, seizures,
developmental delay, or apnea in a
newborn infant may be suggestive of an
inborn error of metabolism (IEM).
Elevated lactic acid is observed in
patients with mitochondrial disorders
and organic acidurias. A serum
ammonia level and a lactic acid and
pyruvic acid ratio may be helpful in the
differentiation of the IEM. (See "Inborn
errors of metabolism: Identifying the
specific disorder".)

Normal anion gap — Patients with

metabolic acidosis and normal anion gap
generally have an underlying disorder that
results from a loss of bicarbonate. Most
pediatric cases with normal anion gap are
due to losses of bicarbonate from the
gastrointestinal tract and are typically
diagnosed based on a history of diarrhea or
abnormal drainage from the small bowel or
pancreas.

If the etiology of the normal anion gap

remains unclear, a urine anion gap may be
useful. In the presence of metabolic acidosis,
a positive value for urine anion gap is
indicative of impaired ammonium excretion
(NH4+), such as is seen in distal (type 1) and
hypoaldosteronism (type 4) renal tubular
acidosis. Conversely, a negative value is
consistent with intact urinary ammonium
excretion as seen in children with metabolic
acidosis due to proximal (type 2) renal
tubular acidosis and gastrointestinal losses
[43]. (See "Urine anion and osmolal gaps in
metabolic acidosis".)

Urine anion gap = (Urine sodium + urine

potassium) – urine chloride

Mixed anion gap — The delta gap ratio may

helpful to confirm mixed metabolic acidosis
when both high and normal anion gap
causes coexist. However, the use of this tool
assumes that the baseline serum anion gap
(AG) and HCO3 concentration are known or
can be accurately estimated and that all
buffering is provided by bicarbonate and is
extracellular. (See "The delta anion gap/delta
HCO3 ratio in patients with a high anion gap
metabolic acidosis".)

The Delta gap ratio = Change in anion

gap (from a normal of 12
mmol/L)/change in bicarbonate (from
normal of 24 mmol/L).

The calculated delta gap ratio may be used to

separate the various forms of metabolic
acidosis based on the delta gap ratio:

● <0.4 – Normal anion gap metabolic

acidosis
● 0.4 to 0.99 – Mixed high and normal
anion gap metabolic acidosis
● 1.0 to 1.6 – High anion metabolic
acidosis
● >1.6 – High anion metabolic acidosis
mixed with metabolic alkalosis

TREATMENT

Whenever possible, the primary focus of

therapy for metabolic acidosis should be
directed at reversing the underlying
pathophysiologic process. Directed treatment
of the acidosis is based on whether the
metabolic acidosis is acute or chronic and the
severity of acidosis.

Acute metabolic acidosis — Acute

metabolic acidosis is generally well tolerated,
but extreme acidemia can be life-threatening.
The best management strategy is to treat the
underlying disorder, such as septic shock or
diabetic ketoacidosis (DKA).

Intravenous bicarbonate therapy — It is

controversial whether sodium bicarbonate or
other buffering agents should be used. In
most cases, sodium bicarbonate therapy
temporarily improves or may even correct
the acidemia, but will not alter the cause of
the metabolic acidosis. If the underlying
cause is not treated, the metabolic acidosis
remains persistent and results in subsequent
re-accumulation of H+. In our practice,
administration of intravenous (IV) sodium
bicarbonate is not routinely administrated.
We reserve the use of IV sodium bicarbonate
for cases of extreme acidosis, when the blood
pH <7.0 or for patients with impaired renal
acid excretion (with renal tubular acidosis,
acute kidney injury, or chronic kidney
disease) when their blood pH <7.2 or when
urine alkalization is needed. However, other
centers rarely use bicarbonate in the setting
of cardiac arrest due to hyperkalemia or
when urine alkalinization is required
therapeutically (severe rhabdomyolysis). (See
"Prevention and treatment of heme pigment-
induced acute kidney injury (including
rhabdomyolysis)", section on 'Bicarbonate'.).

Outcome data have not shown that

bicarbonate therapy during neonatal
resuscitation improves survival or near-term
neurologic outcomes [44]. Similar results was
also observed in adults with no proven
benefit in reducing mortality or end-organ
failure for those receiving IV sodium
bicarbonate compared with placebo. (See
"Approach to the adult with metabolic
acidosis", section on 'Acute metabolic
acidosis'.)

In addition, adverse effects of bicarbonate

therapy have been observed. (See "Primary
drugs in pediatric resuscitation", section on
'Sodium bicarbonate' and "Approach to the
adult with metabolic acidosis", section on
'Acute metabolic acidosis'.).

● Hypertonicity and hypernatremia due to

excessive administration of sodium
bicarbonate. The 8.4 percent sodium
bicarbonate solution has sodium
concentration of 1 mEq/mL (or 1000
mEq/L). When large quantities of IV
sodium bicarbonate are used, sodium
bicarbonate should be mixed in D5 IV
fluid to a concentration of 150 mEq/L to
avoid hypernatremia.

● Hypokalemia can occur with the rapid

correction of a metabolic acidosis. An
increase of 0.1 unit rise in pH can cause
a decrease of serum/plasma potassium
of 0.4 mEq/L as potassium moves
intracellularly to maintain
electroneutrality. (See "Hypokalemia in
children", section on 'Increased
intracellular uptake' and "Potassium
balance in acid-base disorders".)

● In patients with diabetic ketoacidosis,

the routine use of bicarbonate
administration is not recommended as
it has been associated with the
development of cerebral edema,
hypokalemia, and delaying the
resolution of ketosis. (See "Diabetic
ketoacidosis in children: Treatment and
complications", section on 'Metabolic
acidosis'.)

● Animal data demonstrated that rapid

infusion of sodium bicarbonate was
associated with adverse cardiovascular
effects.

Preadministration
considerations — When it is decided that IV
sodium bicarbonate will be used, the clinician
needs to consider the following prior to
administration:

● Effect of sodium bicarbonate on the

level of serum/plasma ionized
calcium – Ionized calcium
concentrations change 0.36 mmol/L for
every pH unit, so ionized calcium values
decrease when sodium bicarbonate is
infused. Ionized calcium levels can be
quickly obtained with a blood gas
measurement. Pre-treatment with IV
calcium is advised if:

• The corrected calcium is <8 mg/dL

• The ionized calcium is <1 mmol/L

IV calcium gluconate (preferred) 100

mg/kg, or IV calcium chloride 10 mg/kg,
can be slowly infused via a central
catheter or a large vein prior to infusing
sodium bicarbonate. Failure to correct
the calcium prior to the sodium
bicarbonate infusion can lead to acute
hypocalcemia due to enhanced binding
of ionized calcium to serum proteins
including albumin as the blood pH
increases. An acute decrease in the
ionized calcium concentration below
0.75 mmol/L (3 mg/dL) or a corrected
calcium <7 to 7.5 mg/dL can cause
cardiac dysrhythmias, seizures, and/or
even tetany.

● Compatibility with other IV

mediations – Sodium bicarbonate can
cause compatibility problems with
medications that are concurrently
infused due to its higher pH. For
example, precipitation of calcium
carbonate can occur when IV
administration of calcium
chloride/calcium gluconate is mixed
with sodium bicarbonate. If there is a
medication compatibility issue due to IV
fluid pH, use of sodium acetate instead
of sodium bicarbonate can be a good
option.

Administration and dosing

● Emergency setting – In an emergency,

8.4 percent sodium bicarbonate
solution is administered at a dose of 1
mEq/kg up to a maximum dose of 50
mEq, as an IV slow push. Five to 15
minutes after administration, blood gas,
ionized calcium, and serum electrolytes
are obtained to determine therapy
effectiveness and/or if there has been
an adverse effect of bicarbonate
therapy (low ionized calcium and
hypokalemia).

● Non-emergency setting repletion – In

a nonemergent setting, the dosing of
sodium bicarbonate is determined by
the calculated estimated bicarbonate
deficit using the following formula:

Estimated bicarbonate deficit =

(Target bicarbonate – current
bicarbonate) x weight (in kg) x 0.4 –
0.5

Half of the estimated bicarbonate deficit

is infused intravenously over 2 to 4
hours. The remaining half of the
bicarbonate deficit is infused over the
following 6 to 24 hours. A longer course
of infusion should be prescribed when
the sodium bicarbonate deficit is large
(>3 mEq/kg).

During and after repletion of the

bicarbonate deficit, blood gas, ionized
calcium, and serum electrolytes are
obtained to determine whether
additional bicarbonate therapy is
required and to detect any adverse
effect of bicarbonate therapy (low
ionized calcium and hypokalemia).

● Ongoing replacement therapy

directed at bicarbonate loss or H+
accumulation – To achieve a goal of
normalizing serum bicarbonate, the
total dose of sodium bicarbonate
delivered over the course of a day
should include not only the amount for
repletion but also the maintenance
dose of sodium bicarbonate needed to
replace ongoing bicarbonate loss or
buffer new H+ accumulation. For
example, patients with acute metabolic
acidosis who also have advanced
chronic kidney disease or distal renal
tubular acidosis may require an
additional 1 to 2 mEq/kg/day of sodium
bicarbonate to maintain normal total
CO2 concentrations from their chronic
condition.

When the patient can tolerate oral

medications, maintenance
administration should be changed to an
oral alkali ( table 8).

Renal replacement therapy — Dialysis

and/or continuous renal replacement therapy
may be needed for treatment of severe, life-
threatening metabolic acidosis unresponsive
to medical therapy, especially if it is
associated with other electrolyte
abnormalities such as hyperkalemia. (See
"Pediatric acute kidney injury (AKI):
Indications, timing, and choice of modality
for kidney replacement therapy (KRT)".)

Chronic metabolic acidosis — Children with

chronic acidosis typically require consistent
administration of exogenous oral alkali
preparations to correct the acidosis thereby
preventing the clinical manifestations of
chronic acidosis. We begin alkali therapy in
children with a primary renal non-anion gap
metabolic acidosis (chronic kidney disease
[CKD] and renal tubular acidosis [RTA]) and a
persistent serum total CO2 <21 mmol/L.

Alkali therapy includes a number of

formulations of sodium bicarbonate, sodium
citrate/citric acid, potassium citrate/citric
acid, and combination of sodium citric acid
and potassium citrate and citric acid (
table 8). The choice of therapy is
dependent on the underlying cause of
chronic metabolic acidosis, availability and
cost of the specific medication, and the
experience of the prescribing clinician.

In our practice, the choice of alkali therapy

and dosing is based on the underlying
etiology:

● Proximal or distal RTA can be

effectively treated with sodium
bicarbonate or sodium citrate-citric acid
therapy. The amount of bicarbonate
equivalent needed in children with
distal RTA is normally 1 to 2
mEq/kg/day. Children with proximal RTA
need a much higher oral alkali dose, 5
to 10 mEq/kg/day, due to the increased
urinary bicarbonate loss, which
increases with therapy. Oral alkali
treatment doses are typically divided
three or four times daily in infants and
two to three times daily in older
children. (See "Treatment of distal (type
1) and proximal (type 2) renal tubular
acidosis".)

● Hypokalemic distal renal tubular

acidosis requires potassium
supplementation. In most of our
pediatric cases, combination of
potassium citric acid/citrate and sodium
citrate oral liquid, which contains per
mL 1 mEq K, 1 mEq Na, and 2 mEq
citrate, is prescribed with an initial dose
of 2 to 4 mEq of bicarbonate equivalent
[45]. Some children, who have more
severe hypokalemia, require citric acid
potassium citrate therapy, which is
formulated with 2 mEq K and 2 mEq
citrate/mL. Some clinicians use a
combination sodium citrate-citric acid
and citric acid-potassium citrate therapy
to allow the separate adjustment of
alkali and potassium dosing in children
who cannot be successfully treated with
a single form of oral alkali.

Children who have nephrolithiasis due

to hypocitraturia are best treated with
either oral liquid citric acid potassium
citrate or potassium citrate tablet
therapy with an initial starting doses
around 1 mEq/kg/day.

Oral potassium-based alkali treatment

doses are typically divided three or four
times daily in infants and two to three
times daily in older children.

● For children with metabolic acidosis in

association with chronic kidney failure,
the goal of therapy is to maintain a total
CO2 at or above 22 mEq/L. We initially
begin sodium bicarbonate therapy at 1
to 2 mEq/kg per day divided into two to
three doses, and the dose is increased
until the clinical target is reached.
Citrate preparations are not suggested
to be used in children with CKD as it
may enhance aluminum absorption. In
addition, potassium-based therapy
should be avoided due to the risk of
developing hyperkalemia. (See "Chronic
kidney disease in children:
Complications", section on 'Metabolic
acidosis'.)

When alkali therapy is initiated, the

smallest does should be used and
increased in a stepwise fashion until the
targeted total CO2/bicarbonate level is
reached. Ongoing testing includes
monitoring acid base status (blood gas
sample), serum sodium, calcium,
potassium, and urine calcium/urine
creatinine ratios. The additional sodium
load with sodium-based oral alkali can
increase urinary calcium excretion,
which may worsen the nephrocalcinosis
frequently seen in children with distal
RTA.

For infants and young children, oral liquid

sodium bicarbonate and sodium citrate-citric
acid are normally provided. However, there
can be challenges in administration due to
poor palatability and burping is a common
side effect due to the rapid conversion of
bicarbonate into water and carbon dioxide in
the acidic environment of the stomach. If
these problems occur, oral alkali can be
mixed into formula or food to improve
palatability and reduce burping. When alkali
is mixed into formula, it is essential to ensure
that the entire volume of formula has been
consumed, otherwise the infant will not
receive the full alkali dose.

Finally, it is important to remember how

challenging giving oral alkali three or more
times per day to a child can be for families.
Before making an oral alkali dose adjustment
based on a laboratory result, it is important
to verify with the family, in a non-threatening
manner, compliance with the prescribed
dosing. If the serum total CO2 is low and
reported dosing by the family falls short of
the prescribed amount, encourage the family
to give the appropriate dose and repeat the
laboratory testing rather than increase the
oral alkali dose.

SUMMARY AND
RECOMMENDATIONS

● Metabolic acidosis is a biochemical

abnormality resulting in an increase in
hydrogen ions (H+) in the serum or
plasma. It can be either an acute or
chronic process and is secondary to a
wide range of underlying disorders.

● The etiology of metabolic acidosis in

children can be classified based on
pathogenesis ( table 1):

• Increased acid concentration (H+)

results in high anion gap metabolic
acidosis due to the overproduction
of endogenous acids, excessive
intake of exogenous acids, or
accumulation of acids due to the
kidney's inability to excrete acid in
sufficient quantities. (See 'Increased
acid concentration: High anion gap
metabolic acidosis' above.)

• Loss of bicarbonate results in normal

anion gap metabolic acidosis due to
losses from the gastrointestinal tract
and kidneys. (See 'Loss of
bicarbonate: Normal anion gap
metabolic acidosis' above.)

• Mixed high and normal gap

metabolic acidosis occurs when
children have coexisting conditions
with high and normal anion gap.
(See 'Mixed high anion and normal
gap acidosis' above.)

• Dilutional metabolic acidosis is

caused by a fall in serum
bicarbonate concentration due to
expansion of the intravascular fluid
volume with large volumes of
intravenous fluids that do not
contain bicarbonate. (See 'Dilutional
metabolic acidosis' above.)

● There are no distinguishing clinical

features of pediatric metabolic acidosis.
Typically, infants and children with
acute metabolic acidosis present with
symptoms related to the underlying
condition and may present with
tachypnea and/or hyperpnea as signs of
compensatory respiratory alkalosis.
Children with chronic metabolic acidosis
may have nonspecific findings including
poor growth, bony abnormalities, and
nephrolithiasis. Neonates are more
vulnerable to developing metabolic
acidosis due to their lower renal
capacity for net acid excretion. (See
'Clinical manifestations' above.)

● Metabolic acidosis is typically detected

by a low serum total CO2 in the
electrolyte panel and less commonly by
a low bicarbonate level within a blood
gas sample. Measurement of the serum
total CO2 in the electrolyte panel may
not be sufficient, as a low concentration
can be seen in metabolic acidosis or as
a compensatory response to a primary
respiratory alkalosis (increased
respiratory effort with lowering partial
pressure of carbon dioxide [PCO2]). To
distinguish between the two, a blood
gas may be needed to determine the
pH. If the patient has a simple
metabolic acidosis, then the patient will
have a low (acidic) pH, and if the patient
has respiratory alkalosis with
compensated metabolic acidosis, the
pH should be elevated (alkalotic). (See
'Detection: Electrolyte panel and blood
gas measurements' above.)

● Normative bicarbonate levels vary and

decrease from late adolescent to
neonates. (See 'Normative total CO2
and bicarbonate levels by age' above.)

● Metabolic acidosis increases

serum/plasma potassium and ionized
(free) calcium and magnesium.

● After confirmation of metabolic

acidosis, a diagnostic evaluation that
includes serum or plasma electrolytes,
calculation of the anion gap, and
elements from the history and physical
examination is usually sufficient to
determine the cause of the metabolic
acidosis and guide therapy (
algorithm 1). (See 'Diagnostic
evaluation' above.)

● Whenever possible, the primary focus of

therapy for metabolic acidosis should
be directed at reversing the underlying
pathophysiologic process. Directed
treatment of the acidosis is based on
whether the metabolic acidosis is acute
or chronic and the severity of acidosis.

• We suggest not to routinely

administer sodium bicarbonate to
children with metabolic acidosis
(Grade 2C). Intravenous bicarbonate
therapy can be considered in cases
of severe acidosis (pH <7.0),
recognizing that this is only a
temporary intervention. Dialysis
and/or continuous renal
replacement therapy may be needed
for life-threatening conditions
associated with metabolic acidosis,
especially if it is associated with
other electrolyte abnormalities such
as hyperkalemia. (See 'Acute
metabolic acidosis' above and
"Pediatric acute kidney injury (AKI):
Indications, timing, and choice of
modality for kidney replacement
therapy (KRT)", section on 'Indication
and timing for KRT'.)

• Children with chronic metabolic

acidosis typically require consistent
administration of exogenous oral
alkali preparations to correct
acidosis, thereby preventing the
clinical manifestations of chronic
acidosis (eg, poor growth, bone
abnormalities, and nephrolithiasis)

ACKNOWLEDGMENTS

The editorial staff at UpToDate acknowledge

Kanwal Kher, MD, MBA; Matthew Sharron,
MD; Mahesh Sharman, MD, FAAP; and Ashok
Sarnaik, MD, FAAP, FCCM, who contributed to
an earlier version of this topic review.

Use of UpToDate is subject to the Terms of

Use.

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