Inborn error of metabolismMANAGEMENT

PEDIATRIC-SPECIFIC PRESENTATIONS · 12 SECTIONS

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530 items

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Cardiovascular Presentations71▾

Respiratory Presentations52▾

Neurological Presentations83▾

Gastrointestinal Presentations74▾

Genitourinary and Reproductive Presentations48▾

Infectious Disease Presentations148▾

Trauma Presentations89▾

Toxicologic Presentations80▾

Psychiatric Presentations26▾

Musculoskeletal and Rheumatologic Presentations96▾

Dermatology Presentations23▾

Environmental and Exposure Presentations27▾

Hematologic and Oncologic Presentations36▾

Pediatric-Specific Presentations19▾

Bronchiolitis Croup Ductal-dependent congenital heart disease Emergency delivery Febrile seizure Hypercyanotic (tet) spell Inborn error of metabolism Intussusception Kawasaki disease Necrotizing enterocolitis Neonatal jaundice Neonatal resuscitation Nursemaid's elbow Pediatric DKA and cerebral edema Pediatric fever 0 to 28 days Pediatric fever 29 to 60 days Pediatric fever 61 to 90 days Pediatric septic shock Pyloric stenosis

Endocrine and Metabolic Presentations45▾

ENT and Maxillofacial Presentations27▾

Ophthalmologic Presentations19▾

Obstetric Presentations23▾

Systemic and Miscellaneous Presentations17▾

01Approach to the Critical Patient/attcp34

Immediate priorities

›Suspect an inborn error of metabolism in any neonate, infant, child, or adult with unexplained encephalopathy, high anion gap acidosis, hypoglycemia, or hyperammonemia

›Co-manage as sepsis until cultures and course allow it to be excluded, because sepsis both mimics and precipitates metabolic decompensation

›Point-of-care glucose is a first-line vital sign and is checked before any other investigation

›Draw the critical diagnostic sample at first venous access, but never delay dextrose, ammonia-lowering, or antibiotics to complete it

›Reverse catabolism immediately with a high glucose infusion rate

›Dextrose 10% infusion titrated to a glucose infusion rate of 8 to 10 mg/kg/min is the single most important early intervention

›Stop all protein and enteral feeds pending specialist advice, for no longer than 24 to 48 hours

›Treat fever aggressively because the catabolic stress of fever drives further decompensation

›Identify and treat immediately reversible threats to life

›Hypoglycemia below 3.3 mmol/l corrected with intravenous dextrose

›Dextrose 10% 2 to 5 mL/kg intravenous bolus, equal to 0.2 to 0.5 g/kg

›Verify against current pediatric guideline before use

›Severe hyperammonemia above 400 to 500 micromol/l triggers immediate nephrology and dialysis activation

›Seizures, cerebral edema, and impending herniation managed in parallel with metabolic therapy

›Mobilize the people who change outcome

›Telephone the on-call biochemical geneticist or regional metabolic service before results return

›Activate pediatric or adult intensive care and, where ammonia is high or rising, the renal replacement team

›If a diagnosis is known, retrieve and follow the individualized emergency treatment protocol and call the patient's metabolic centre

When to suspect an inborn error of metabolism

›Clinical patterns that should trigger metabolic workup

›Symptom-free interval of 24 to 72 hours after birth followed by rapid deterioration in a term neonate

›Recurrent unexplained episodes of vomiting, lethargy, ataxia, or coma, often with intercurrent illness or fasting

›Sepsis-like presentation with negative cultures, or repeated Reye-like or apparent life-threatening events

›Encephalopathy out of proportion to a modest illness, or developmental regression after a catabolic stressor

›Biochemical patterns that should trigger metabolic workup

›High anion gap metabolic acidosis with ketonuria disproportionate to the illness

›Hyperammonemia at any age without chronic liver disease

02History/hx42

Presenting illness and neurological course

›Timeline of the current episode

›Age at symptom onset and interval since last entirely well

›Rate of progression over hours versus days

›Prior identical episodes, their triggers, and what treatment aborted them, including intravenous dextrose at another facility

›Neurological symptoms

›Lethargy, irritability, altered behavior, or a drunken unsteady gait

›Poor feeding, food refusal, or long-standing self-selected protein aversion

›Seizures, abnormal posturing, or focal weakness suggesting a metabolic stroke

›Apnea, abnormal breathing pattern, or deep sighing respirations

›Systemic symptoms

›Vomiting, especially cyclical or recurrent and unexplained

›Bilious vomiting or abdominal distension, which also raises a surgical mimic such as malrotation with volvulus

›Reduced urine output, dark urine, or muscle pain suggesting rhabdomyolysis

Precipitants, feeding, and current regimen

›Catabolic triggers in the preceding hours to days

›Febrile illness, gastroenteritis, or reduced oral intake

›Prolonged fast, missed overnight feed, or preoperative fasting

›Surgery, anesthesia, trauma, immunization, or strenuous exercise

›High-protein meal, dietary change, weaning from breast milk, or introduction of fruit or sucrose

›Postpartum state in a woman, which can unmask ornithine transcarbamylase deficiency

›Dietary and fasting recall

›Detailed 24 to 48 hour food and fluid intake

›Exact duration of fasting immediately before presentation

›Known inborn error of metabolism and its management

›Specific diagnosis, treating centre, and whether an emergency letter or protocol exists

›Usual diet, special formula, and supplements such as carnitine, cofactors, or nitrogen scavengers

›Baseline and most recent metabolite levels, and recent adherence

03Physical Exam/exam40

Vital signs and growth parameters

›Age-specific respiratory rate and pattern

›Tachypnea defined as above 60/min in infants, above 40/min at 1 to 5 years, above 30/min over 5 years

›Kussmaul or deep sighing respirations indicate metabolic acidosis

›Tachypnea without hypoxemia or chest findings suggests acidosis compensation or central hyperventilation from hyperammonemia

›Heart rate, blood pressure, and perfusion

›Tachycardia above 160/min in infants or above 140/min in toddlers

›Hypotension defined as systolic below 60 mmHg in neonates and below 70 plus twice the age in years mmHg from 1 to 10 years

›Higher blood pressure targets apply in known chronic hypertension, coarctation, or renal disease

›Prolonged capillary refill, cool peripheries, or differential pulses suggesting a ductal-dependent cardiac lesion

›Temperature and glucose

›Fever as a decompensation trigger, or hypothermia in neonatal collapse

›Point-of-care glucose recorded as a vital sign

›Oxygenation

›Target oxygen saturation 94 to 98% in most patients

›Accept 75 to 85% in known cyanotic congenital heart disease, and use the patient's baseline in chronic lung disease or pulmonary hypertension

›Growth and hydration

›Weight, length, and head circumference plotted against prior values

›Macrocephaly in glutaric aciduria type 1 or Canavan disease, microcephaly in maternal phenylketonuria

›Dehydration assessed by mucous membranes, capillary refill above 3 seconds, skin turgor, and fontanelle

Neurological examination

›Level of consciousness and encephalopathy grade

›Serial Glasgow Coma Scale or AVPU with time-stamped entries

›Pupillary size and reactivity and any asymmetry

›Tone and movement

›Hypotonia, dystonic posturing, or abnormal involuntary movements

›Focal deficit indicating basal ganglia injury in organic acidemia or glutaric aciduria

›Signs of raised intracranial pressure

04Differential Diagnosis/ddx26

Life-threatening mimics to treat in parallel

›Sepsis and central nervous system infection

›Bacterial sepsis, meningitis, and encephalitis treated empirically alongside metabolic therapy

›Neonatal herpes simplex infection covered with intravenous acyclovir when plausible

›Cardiac and circulatory mimics

›Ductal-dependent congenital heart disease presenting with shock and acidosis in the first weeks of life

›Cardiogenic shock from a metabolic cardiomyopathy

›Endocrine and other metabolic mimics

›Diabetic ketoacidosis from new-onset type 1 diabetes

›Congenital adrenal hyperplasia with a salt-wasting crisis, marked by hyponatremia, hyperkalemia, and hypoglycemia

›Non-metabolic hypoglycemia from hyperinsulinism or cortisol and growth hormone deficiency

›Toxic and traumatic mimics

›Toxic alcohol, salicylate, iron, or metformin ingestion producing a high anion gap acidosis

›Abusive or accidental head trauma with intracranial hemorrhage

Metabolic causes by mechanism

›Intoxication disorders with a symptom-free interval

›Urea cycle defects producing hyperammonemia with respiratory alkalosis and a normal anion gap

›Organic acidemias such as methylmalonic, propionic, and isovaleric acidemia producing high anion gap ketoacidosis with secondary hyperammonemia

›Maple syrup urine disease producing encephalopathy, ketosis, and cerebral edema

›Galactosemia, hereditary fructose intolerance, and tyrosinemia producing liver failure and renal tubular dysfunction

›Energy deficiency disorders

›Fatty acid oxidation defects producing hypoketotic hypoglycemia, cardiomyopathy, arrhythmia, and rhabdomyolysis

›Glycogen storage and gluconeogenesis defects producing hypoglycemia with hepatomegaly and lactic acidosis

›Pyruvate dehydrogenase deficiency and mitochondrial respiratory chain disorders producing lactic acidosis and stroke-like episodes

›Ketogenesis and ketolysis defects producing hypoketotic hypoglycemia or overwhelming ketoacidosis

›Ranking principle

›Rank the workup by prevalence-weighted danger, placing sepsis, ductal-dependent cardiac disease, and hypoglycemia ahead of rarer specific enzymopathies

›A differential must account for every presenting sign the patient shows, not only the most suggestive one

05Laboratory Tests/lt49

First-line bloodwork

›Immediate bedside and blood gas testing

›Point-of-care glucose

›Venous or arterial blood gas with pH and pCO2 in mmHg

›Calculated anion gap using measured sodium, chloride, and bicarbonate

›Core metabolic panel

›Sodium, potassium, chloride, bicarbonate, urea, and creatinine, noting that a low urea supports a urea cycle defect

›Calcium, magnesium, and phosphate

›Lactate drawn free-flowing and processed promptly

›Blood ketones measured as beta-hydroxybutyrate

›Ammonia

›Free-flowing venous or arterial sample, transported on ice, analyzed within 15 to 30 minutes

›Interpret against age norms, roughly below 110 micromol/l in neonates and below 50 micromol/l in adults

›Do not delay treatment of a markedly elevated value while awaiting a repeat

›Organ and hematologic panels

›Liver enzymes, bilirubin, and coagulation profile

›Creatine kinase where rhabdomyolysis is possible

›Complete blood count, noting neutropenia and thrombocytopenia in organic acidemias

›Urinalysis for ketones, pH, reducing substances, and myoglobin

›Parallel exclusion tests

›Blood culture and, in neonates, cerebrospinal fluid analysis when safe

›Salicylate and toxic alcohol screen and serum osmolar gap when ingestion is possible

›Cortisol with a paired glucose when adrenal insufficiency is considered

The critical diagnostic sample

›Timing

›Collect at the moment of hypoglycemia or acute decompensation, because values become uninterpretable once corrected

›Collection must not delay dextrose or ammonia-lowering therapy

›Blood analytes to send or freeze

›Plasma amino acids and plasma acylcarnitine profile

›Free fatty acids and beta-hydroxybutyrate drawn together to assess the fatty acid oxidation ratio

›Insulin, C-peptide, cortisol, and growth hormone

›Extra plasma and serum separated and frozen

›Urine analytes

›First-void urine for organic acids, saved and frozen

›Urine ketones and urine reducing substances

›Sample handling

›Confirm whether the newborn screening specimen was taken and request expedited analysis

›Label every frozen sample with the exact collection time relative to the last feed

Result interpretation traps

›Ammonia pitfalls

›A struggling draw, tourniquet stasis, capillary sampling, hemolysis, or delayed processing falsely elevate ammonia, so repeat a borderline value correctly before acting

›Hyperammonemia with respiratory alkalosis and a normal anion gap points to a urea cycle defect and the scavenger and arginine pathway

›Hyperammonemia with a high anion gap acidosis and ketosis points to an organic acidemia and the carnitine and cofactor pathway

›Glucose and ketone pitfalls

›A normal glucose does not exclude an inborn error of metabolism, because intoxication disorders are often normoglycemic

›Absent or low urine and blood ketones during hypoglycemia in an infant is abnormal and points to a fatty acid oxidation defect

›Massive ketosis in a young infant is abnormal and points to an organic acidemia, maple syrup urine disease, or a ketolytic defect

›Acid-base and other pitfalls

›Hypoalbuminemia lowers the apparent anion gap and can mask organic acid accumulation

›Lactate is falsely raised by a struggling draw, an intraosseous sample, or delayed processing, so confirm a persistent elevation

›Mild transaminase rise with coagulopathy and hyperammonemia mislabeled as viral hepatitis or Reye syndrome may be a fatty acid oxidation, urea cycle, or mitochondrial disorder

›A normal newborn screen can be a false negative from early sampling, prior transfusion, or a disorder not on the panel

06Diagnostic Tests/dt34

Scoring Systems

›No validated emergency department score identifies or excludes an inborn error of metabolism

›Diagnosis rests on the biochemical pattern of glucose, gas, anion gap, ammonia, lactate, and ketones

›Serial Glasgow Coma Scale or AVPU is used to track encephalopathy rather than to diagnose

›Decision thresholds that function as action triggers

›Ammonia above 400 to 500 micromol/l, or coma, or a level rising despite scavenger therapy, triggers hemodialysis or continuous renal replacement

›A lower ammonia threshold and earlier dialysis apply in neonates and when the level is rising rapidly regardless of the absolute value

›Duration of hyperammonemic coma is the strongest predictor of neurodevelopmental outcome and drives urgency

›Screening panel reference

›Newborn screening panel content varies by jurisdiction and is defined by bodies such as the American College of Medical Genetics Recommended Uniform Screening Panel

›Knowing which disorders the local panel covers guides how much a normal result reassures

›Indications

›Non-contrast head CT to exclude hemorrhage or a mass lesion in the encephalopathic patient

›Assessment for diffuse cerebral edema in suspected hyperammonemia or maple syrup urine disease

›Interpretation and limits

›Early imaging is often normal and a normal scan does not exclude evolving edema

›Do not delay ammonia-lowering therapy or dextrose to obtain imaging

›Minimize repeat CT in children and move to MRI once the patient is stable

MRI

›Indications

›Brain MRI after stabilization to characterize the pattern of injury

›Magnetic resonance spectroscopy to detect a lactate peak in mitochondrial disease or a branched-chain resonance in maple syrup urine disease

›Characteristic patterns

›Bilateral globus pallidus injury in methylmalonic and propionic acidemia

›Cytotoxic edema of deep cerebellar and brainstem tracts in maple syrup urine disease

›Frontotemporal atrophy with wide sylvian fissures and subdural collections in glutaric aciduria type 1

›Stroke-like cortical lesions not respecting vascular territories in mitochondrial encephalopathy

07Disposition/dispo19

Consultation and specialist involvement

›Immediate telephone consultation

›On-call biochemical geneticist or metabolic physician, contacted before laboratory results return

›Poison centre or a 24-hour metabolic hotline when no local service is identified

›The patient's own metabolic centre when a diagnosis is already known

›Multidisciplinary activation

›Pediatric or adult intensive care for airway risk, vasoactive need, or dialysis

›Nephrology and the renal replacement team when ammonia is above 400 to 500 micromol/l or rising

›Metabolic dietitian and pharmacy for scavenger, cofactor, and special-formula preparation

Admission, transfer, and discharge criteria

›Admission and level of care

›Any suspected acute metabolic decompensation is admitted, usually to an intensive care setting

›Continuous cardiorespiratory monitoring, hourly neurological observations, and strict fluid balance

›Transfer criteria from a non-tertiary emergency department

›No on-site metabolic service, no pediatric dialysis capability, or a rising or high ammonia

›Encephalopathy, refractory acidosis, or hemodynamic instability

›Start dextrose 10% at a glucose infusion rate of 8 to 10 mg/kg/min, contact the receiving metabolic team before transport, and send the frozen critical sample with the patient

›Discharge criteria

›Reserved for a stable patient with a known diagnosis, a minor and resolved trigger, and explicit metabolic-team agreement

›Alert and at neurological baseline, tolerating oral carbohydrate, with normal glucose and with ammonia and blood gas at baseline

›Reliable caregivers, a written emergency regimen in hand, and metabolic clinic follow-up within 1 to 3 days

08Treatment/t161

Airway, breathing, and ventilation targets

›Indications for intubation

›Inability to protect the airway or Glasgow Coma Scale of 8 or less

›Progressive hypoventilation or refractory seizures

›Ventilation strategy

›Match minute ventilation to the pre-intubation respiratory pattern so that compensatory hyperventilation for metabolic acidosis is preserved

›Target pCO2 35 to 40 mmHg and avoid permissive hypercapnia, which worsens acidemia and raises intracranial pressure in hyperammonemia

›Use the patient's own baseline in pre-existing chronic hypercapnia from neuromuscular disease

›Induction and paralysis

›Ketamine 1 to 2 mg/kg intravenous

›Verify against current pediatric guideline before use

›Rocuronium 1 to 1.2 mg/kg intravenous, preferred over succinylcholine when hyperkalemia or rhabdomyolysis is possible

›Verify against current pediatric guideline before use

›Avoid etomidate when adrenal insufficiency is in the differential

›Avoid a maintenance propofol infusion because propofol-related infusion syndrome overlaps fatty acid oxidation and mitochondrial pathology

›A single induction dose of propofol 1 to 2 mg/kg is acceptable if unavoidable

›Verify against current pediatric guideline before use

Circulation, fluids, and sepsis co-treatment

›Fluid resuscitation

›Isotonic crystalloid, either 0.9% sodium chloride or a balanced isotonic solution, 10 to 20 mL/kg intravenous over 15 to 30 minutes, reassessed after each aliquot

›Verify against current pediatric guideline before use

›Avoid lactated Ringer's solution because the lactate load confounds serial lactate interpretation

›Avoid hypotonic maintenance fluid because free water worsens cerebral edema and hyponatremia

›Vasoactive support for fluid-refractory shock

›Epinephrine infusion 0.05 to 0.3 mcg/kg/min intravenous for cold shock

›Verify against current pediatric guideline before use

›Norepinephrine infusion 0.05 to 0.3 mcg/kg/min intravenous for warm shock

›Verify against current pediatric guideline before use

›Vasopressors restore perfusion but do not correct the metabolic substrate problem, so dextrose and toxin removal continue

›Empiric antimicrobial cover because sepsis both mimics and triggers decompensation

›Ampicillin 50 mg/kg/dose intravenous, every 8 to 12 hours in the first week of life and every 6 hours thereafter

›Ampicillin monotherapy is inadequate under 12 weeks of age and must be paired with a Gram-negative agent

›Cefotaxime 50 mg/kg/dose intravenous every 6 to 8 hours, or gentamicin 4 to 5 mg/kg once daily where cefotaxime is unavailable

›Acyclovir 20 mg/kg/dose intravenous every 8 hours when neonatal herpes simplex infection is plausible

›Beyond the neonatal period, use the local pediatric sepsis regimen adjusted for renal function

Dextrose and anti-catabolic therapy

›Correct hypoglycemia

›Dextrose 10% 2 to 5 mL/kg intravenous bolus, equal to 0.2 to 0.5 g/kg, for glucose below 3.3 mmol/l

›Use dextrose 10% in neonates and avoid dextrose 50% in young children because of vascular injury and rebound hypoglycemia

›Verify against current pediatric guideline before use

›Continuous dextrose to suppress catabolism

›Dextrose 10% infusion titrated to a glucose infusion rate of 8 to 10 mg/kg/min, roughly 1.5 times maintenance volume

›Escalate to 10 to 12 mg/kg/min if metabolites remain elevated, using central access when the concentration exceeds 12.5%

›Verify against current pediatric guideline before use

›Target blood glucose 5 to 8 mmol/l

›Accept a floor near 2.6 to 3.3 mmol/l transiently in neonates and a higher target when hyperinsulinism is confirmed

›Add insulin infusion 0.02 to 0.05 units/kg/hour if hyperglycemia above 10 mmol/l develops, rather than reducing the dextrose, so that anabolism is maintained

›Monitor glucose every 30 to 60 minutes and potassium every 2 hours during insulin use

›Nutritional principles

›Stop all protein and enteral feeds initially, then reintroduce protein within 24 to 48 hours to avoid provoking further catabolism

›Provide non-protein calories with dextrose and, once a fatty acid oxidation defect has been excluded, intravenous lipid emulsion 1 to 3 g/kg/day

›Do not give intravenous lipid emulsion when a fatty acid oxidation defect is suspected and not yet excluded

Ammonia-lowering therapy

›General measures

›Stop protein, maximize the glucose infusion rate to 8 to 10 mg/kg/min, and restore intravascular volume to support renal clearance

›Remove reversible nitrogen loads such as gastrointestinal bleeding and constipation

›Avoid valproate and systemic corticosteroids, which raise ammonia

›Nitrogen scavengers

›Sodium phenylacetate with sodium benzoate combined injection, loading 250 mg/kg of each component intravenous in dextrose 10% over 90 to 120 minutes, then the same total dose as a 24-hour maintenance infusion

›Give through a central line because extravasation causes severe tissue injury

›Anticipate hypokalemia, nausea, and hypotension, and monitor potassium every 2 hours

›Verify against current pediatric guideline before use

›Continue scavengers during dialysis

›Arginine and carnitine

›Arginine hydrochloride 200 to 600 mg/kg intravenous loading over 90 to 120 minutes, using the lower end for suspected proximal urea cycle defects and the higher end for citrullinemia and argininosuccinic aciduria

›Limit arginine if arginase deficiency is suspected

›Verify against current pediatric guideline before use

›Levocarnitine 100 mg/kg intravenous when an organic acidemia is possible

›Verify against current pediatric guideline before use

›Extracorporeal removal

›Hemodialysis or continuous renal replacement for ammonia above 400 to 500 micromol/l, coma, or a level rising despite scavengers and arginine

›Hemodialysis clears ammonia many times faster than peritoneal dialysis, and peritoneal dialysis and exchange transfusion are inadequate and should not be relied upon

›Recheck ammonia every 2 to 3 hours during the crisis and 1 hour after each dialysis run

Disorder-specific therapy

›Organic acidemias

›Levocarnitine 100 mg/kg/day intravenous in divided doses

›Verify against current pediatric guideline before use

›Hydroxocobalamin 1 mg intramuscular or intravenous daily for possible cobalamin-responsive methylmalonic acidemia

›Biotin 10 to 20 mg/day enteral or intravenous for possible multiple carboxylase or biotinidase deficiency

›Glycine 150 to 250 mg/kg/day with levocarnitine for isovaleric acidemia

›High glucose infusion rate, volume for urinary clearance, and correction of acidosis

›Maple syrup urine disease

›Drive anabolism with dextrose 10%, intravenous lipid emulsion, and insulin 0.02 to 0.05 units/kg/hour titrated to glucose

›Remove branched-chain amino acids by stopping protein and starting branched-chain-free feeds with the metabolic team

›Thiamine 10 mg/kg/day, to a maximum of 500 mg per day, for a possible thiamine-responsive variant

›Verify against current pediatric guideline before use

›Hemodialysis or continuous renal replacement for rapidly rising leucine or worsening encephalopathy or cerebral edema

›Monitor sodium closely and avoid hypotonic fluid because cerebral edema is the main threat

›Fatty acid oxidation defects

›Dextrose 10% titrated to a glucose infusion rate of 10 to 12 mg/kg/min to stop lipolysis, avoiding fasting beyond 4 hours

›Verify against current pediatric guideline before use

›Do not give intravenous lipid emulsion, and discuss carnitine use with the metabolic team because high-dose carnitine in long-chain defects may promote arrhythmia

›Continuous cardiac monitoring for arrhythmia and serial assessment for rhabdomyolysis and cardiomyopathy

›Galactosemia and hereditary fructose intolerance

›Remove lactose, galactose, sucrose, and fructose from all intake

›Supportive care for liver failure and coagulopathy, with empiric cover for Escherichia coli sepsis in suspected galactosemia

›Known-patient emergency regimen

›Follow the individualized written protocol and give the patient's own scavenger, cofactor, and glucose-polymer regimen

›Contact the patient's metabolic centre to co-direct therapy

Empiric cofactor and vitamin therapy

›Rationale and timing

›Some crises are cofactor-responsive, and an empiric trial is low-risk and potentially decisive

›Give cofactors only after the critical diagnostic sample has been drawn

›Agents and doses

›Hydroxocobalamin 1 mg intramuscular or intravenous

›Biotin 10 to 20 mg enteral or intravenous

›Riboflavin 50 to 100 mg enteral

›Thiamine 10 mg/kg intravenous, to a maximum of 500 mg per dose

›Verify against current pediatric guideline before use

›Levocarnitine 100 mg/kg intravenous

›Verify against current pediatric guideline before use

›Pyridoxine 100 mg intravenous for refractory neonatal seizures, with apnea monitoring during administration

›Verify against current pediatric guideline before use

›Folinic acid 5 mg for folinic-acid-responsive seizures

Acidosis, electrolytes, and monitoring

›Metabolic acidosis

›Sodium bicarbonate 1 to 2 mmol/kg intravenous slow push, or an infusion, only for pH below 7.1 or bicarbonate below 10 mmol/l with hemodynamic compromise

›Anticipate hypokalemia, hypocalcemia, sodium loading, and paradoxical central nervous system acidosis

›Correcting catabolism and restoring perfusion lowers organic acid production more reliably than bicarbonate

›Large ongoing base deficits in organic acidemia may require repeated replacement or dialysis

›Electrolyte and refeeding surveillance

›Potassium every 2 hours during scavenger, insulin, or bicarbonate therapy, replacing as needed

›Calcium, magnesium, and phosphate every 4 to 6 hours, anticipating refeeding-related falls

›Venous gas, lactate, and electrolytes every 2 to 4 hours until stable

›Electrocardiographic monitoring during electrolyte shifts

›Baseline 12-lead electrocardiogram and continuous telemetry, because scavengers, insulin, bicarbonate, and refeeding all lower potassium

›Hypokalemia produces U waves, flat T waves, QT prolongation, and ectopy, and hypocalcemia and hypomagnesemia prolong the QT interval

›Long-chain fatty acid oxidation defects cause conduction block and ventricular arrhythmia, and propionic acidemia causes QT prolongation and cardiomyopathy

›Correct potassium, magnesium, and calcium before and during dialysis, and watch the QT interval when giving ondansetron 0.15 mg/kg intravenous to a maximum of 4 mg per dose for vomiting

Seizures, cerebral edema, and raised intracranial pressure

›Seizure management

›Correct glucose, sodium, calcium, and magnesium first

›Lorazepam 0.1 mg/kg intravenous, to a maximum of 4 mg per dose, or midazolam 0.15 mg/kg intramuscular

›Verify against current pediatric guideline before use

›Levetiracetam 40 to 60 mg/kg intravenous, to a maximum of 4.5 g, as the second-line agent

›Verify against current pediatric guideline before use

›Avoid valproate, otherwise loaded at 20 to 40 mg/kg intravenous for status epilepticus, because of hepatotoxicity, rising ammonia, and fatal decompensation in mitochondrial and urea cycle disorders

›Obtain electroencephalography for non-convulsive status when encephalopathy persists without a metabolic explanation

›Cerebral edema and raised intracranial pressure

›Head of bed at 30 degrees, normocapnia at pCO2 35 to 40 mmHg, normonatremia to mild hypernatremia, and treatment of fever

›Hypertonic saline 3% 3 to 5 mL/kg intravenous over 10 to 20 minutes for signs of herniation

›Verify against current pediatric guideline before use

›Mannitol 0.5 g/kg intravenous as an alternative osmotic agent

›Verify against current pediatric guideline before use

›Cerebral edema is most likely in hyperammonemia and maple syrup urine disease and mandates intensive care and neurosurgical involvement

Iatrogenic harms and drugs to avoid

›Airway and sedation harms

›Intubation with an unmatched ventilator rate lets pCO2 rise and can precipitate fatal cerebral edema in hyperammonemia, so match minute ventilation and target pCO2 35 to 40 mmHg

›A prolonged propofol infusion is contraindicated, and a single induction dose of propofol 1 to 2 mg/kg is acceptable if unavoidable

›Etomidate is avoided when adrenal insufficiency is in the differential

›Fluid and glucose harms

›Hypotonic and lactate-containing fluids are avoided in favor of isotonic fluid and dextrose 10%

›Prolonged fasting for procedures is dangerous, and a dextrose 10% infusion at a glucose infusion rate of 8 to 10 mg/kg/min must run through any nil-by-mouth period

›Circulatory support harms

›Vasopressors do not correct energy failure and may raise lactate, but remain indicated for shock

›An intra-aortic balloon pump is not used in infants, and venoarterial extracorporeal membrane oxygenation is considered only as a bridge in reversible fatty acid oxidation cardiomyopathy or arrhythmia in discussion with cardiology and metabolic teams

›Anticoagulation, fibrinolysis, and analgesia

›No specific contraindication to therapeutic anticoagulation, and homocystinuria carries a prothrombotic risk that may require it

›Fibrinolysis is not indicated, and hepatic coagulopathy is corrected with vitamin K 1 to 10 mg intravenous and fresh frozen plasma for active bleeding

›Acetaminophen 15 mg/kg every 6 hours, to a maximum of 75 mg/kg and 4 g in 24 hours, is dose-reduced in hepatic dysfunction from tyrosinemia, galactosemia, or a fatty acid oxidation defect

›Nonsteroidal anti-inflammatory drugs such as ibuprofen 10 mg/kg every 6 to 8 hours are avoided with renal impairment, dehydration, or rhabdomyolysis

›Opioids are reduced in dose and monitored closely when encephalopathy is present

›Specific drugs to avoid

›Valproate, salicylates, systemic corticosteroids, and metformin each precipitate or worsen decompensation and are withheld unless a specific indication exists

›Oxygen is titrated to a saturation of 94 to 98%, accepting 75 to 85% in cyanotic congenital heart disease and the patient's baseline in chronic lung disease or pulmonary hypertension

›Therapy-is-not-working troubleshooting

›Ammonia not falling within 4 to 6 hours of scavengers, arginine, and a high glucose infusion rate: escalate to dialysis now and search for ongoing catabolism, occult infection, inadequate calories, a missed protein source, or gastrointestinal bleeding

›Persistent acidosis: increase the glucose infusion rate, add insulin, ensure renal perfusion, consider dialysis, and re-evaluate for sepsis or a toxic ingestion

›Hypoglycemia despite a glucose infusion rate above 12 mg/kg/min: check the delivered rate and the line, involve endocrinology for hyperinsulinism, and give hydrocortisone 1 to 2 mg/kg intravenous if adrenal insufficiency is possible

›Worsening encephalopathy with normal ammonia and glucose: reassess for cerebral edema, non-convulsive seizures, hyponatremia, rising leucine, or an intracranial event

09Special Populations/sp40

Pregnancy

›Postpartum hyperammonemic crisis

›A previously asymptomatic woman who is a carrier of ornithine transcarbamylase deficiency can decompensate in the first 3 weeks postpartum from involutional catabolism

›Hyperemesis, labor, and antenatal corticosteroids are additional triggers

›Suspect it in postpartum encephalopathy with respiratory alkalosis and a low urea, and treat with dextrose 10%, protein restriction, arginine, nitrogen scavengers, and dialysis

›Maternal disease pointing to a fetal defect

›Acute fatty liver of pregnancy or HELLP syndrome in the mother should prompt testing of the newborn for a long-chain fatty acid oxidation defect

›A prior unexplained neonatal death in the family adds weight to this workup

›Pregnancy in a woman with a known inborn error of metabolism

›Decompensation risk is highest peripartum and immediately postpartum, so continue the emergency regimen and run dextrose 10% through labor rather than fasting

›Maternal phenylketonuria with poor control is teratogenic, causing microcephaly and congenital heart disease

›Drug considerations

›Valproate is contraindicated

›Sodium phenylacetate with sodium benzoate is reserved for life-threatening hyperammonemia, when maternal benefit outweighs fetal risk

›Levocarnitine and levo-arginine are considered acceptable, and management is shared with maternal-fetal medicine

Geriatric

›Late first presentation of a partial defect

›Adult-onset ornithine transcarbamylase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, citrullinemia type 2, late-onset Pompe disease, and mitochondrial disease can first decompensate in later life

›Triggers include a high-protein supplement, bariatric surgery, corticosteroids, chemotherapy, parenteral nutrition, a gastrointestinal bleed, and starting valproate

›Adult hyperammonemic encephalopathy differential

›Cirrhosis and portosystemic shunting are the commonest causes, alongside valproate, urease-producing urinary tract infection with urinary retention, post-transplant hyperammonemia syndrome, and a gastrointestinal bleed

›Check ammonia in unexplained adult encephalopathy rather than assuming a normal liver excludes it

›Physiologic and pharmacologic caveats

›Reduced renal function alters scavenger and carnitine clearance and lowers the dialysis threshold

›Reduced reserve and polypharmacy justify a lower threshold for intensive care and dialysis

›A mitochondrial stroke-like episode mimics ischemic stroke, so avoid unnecessary thrombolysis and consider intravenous arginine

Pediatrics

›Neonate from birth to 28 days

10Background/b36

Epidemiology

›Collective and individual frequency

›Inborn errors of metabolism collectively affect roughly 1 in 800 to 1 in 2500 live births, while most individual disorders are rarer than 1 in 100,000

›Expanded tandem mass spectrometry screening detects an amino acidopathy, organic acidemia, or fatty acid oxidation defect in roughly 1 in 3000 to 1 in 4000 newborns

›Representative disorder frequencies

›Medium-chain acyl-CoA dehydrogenase deficiency about 1 in 15,000 to 1 in 20,000, the commonest fatty acid oxidation defect

›Phenylketonuria about 1 in 10,000 to 1 in 15,000, and galactosemia about 1 in 30,000 to 1 in 60,000

›Urea cycle disorders collectively about 1 in 35,000, with ornithine transcarbamylase deficiency the commonest and X-linked

›Maple syrup urine disease about 1 in 185,000 overall but as frequent as 1 in 400 in some consanguineous populations

›Burden and outcome

›Inborn errors are a recognized cause of neonatal death and of apparent life-threatening events

›The duration of hyperammonemic coma is the strongest predictor of neurodevelopmental outcome

›Consanguinity raises the pooled risk severalfold because most disorders are autosomal recessive

Pathophysiology

›Intoxication disorders

›A block in a catabolic pathway lets a small toxic molecule accumulate proximal to the enzyme defect

›Urea cycle defects accumulate ammonia with respiratory alkalosis, organic acidemias accumulate organic acids with high anion gap ketoacidosis and secondary hyperammonemia, and maple syrup urine disease accumulates branched-chain amino and keto acids

›A symptom-free interval precedes the first crisis, which is triggered by catabolism or a protein load

›Energy deficiency disorders

›Fatty acid oxidation, ketogenesis, gluconeogenesis, glycogenolysis, pyruvate metabolism, and respiratory chain defects impair adenosine triphosphate production

›The result is fasting intolerance, hypoketotic or hyperketotic hypoglycemia, lactic acidosis, cardiomyopathy, myopathy, and hepatopathy

›Complex molecule disorders

›Lysosomal, peroxisomal, and glycosylation disorders are usually chronic and progressive and less often present as an acute emergency department crisis

›Exceptions that can be acute include a peroxisomal disorder presenting with neonatal seizures and profound hypotonia

›Mechanism of neurological injury

›Ammonia drives astrocytic glutamine accumulation, osmotic swelling, cerebral edema, and raised intracranial pressure, and also impairs neurotransmission and mitochondrial function

›Secondary carnitine depletion from organic acid conjugation and urinary loss further impairs fatty acid oxidation

11Patient Discharge Instructions/pdi27

When emergency department discharge is appropriate

›Preconditions

›A patient with a known diagnosis, a minor and fully resolved trigger, and explicit agreement from the metabolic team

›Alert and at neurological baseline, tolerating oral carbohydrate, with normal glucose and with ammonia and blood gas at baseline

›Safety net before leaving

›A written emergency regimen in hand and a confirmed metabolic clinic contact within 1 to 3 days

›Caregivers able to describe the return precautions and the home glucose threshold

copy discharge instructions

›Start the home emergency regimen at the first sign of illness

›Begin the prescribed high-carbohydrate emergency drink, the glucose-polymer solution, at the first fever, vomiting, or drop in eating

›Give the emergency feed every 2 hours day and night until the child is well and eating normally

›Do not restart normal protein, and do not stop carnitine, cofactors, or special formula, until your metabolic team advises

›Do not let the child go without carbohydrate

›No child with a suspected or confirmed metabolic disorder should go more than 4 hours without a carbohydrate source when unwell

›When well, follow the maximum overnight fast your metabolic team has set, commonly 6 to 8 hours

›Control fever to reduce metabolic stress

›Acetaminophen 15 mg/kg by mouth every 6 hours, not exceeding 5 doses or 75 mg/kg in 24 hours and not exceeding 4 g in 24 hours

›Avoid ibuprofen 10 mg/kg by mouth every 6 to 8 hours unless your metabolic team has approved it, and avoid all aspirin-containing products

›Return immediately or call emergency services if

›More than one episode of vomiting, or the emergency drink cannot be kept down for more than 4 to 6 hours

›Unusual sleepiness, difficulty waking, confusion, or irritability

›Fast or deep breathing, floppiness, twitching, or a seizure

›A home glucose reading below 3.5 mmol/l

›Carry your documentation to every visit

›Bring the emergency letter and the metabolic centre's 24-hour phone number and show them at triage

›Ask staff to telephone the metabolic team before giving or withholding treatment

›Follow-up

›Metabolic clinic within 1 to 3 days, primary care within 48 hours, and keep every repeat newborn screen or metabolite blood draw

12References/r22

Acute metabolic decompensation guidelines

›Urea cycle disorder management

›Haberle J and colleagues, Suggested guidelines for the diagnosis and management of urea cycle disorders, first revision, Journal of Inherited Metabolic Disease, 2019

›Enns GM and colleagues, Survival after treatment with sodium phenylacetate and sodium benzoate for urea cycle disorders, New England Journal of Medicine, 2007

›Organic acidurias and cobalamin disorders

›Baumgartner MR and colleagues, Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia, Orphanet Journal of Rare Diseases, 2014

›Huemer M and colleagues, Guidelines for diagnosis and management of the cobalamin-related remethylation disorders, Journal of Inherited Metabolic Disease, 2017

›General emergency protocols

›British Inherited Metabolic Disease Group emergency management guidelines for adults and children

›Society for Inherited Metabolic Disorders and American College of Medical Genetics ACT sheets and diagnostic algorithms for newborn screening follow-up

Disorder-specific guidelines

›Maple syrup urine disease

›Frazier DM and colleagues, Nutrition management guideline for maple syrup urine disease, Molecular Genetics and Metabolism, 2014

›Strauss KA and colleagues, Classical maple syrup urine disease, natural history and management review, current edition

›Glutaric aciduria type 1

›Boy N and colleagues, Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I, revised, Journal of Inherited Metabolic Disease, 2017

›Nitrogen scavenger therapy

›Sodium phenylacetate and sodium benzoate injection, United States prescribing information

Resuscitation and supportive care

›Pediatric resuscitation and sepsis

›American Heart Association Pediatric Advanced Life Support guidelines, current edition

›Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children, 2020

›Reference texts

›Saudubray JM and colleagues, Inborn Metabolic Diseases, Diagnosis and Treatment, current edition

›GeneReviews chapters on urea cycle disorders, organic acidemias, and fatty acid oxidation defects

Evidence & Review

Reviewed by SymptomDx Medical Team · Last reviewed September 13, 2026

SymptomDx is an educational tool for medical professionals. It does not replace clinical judgment. Verify all clinical data and drug dosages with authoritative sources.