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alkaline phosphatase, and International Normalized Ratio, INR, of prothrombin time), CK, creatinine, plasma urea, and urate
4 Emergency Management of Metabolic Diseases
and the results of the basic investigations; these may include serum or plasma
levels of insulin, carnitine in plasma and/or urine, plasma total homocysteine,
urine orotic acid, and urine-reducing substances.
Dangers/Pitfalls
In a healthy, full-term neonate, acute sepsis, often the initial diagnosis,
is also uncommon; and inherited metabolic disease should always be
investigated in parallel from the beginning with basic as well as special
metabolic investigations.
Ammonia must be assayed, whenever a septic screen is considered.
Hypoglycemiaa Administer glucose at up to 10 mg/kg per min, monitoring plasma glucose frequently. If require-
ments exceed 12 mg/kg per min, suspect hyperinsulinism and administer glucagon as constant
intravenous infusion at 1 mg/24 h
Ketoacidosisb Administer glucose at up to 10 mg/kg per min
If the plasma bicarbonate is < 10 mmol/l, treat acidosis by administration of sodium bicarbonate:
administer an amount sufcient to half correct the calculated base decit. This may be repeated
whilst taking care not to overcorrect, causing metabolic alkalosis
Lactic acidosis In the case of secondary lactic acidosis, caused by hypoxemia, major organ failure, or intoxication,
by treating the underlying disorder
In the case of primary lactic acidosis, caused by pyruvate carboxylase deciency, pyruvate
dehydrogenase deciency, or mitochondrial respiratory chain defects, treat acidosis by adminis-
tration of sodium bicarbonate, giving an amount sufcient to maintain the plasma bicarbonate
> 10 mmol/l. The hypernatremia caused by the need to administer large amounts of sodium bi-
carbonate is treated by: (a) concomitant administration of furosemide, up to 2 mg/kg per dose,
along with sufcient potassium to prevent life-threatening hypokalemiac ; (b) hemodialysis,
continuous venous-venous hemoltration, or peritoneal dialysis; (c) use of THAM as bufferd
Consider administration of sodium dichloroacetate, 50 mg/kg, intravenously initially
Hyperammonemiae Stop all protein intake
Administer intravenous uids at 1.5 times the calculated maintenance to accelerate ammonium
excretion by water diuresis
Administer glucose, 10 mg/kg per min, to minimize endogenous protein breakdown and reliance
on amino acid oxidation for energy
Administer nitrogen wasting drugs: (a) sodium benzoate, 250 mg/ kg initially, then 250 mg/ kg per
24 h; (b) sodium phenylacetate or phenylbutyrate, 250 mg/ kg initially, then 250 mg/ kg per 24 h
Consider hemodialysis or continuous venous-venous hemoltration/dialysisf
Intractable Administer pyridoxine, 100 mg, intravenously to start, then 30 mg/kg per 24 h given orallyg
seizures Administer folinic acid, 5 mg/kg, intravenously to start, then 5 mg/kg per 24 h, orally or intra-
venously, divided into 3 equal doses
Administer pyridoxal phosphate, 30 mg/kg per 24 h, orally divided into 3 equal doses
Acute metabolic Removal of endogenous toxins, such as accumulate in maple syrup urine disease, organic
encephalopathy acidurias, urea cycle enzyme defects, etc.h
Ventilatory support, avoidance of overhydration, administration of mannitol for treatment of
cerebral edema, ionotropic drugs, etc.
Acute liver failure Removal of endogenous toxins, such as accumulate in hereditary tyrosinemia type Ih
Ventilatory support, replacement of essential products of liver metabolism (e. g., fresh frozen
plasma, albumin, etc.), ionotropic drugs, diuretics, etc.
a Caused either by impaired glucose production, i. e., glycogen storage diseases or disorders of gluconeogenesis (generally
associated with ketosis) or increased glucose utilization, i. e., either hyperinsulinism or fatty acid oxidation defects (see
Chaps. 15 and 35)
b Ketosis is generally an indication of impaired production or utilization of glucose
c This must be done with a central venous line in place and constant monitoring by electrocardiogram and serial plasma
electrolyte measurements
d The use of THAM for the correction of metabolic acidosis is controversial
e See Chap. 11
f Peritoneal dialysis is slow and relatively ineffective compared with hemodialysis, but it may be the only approach that is
It is probable that many metabolic patients who present in the rst days of life
with catastrophic illness die undiagnosed. Characteristically, there is an asymp-
tomatic interval in which toxic metabolites accumulate. In protein-dependent
metabolic disorders (aminoacidopathies, organic acidurias, urea cycle disor-
ders) and long-chain fatty acid oxidation defects, there is exogenous as well
as endogenous intoxication. Exogenous intoxication results from the intake of
specic substrates, and endogenous intoxication results from breakdown of
muscle protein or body fat during episodes of catabolism such as prolonged
fasting or intercurrent infections. If defects of the pyruvate dehydrogenase
complex (PDHC), the Krebs cycle, and the respiratory electron transport chain
present with catastrophic illness at birth or during infections or minor illnesses,
there is mostly not a symptom-free interval. However, these disorders present
more commonly as chronic progressive disease or with episodic deterioration.
By proposing the classication of clinical conditions and institution of ratio-
nal therapy in a suspected metabolic emergency in Table A.2, we are well aware
that different metabolic centers may treat differently and that evidence base is
lacking in several therapeutic strategies. Doses of drugs that are essential in the
acute emergency treatment and therefore should be available in every intensive
care unit are listed in Table A.3.
l-Carnitine Organic acidurias; carni- Bolus (only with org. acid.): x Bolus; CI
tine transporter defect; 100 mg/kg, then CI:
MCAD deciency; mito- 50100200 mg/kg per day
chondrial disorders
l-Arginine HCl Hyperammonemia SI: 2 mmol (350 mg)/kg over x SI; CI
90 min; after that, CI: 24 mmol
(350700 mg)/kg per day
Na-Benzoate Hyperammonemia SI: 250 mg/kg over 90 min, then x x SI; CI
CI: 250 mg/kg per day
Na-Phenyl- Hyperammonemia 250 mg/kg per day x x 3 SD
butyrate
Na-Phenyl- Hyperammonemia 250 mg/kg per day x 3 SD
acetate
Na-Dichlor- Lactic acidosis 50 mg/kg per dose x x Bolus; CI
acetate
Carbamylglutamate Hyperammonemia 100 mg/kg per day x 3 SD
Hydroxocobalamin Methylmalonic acidurias; 1 (5) mg/day i.m. or i.v. x 1 SD
(B12 ) disorders of cobalamin
metabolism; transcobal-
amin II deciency;
disorders of homocysteine
metabolism
Emergency Management (While Awaiting Diagnosis) 7
and glucose infusions can result in a further increase in lactate. The correction
of metabolic acidosis may require large amounts of sodium bicarbonate. In as
many as 20% of children with mitochondrial disease, the acute decompensa-
tion may be complicated by renal tubular acidosis, and this may increase the
requirement for sodium bicarbonate or trometamol (THAM).
In patients with mitochondrial disease, replacement of cofactors is com-
monly undertaken. The only documented evidence in support is the posi-
tive response to biotin in multiple carboxylase deciency and to riboavin
in some patients with multiple acyl-CoA dehydrogenase deciency. In severe
lactic acidemia and a history of insufcient food intake, a trial with thiamine
should be performed (Mayatepek and Schulze 1999).
If liver failure is the presenting feature, enteral feeding should be discon-
tinued, and glucose should be started via a peripheral i.v. line at 150 ml/kg
per day of a 10% solution in a neonate or infant while awaiting the results
of specic metabolic investigations, i. e., reducing substances, succinylacetone
and bile acids in urine, amino acids and galactose in plasma, and the enzyme
activity of galactose-1-phosphate uridyltransferase as well as acylcarnitines in
blood spots. Two diagnostic pitfalls must be remembered. Galactose is cleared
rapidly in a few hours from the body after discontinuation of enteral feeds, and
the determination of galactose-1-phosphate uridyltransferase activity is falsely
negative after a blood transfusion.
In summary a suspected metabolic emergency calls for prompt diagnos-
tic and therapeutic measures, giving a generous energy supply, promotion of
anabolism, and the use of pharmacological, and if necessary extracorporeal
detoxication. Early intervention is essential. Prior to the advent of programs
of expanded neonatal screening, many infants probably died without the benet
even of a diagnosis.
A.3 Anesthesia
Barbiturates Generally safe; however, they inhibit complex I of the mitochondrial respiratory chain
at high concentrations
Benzodiazepines Generally safe; however, they inhibit the transport of adenine nucleotides into mito-
chondria
Propofol Inhibits fatty acid transport and oxidation. Should not be used in patients with fatty
acid oxidations defects, and should be used with caution in patients with mitochondrial
respiratory chain defects
Halothane May precipitate cardiac arrhythmias in patients with mitochondrial respiratory chain
defects or fatty acid oxidation defects
Nitrous oxide Causes impairment of mitochondrial respiratory chain energy generation. It is specif-
ically contraindicated in patients with Vitamin B12 deciency (partially treated PKU)
and defects of 1C metabolism including cobalamin defects and methylenetetrahydro-
folate reductase deciency
Nondepolarizing muscle Increase risk of prolonged apnea in patients with metabolic myopathies
relaxants
Bupivacaine Inhibits ATP production in cardiac muscle; increased risk of cardiac arrhythmias in
patients with mitochondrial respiratory chain defects
General anesthesia and the stress of surgery can be responsible for acute
breakdown of tissue and consequently metabolic decompensation. This has
been observed in all groups of disorders which lead to endogenous intoxica-
tion. These are the protein-dependent metabolic disorders, aminoacidopathies,
organic acidurias, urea cycle disorders, as well as defects of fatty acid oxida-
tion. The main objective in the management of anesthesia and surgery in such
patients is to minimize catabolism. This objective is met best by avoiding anes-
thesia and surgery, if at all possible, until the patient is in an optimal metabolic
state and well over any infection. Elective surgery should then be scheduled in
a center with a team experienced in the acute management of this particular
metabolic disorder, including in-house facilities of a metabolic laboratory. As
a general principle, fasting must be avoided by a continuous supply of intra-
venous caloric infusions, and stopping and restarting enteral feeds as late as
possible and as soon as possible, respectively.
Surgery and anesthesia may also induce a metabolic crisis in Refsum disease
via mobilization of phytanic acid in fat stores. The same preventive approaches
apply. Disorders with a reduced fasting tolerance or with a disturbed energy
metabolism will also need very close monitoring and carefully monitored and
adjusted intravenous therapy.
Specic risks of general anesthesia are well recognized in patients with
mucopolysaccharidosis type IV (Morquio disease), but also types II and VI.
General anesthesia should be undertaken in these patients only in centers in
which anesthesiologists have had experience with patients with these diseases.
Wherever possible, local anesthesia is preferable, but, in young or uncooperative
patients such as those with Hunter or Sanlippo syndromes, this may not be
12 Emergency Management of Metabolic Diseases
Table A.5. Specimens to be considered for postmortem investigations in suspected metabolic disease
References