Review Article

Treatment strategies for acute metabolic dis-

orders in neonates
Sarar Mohamed
Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud
University, Riyadh, Saudi Arabia

ABSTRACT potentially treatable inborn errors of metabolism

Acute metabolic emergencies in neonates represent (IEM) cannot be overemphasized [15, 16]. The
a challenge to the medical and nursing staff. If not prognosis of IEM is dictated by the initial treatment
treated optimally, these disorders are associated with measures put in place in the early phase of clinical
poor outcome. Early diagnosis, supportive therapy presentation [17-20]. Having a practical and a
and specific measures addressing the derranged scientific sound approach dose not only facilitate the
metabolic process are the gold standards for favorable clinical diagnosis and management but also improve
results. This review highlights treatment strategies for the outcome. This article starts where the previous
Inborn Errors of Metabolism (IEM) presenting in the related one in this journal ends [21]. It deals with what
neonatal period. to do when a diagnosis is suspected and later when it
Key words: Inborn errors, Metabolism, Neonate. is confirmed. Therefore, the aim of this review is to
outline the principals of treatment measures that can
be applied comfortably at a general pediatric setting.
Acute metabolic disorders often manifest with life
threatening episodes in the neonatal period. [1-7]. The Treatment strategies
advances in technology, especially with the utilization Protein disorders such as urea cycle defects [22],
of tandem mass spectroscopy in the screening and maple syrup urine disease [23], and organic aciduria
diagnosis of metabolic disorders, mandate general [24-26] account for the majority of sick neonates
pediatricians to acquire basic knowledge and with IEM. Basic measures such as discontinuation
experience that help them to effectively manage of protein intake, supportive therapy and removal of
these growing disorders [8-14]. Early detection of toxic metabolites may improve the outcome of these

Correspondence to: How to cite this article:

Dr. Sarar Mohamed Mohamed S. Treatment strategies for acute metabolic
Department of Pediatrics (39), disorders in neonates. Sudan J Paediatr 2011;11(2):6-
King Khalid University Hospital and 13.
College of Medicine,
P. O. Box 2925,
King Saud University,
Riyadh 11461, Saudi Arabia
E-mail: [email protected]
 disorders [1, 2, 4, 5]. provision of high calories that fixes most of the
Energy insufficiency disorders such as unwanted metabolic effects, promote anabolism and
hyperinsulinism, and glycogen storage diseases inhibit catabolism. These strategies are listed in six
contribute to the adverse outcome of IEM in neonates measures (Table 1)
[27-29]. Treatment strategies for this group include

Treatment strategies for acute presented metabolic

disorders
Strategy Example
A. Suppress toxic metabolite production Stop oral feedings
B. Supportive therapy ----------------------
C. Removal of toxic metabolite Ammonia, leucine
D. Provision of optimum vitamins and Cobalamin, thiamine
cofactors
E. Specific (drugs and enzyme replacement) Carnitine, diazoxide
F. Special dietary management Low protein, galactose free formula

1- Supportive therapy
The vast majority of neonates with acute IEM and electrolytes are closely observed and corrected
present to medical facilities sick and often unstable. according to the clinical and laboratory findings. This
These patients need admission to high dependency is achieved by careful measurement of fluid balance
or intensive care unit where experienced staff, and frequent monitoring of serum electrolytes. The
who are familiar with management of acutely sick maintenance fluid of choice is usually Dextrose 10%
patients, are available. The priority step is to secure with added salts. Insulin infusion, 0.05 unit/ kg/ hour,
a patent airway (Table 2). Assisted ventilation may may be needed should hyperglycemia occurs. This
occasionally be needed should respiratory effort will maximize the calories, push glucose into cells,
becomes inadequate. Two peripheral intravenous and prevent osmotic diuresis. High calories promote
accesses should be inserted. A central venous line is anabolic process and inhibit catabolism leading to
necessary. Hypovolemic shock, if present, is treated decrease load on the affected metabolic pathways
by intravenous boluses of isotonic saline. Fluids with possible decrease in accumulation
of harmful abnormal metabolites. Discontinuation
of protein intake is a preventive measure as most of
IEM presenting with decompensation early in life
are protein metabolic disorders. Cardiac support in
terms of starting positive intropes helps patients
with circulatory compromise. Correction of
acidosis by intravenous sodium bicarbonate
infusion enhances cellular metabolic functions and
decreases the impact of metabolic decompensation
particularly on the central nervous system and the
contractility of the heart [30], Correction of
hypothermia and treatment of cerebral edema by
manitol are important measures to stabilize patients
with IEM.
Acute metabolic decompensation may occasionally
be induced by sepsis. Both sepsis and IEM may
show non specific symptoms early in the course of
the disease. Sepsis is well known to be associated
with certain IEM such as classic galactosemia [31].
So, it is sometimes difficult to know whether sepsis
is a cause or an effect of IEM especially early in the
course of the disease when a definitive diagnosis is
not reached. For all these reasons covering neonates
with broad spectrum antibiotics is essential if IEM
is suspected.
2- Removal of toxic metabolites worker [36]. Supportive measures as outlined
Removal of abnormally accumulated toxic metabolites above are the corner stone in the treatment. When
is an important strategy in the management of neonates serum ammonia level is above 200 µmol/l ammonia
with acute metabolic decompensation. Urea cycle lowering medications are commenced [37]. These
defects lead to accumulation of ammonia in the blood include intravenous infusion of arginine, sodium
[32]. Ammonia is normally converted to urea in a benzoate and sodium phenylbuturate. Dialysis is
cascade of biochemical reactions [33]. While ammonia indicated when ammonia level is above 400 µmol/l
is lipid soluble, urea is water soluble and accordingly [32-38]. Low protein special formula is started when
is excreted through the kidneys. High level of serum the patient is stable and ammonia has normalized.
ammonia is toxic to the body especially the central Maple syrup urine disease (MSUD) is caused by
nervous system leading to acute encephalopathy, deficiency of the enzyme branched- chain α ketoacid
seizures, and cerebral edema [34]. Early measurement dehydrogenase [23, 39]. The hallmark of this disorder
of serum ammonia in neonates with possible is accumulation of the amino acid leucine. Abnormal
metabolic disease is crucial [35]. Management accumulation of leucine is toxic to the brain leading
of hyperammonemia in neonates with urea cycle to acute encephalopathy and cerebral edema [23].
defects is summarized in Table 5. Management of Assay of serum amino acid early in the course of
hyperammonemia requires a multidsplinary approach the disease is usually diagnostic of this condition. If
with involvement of all relevant health professionals high serum leucine does not respond to the general
such as intensivist, nephrologist, pediatric surgeon, supportive measures, dialysis is indicated to remove
pharmacist, laboratory staff, dietician, and social leucine from blood [23].
 B) Supportive therapy for acute metabolic disorders
Goal Action
1. Respiratory support Oxygen, ventilation
2. Circulatory support Fluids, inotropes
 IV hydration if pH >7.2
3. Correction of acidosis
 Add IV bicarbonate if pH <7.2
 Sodium bicarbonate (1 mEq/mL
solution), 1 mEq/kg IV push at <1
mEq/min
 May repeat × 3 until pH >7.2; maximum
dose 7 mEq/kg/24 h

4. Fluid and electrolyte Adjust type of fluids according to electrolyte

correction level
5. Promote anabolism Provide high calories (Dextrose 10% or more)
6. Treat hypoglycemia IV dextrose-containing fluid infusion
7. Treat infection Appropriate infectious disease laboratory
evaluation and antibiotic therapy

3- Provision of optimum vitamins and cofactors to vitamin B 12 while few patients with MSUD
A number of deficient enzymes implicated in the
pathogenesis of IEM are catalyzed by certain vitamins
and cofactors. Supplying patients with these cofactors
augment and enhance the enzyme residual activity [1-
4]. Some variants of methylmalonic aciduria respond
improve when given thiamin [1-3]. Table 3 shows
vitamins and cofactors used in the treatment of IEM.
 4) Vitamins and cofactors used in acute metabolic disorders
Vitamin or cofactor Disorder
Thiamine Maple syrup urine disease

Riboflavin Gluteric aciduria type 2

Vitamin B12 Methylmalonic aciduria

Biotin Proprionic aciduria

Vitamin B6 Homocystinuria

4- Specific drugs and enzyme replacement therapy Oxidation of fatty acid takes place inside the
for IEM
Some IEM presenting in the neonatal period have
specific drug therapy. Table 4 shows the drugs used
in the treatment of these IEM. The role of arginine,
sodium benzoate, and sodium phenylbuturate in
treating hyperammonemia is already discussed.
Congenital hyperinsulinism (CH) is a potentially
treatable condition [40]. Newborn babies with CH
present with persistent hypoglycemia [41]. Their
glucose requirement is above 12 mg/kg/minutes [42].
The principal of treating CH is to provide adequate
carbohydrate supply and to inhibit insulin release
by pancreatic β cells. Neonates with CH respond to
glucagon, octreotide, and diazoxide [40-44]. Near
total pancreatectomy is indicated when medical
treatment fails [42-44].
Tyrosinemia type 1 is caused by deficiency of
the enzyme fumaryl acetoacetase [45]. This leads
to accumulation of tyrosine and the hepatotoxic
metabolite, succenylacetone that leads to acute
porphyria like crisis, as well as liver and kidney
damage [46]. 2-nitro-4-trifluoromethylbenzyl 1,
3 cyclohexanedione (NTBC) inhibits the enzyme
4-hydroxyphenylpyruvate dioxygenase, which is
required in an early step in the catabolism of tyrosine,
thus preventing the formation of succenylacetone
[45-47]. If started shortly after birth, NTBC prevents
development of progressive liver disease, and possibly
hepatoma [45, 46].
mitochondria [48]. To enter the mitochondria, long
chain fatty acids need to be bound to carnitine
which acts as a vehicle [49-51]. Carnitine itself
enters cells via the plasma membrane [51]. Primary
carnitine deficiency results from carnitine
transporter defect which is an autosomal recessive
condition that presents with cardiomyopathy in the
neonatal period [51-53]. This condition responds
well to carnitine replacement therapy and
represents one of the few treatable causes of
cardiomyopathy in neonates [51- 53]. Secondary
carnitine deficiency that may require replacement
therapy is associated with different types of fatty
acid oxidation defects and some of the organic
aciduria [51, 52].
Enzyme replacement therapy was a breakthrough in
the treatment of some of IEM like Pompe disease
[54, 55]. The deficient enzyme in Pompe disease is
lysosomal acid maltase
(α glucosidase). These patients may show evidence
of cardiomyopathy and hypotonia early in the
neonatal period. Enzyme replacement therapy for
these patients has shown remarkable effects with
improvement in cardiomyopathy, hypotonia and
developmental milestones [54-56].
 5) Specific drugs used in treatment of acute metabolic disorders
Drug Disorder
NTBC Tyrosinemia
Carnitine Carnitine transporter defect, organic aciduria
Betaine Homocystinuria
Carglumic acid N-acetylglutamate synthetase deficiency
Sodium benzoate Urea cycle defects
Sodium phenylbutyrate Urea cycle defects
Arginine Urea cycle defects
Glucagon Hyperinsulinism
Octreotide Hyperinsulinism
Diazoxide Hyperinsulinism

NTBC - 2-nitro-4-trifluoromethylbenzyl 1, 3 cyclohexanedione

5- 7- Diet Management
6-

C) Treatment of hyperammonemia
Goal Action
- Supportive therapy
- Promote acidosis Discontinue protein intake, intravenous 10% Dextrose, and
intravenous intralipids.
- Ammonia lowering  If ammonia 100- 200μmol/L Nutrition advice
drugs  If ammonia >150μmol/L in child or >200μmol/L in a
neonate, repeat immediately + give IV fluid therapy
 If repeat ammonia is > 200 µmol/l, start intravenous
infusion of arginine, Sodium benzoate, and sodium
phenylbutyrate.
 Repeat plasma ammonia after 3 hours –
• If   haemofiltration + PICU.
• If same or, continue with the same treatment and
monitor 3 hourly.
- Carglumic acid If acetylglutamate synthetase deficiency is suspected
- Haemofiltration or Plasma ammonia is >500μmol/L or >300μmol/L with
haemodialysis encephalopathy Intensive care (PICU)
- Low protein Start when ammonia is normal or near normal
formula
 6) Special dietary formula for acute metabolic disorders in the neonatal period
Special formula Disorder
Low tyrosine Tyrosinemia
Low methionine Homocystinuria
Low leucine, isoleucine, and valine Maple syrup urine disease
Low isoleucine, valine, methionine, and threonine propionic/ methylmalonic
aciduria Low protein Urea cycle defects
Galactose free Galactosemia
Frequent glucose and glucose polymers Glycogen storage disease

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The families should be taught to recognize precipitating factors (such as fasting and
infections) and early symptoms (malaise, anorexia, vomiting, ataxia or, in some
conditions, hyperventilation). Each patient is different.
The family should have clear written instructions and a tele- phone number for advice.
Almost invariably, treatment at home involves a high carbohydrate drink given
frequently, including during the night. The family should always carry information
about the condition and its acute management. Details of the emergency regimens can
be found in Dixon and Leonard (1992).