Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.
Inborn errors of metabolism and decompensation
Paediatrics and child health · UK scope · Sources checked 27 Aug 2026 · Clinical review pending
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Encephalopathy with hyperammonaemia or metabolic collapse
A newborn or child with rapidly falling consciousness, respiratory alkalosis, severe acidosis, hypoglycaemia or liver dysfunction may accumulate a neurotoxic metabolite while ongoing catabolism accelerates the crisis.
Action: Use ABCDE, call paediatric metabolic and intensive-care teams, check glucose, gas, lactate, electrolytes, liver and coagulation and send an urgently handled ammonia plus metabolic blood and urine samples. Start the current BIMDG high-energy emergency regimen or IV glucose, stop natural protein temporarily when indicated and mobilise scavenger therapy and haemofiltration early for severe or rising ammonia.
Overview
Recognise metabolic decompensation in a newborn or child with encephalopathy, hypoglycaemia, acidosis, hyperammonaemia or organ failure, stop catabolism immediately and obtain time-critical diagnostic samples while specialist detoxification and dialysis are mobilised.
Inborn errors of metabolism are individually rare but collectively important causes of neonatal and childhood collapse. Enzyme, transporter or cofactor defects interrupt fuel use or waste disposal. The child may accumulate a toxic substrate, lack an essential product, fail to produce energy during fasting or combine these mechanisms. Affected newborns can appear normal until milk protein intake, fasting or infection exposes the block. A normal antenatal course and examination at birth do not provide reassurance.
Ask about consanguinity, sibling or unexplained neonatal deaths, miscarriages, developmental regression, unusual odour, feeding intolerance, recurrent vomiting, fasting episodes, cardiomyopathy, liver disease and medicines. Establish the exact time since last effective carbohydrate and protein intake. In a known disorder, find the emergency letter and call the named metabolic centre. The letter's glucose-polymer concentration, safe fasting interval, protein plan and special medicines take priority over generic advice.
Practice
Two practice questions
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Question 1 of 2
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Paediatrics and child healthOriginal SBA
First biochemical priority
A 4-day-old who fed normally for two days develops vomiting, tachypnoea, abnormal tone and worsening drowsiness. Blood gas shows respiratory alkalosis and glucose is normal. Which urgent test is most important?
Sources and review status4 sources · checked 27 Aug 2026 · clinical review pending+
Sources
Sources and review status
National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.
BIMDG paediatric emergency guidelinesDiagnosis-specific UK emergency regimens, glucose delivery, medicines, monitoring and escalation for known metabolic disorders.
BIMDG undiagnosed emergency problemsInitial investigation and management of hypoglycaemia, hyperammonaemia and unexplained metabolic deterioration.
Presentation patterns guide but do not prove diagnosis. Urea-cycle defects often cause poor feeding, vomiting, tachypnoea from respiratory alkalosis and rapidly progressive encephalopathy with very high ammonia and little initial acidosis. Organic acidaemias more often produce high-anion-gap acidosis, ketosis, lactate and secondary hyperammonaemia. Fatty-acid oxidation disorders cause hypoketotic hypoglycaemia, liver or cardiac dysfunction after fasting. Maple-syrup urine disease causes encephalopathy, abnormal tone and a characteristic odour but should not be diagnosed by smell alone.
Use ABCDE and check glucose immediately. Treat hypoglycaemia with paediatric-dose 10% glucose and maintain an age-appropriate high glucose delivery to suppress catabolism. If oral intake is safe and the child has a diagnosis-specific regimen, start the prescribed glucose-polymer drink; nasogastric delivery can be used when alertness and airway permit. Vomiting, reduced consciousness, circulatory compromise or failure of enteral energy requires IV glucose and critical-care monitoring.
Send an urgent plasma ammonia for unexplained encephalopathy, respiratory alkalosis, seizures or liver dysfunction. A falsely high result follows difficult sampling, haemolysis, delay or poor handling, so repeat promptly from a free-flowing sample while contacting the metabolic team if the value or phenotype is concerning. Do not await a second result before resuscitation or specialist discussion in a deteriorating child. Ammonia is neurotoxic, and duration of exposure affects outcome.
Take blood gas, lactate, glucose, electrolytes, urea, creatinine, liver tests, coagulation, calcium, magnesium, phosphate, creatine kinase, full blood count and infection cultures as indicated. Save plasma for amino acids and acylcarnitines. During hypoglycaemia add beta-hydroxybutyrate, free fatty acids, insulin, C-peptide, cortisol and growth hormone. Obtain urine early for ketones, organic acids and reducing substances where relevant. Samples taken after glucose remain useful, but the untreated pattern can be more discriminating.
Stop natural protein temporarily when hyperammonaemia, organic acidaemia or branched-chain amino-acid toxicity is suspected, while providing non-protein energy. This is a short emergency measure, not prolonged starvation; specialist dietitians reintroduce controlled essential protein, often within 24 to 48 hours, to prevent endogenous protein breakdown. Continue diagnosis-specific cofactors or scavengers if the emergency plan instructs, and avoid medicines known to worsen the suspected disorder, such as valproate in hyperammonaemia.
The metabolic team may prescribe intravenous sodium benzoate, sodium phenylbutyrate or phenylacetate, arginine, carglumic acid, carnitine, hydroxocobalamin or other antidotal and cofactor treatment according to the mechanism. These are high-risk, weight- and diagnosis-specific regimens requiring exact BIMDG or centre protocols, pharmacy preparation and biochemical monitoring. An empirical cocktail without specialist direction can delay the therapy that matters or add sodium, nitrogen or toxicity.
Escalate early for extracorporeal toxin removal. Severe or rising hyperammonaemia, neurological deterioration, cerebral oedema, refractory acidosis or a toxin concentration unlikely to clear promptly may require continuous haemofiltration or haemodialysis. Line placement, transfer and circuit preparation take time, so consultation begins before final thresholds are reached. Peritoneal dialysis removes ammonia too slowly for many severe crises.
After survival, determine the trigger, update safe fasting time and emergency feeding, replace expired products and give written plans to family, school, emergency department and GP. Genetic confirmation supports recurrence counselling and family testing but does not replace biochemical emergency care. Development, hearing, vision, nutrition, growth, movement, liver, renal and cardiac outcomes require disease-specific surveillance. Explain that newborn screening covers only selected disorders and cannot exclude metabolic disease in a symptomatic child.
Key points
Suspect an inborn error when a previously well newborn deteriorates after feeding, illness causes disproportionate encephalopathy or a child has recurrent fasting collapse, unexplained acidosis, hyperammonaemia, hypoglycaemia or liver dysfunction.
Metabolic and infectious emergencies coexist in the differential: use ABCDE, treat sepsis when indicated and contact the regional paediatric metabolic service and intensive care immediately.
First-line emergency tests are bedside glucose, blood gas, lactate, electrolytes, liver tests, coagulation, ketones and an urgently handled plasma ammonia; repeat an unexpected ammonia promptly from a clean free-flowing sample without delaying action.
Before treatment changes the pattern, save plasma amino acids, acylcarnitine profile, free fatty acids, insulin and C-peptide during hypoglycaemia and urine organic acids and ketones, but never postpone resuscitation to complete sampling.
Reverse catabolism with the child's current BIMDG emergency regimen or intravenous glucose when oral or nasogastric intake is unsafe; a normal glucose at presentation does not mean catabolism is controlled.
Hypoglycaemia with few or no ketones suggests fatty-acid oxidation disease or inappropriate insulin action, while marked ketosis and acidosis suggests organic acid, glycogen or fasting-related mechanisms.
Aetiology
01
Amino-acid and organic-acid disorders
Enzyme blocks in protein catabolism accumulate neurotoxic organic acids or amino acids and can generate acidosis, ketosis and hyperammonaemia.
02
Urea-cycle defects
Failure to convert nitrogen into urea causes rapid ammonia accumulation, especially after protein intake or catabolic illness.
03
Fatty-acid oxidation defects
Inability to mobilise energy from fat during fasting causes hypoketotic hypoglycaemia and may injure liver, muscle or heart.
04
Carbohydrate and organelle disease
Glycogen, gluconeogenesis, mitochondrial, lysosomal and peroxisomal disorders disrupt energy, storage or cellular recycling across multiple organs.
Pathophysiology
1
Toxic substrate accumulation
A blocked pathway raises upstream compounds that impair brain function, acid-base balance, liver, marrow, kidney or other tissues.
2
Product and energy deficiency
Missing downstream fuel or cofactor prevents ATP generation and physiological adaptation during fasting, infection or rapid growth.
3
Catabolic amplification
Illness and fasting break down body protein and fat, rapidly increasing substrate flux through the defective pathway.
4
Ammonia neurotoxicity
Astrocyte glutamine accumulation and disturbed neurotransmission cause cerebral swelling, seizures, coma and lasting cognitive and motor injury.
5
Alternative fuel signature
The presence or absence of ketones, lactate and free fatty acids reveals which compensatory energy pathways are functioning.
Clinical features and red flags
Well-then-unwell neonate
Normal initial transition is followed by poor feeding, vomiting, tachypnoea, abnormal tone, lethargy or seizure after feeds begin.
Hyperammonaemic encephalopathy
Vomiting, irritability and rapid neurological decline occur with respiratory alkalosis and unexpectedly raised plasma ammonia.
Fasting illness causes hypoglycaemia with inappropriately few ketones, liver dysfunction, muscle injury or cardiomyopathy.
Recurrent catabolic crises
Similar episodes follow vomiting, overnight fasting, vaccination, surgery or infection with incomplete development between attacks.
Severe metabolic decompensationRed flag
Coma, refractory acidosis, rising ammonia, cerebral signs or multiorgan failure requires immediate metabolic intensive care and dialysis planning.
Red flags requiring action
Any raised ammonia with neurological deterioration requires urgent repeat sampling and immediate metabolic specialist discussion.
Respiratory alkalosis in an encephalopathic newborn is a classic warning for a urea-cycle defect.
Hypoglycaemia with absent or minimal ketones is not normal fasting adaptation and suggests fat-oxidation failure or hyperinsulinism.
Investigations
01First-line glucose, gas and lactateFirst stepFirst line
Why
Detect immediately treatable hypoglycaemia and define respiratory alkalosis, metabolic acidosis and tissue stress.
Interpretation and limitations
The combination and anion gap organise mechanisms; a normal glucose does not exclude dangerous catabolism or hyperammonaemia.
02Urgent plasma ammonia
Why
Identify neurotoxic nitrogen accumulation in unexplained encephalopathy, seizure, liver dysfunction or respiratory alkalosis.
Interpretation and limitations
Repeat an unexpected elevation from a clean rapidly processed sample, but treat and refer during confirmation when illness is severe.
03Electrolyte, liver and coagulation profile
Why
Assess anion gap, renal function, hepatocellular injury, synthetic failure and suitability for medicines or dialysis.
Interpretation and limitations
Coagulopathy with relatively modest transaminases can occur in metabolic liver failure and increases procedural risk.
04Plasma amino acids and acylcarnitines
Why
Detect pathway-specific amino-acid accumulation and fatty-acid or organic-acid conjugate patterns.
Interpretation and limitations
Acute illness and treatment alter concentrations, so relate results to sampling time and confirm through specialist testing.
Differential diagnosis
01
Sepsis and meningitis
Infection causes shock, acidosis, hypoglycaemia and encephalopathy and can precipitate metabolic decompensation, requiring parallel antimicrobial assessment.
02
Hypoxic or structural brain disease
Birth injury, haemorrhage, stroke and malformation produce seizures and altered tone without the same biochemical fuel pattern.
03
Endocrine hypoglycaemia
Hyperinsulinism, cortisol deficiency and growth-hormone deficiency cause recurrent low glucose with hormone and ketone patterns distinct from many metabolic defects.
04
Poisoning
Salicylate, alcohol, valproate and other toxins can reproduce acidosis, hyperammonaemia or altered consciousness and need targeted assays.
05
Primary liver failure
Viral, immune and drug-related hepatic failure causes coagulopathy, hypoglycaemia and ammonia elevation but may overlap with metabolic liver disease.
Management
01Unknown metabolic collapseSample rapidly and stop catabolismFirst stepA newborn or child has unexplained encephalopathy, acidosis, hypoglycaemia, ammonia elevation or organ failure.+
1Use ABCDE and treat sepsis and hypoglycaemia while contacting metabolic and intensive-care teams and retrieving family history.
2Send urgent ammonia, glucose, gas, lactate, organ tests and saved plasma and urine metabolic samples without delaying resuscitation.
3Begin IV glucose or the age-appropriate BIMDG high-energy regimen and withhold natural protein briefly when the biochemical mechanism supports it.
02Known disorderUse the diagnosis-specific emergency letterA child with an established metabolic condition develops fever, vomiting, reduced intake, unusual sleepiness or neurological change.+
1Find the current emergency letter, record fasting duration and start its prescribed glucose-polymer feeds and usual special medicines immediately.
Complications
01
Cerebral oedema and injury
Prolonged ammonia or organic-acid exposure causes swelling, seizures, infarction, movement disorder and permanent severe neurodevelopmental disability.
02
Cardiac and rhythm failure
Energy defects, acidosis and electrolyte disturbance can produce cardiomyopathy, conduction disease, dangerous arrhythmia and circulatory collapse.
03
Acute liver failure
Toxic metabolites or energy failure cause coagulopathy, hypoglycaemia, encephalopathy and later chronic liver or cancer risk.
04
Renal and muscle injury
Organic acids, rhabdomyolysis and hypoperfusion can cause tubular dysfunction, acute kidney injury and dangerous potassium release.
05
Treatment-related catabolism
Insufficient glucose or prolonged protein withdrawal breaks down endogenous tissue, paradoxically increasing toxic substrate production and delaying recovery.
Monitoring and follow-up
Repeat ammonia at the interval set by the metabolic and intensive-care team until a sustained fall and neurological recovery are established.
Track consciousness, pupils, seizures, tone, respiration and signs of cerebral oedema continuously during severe intoxication.
Measure glucose frequently during high-energy infusion and adjust substrate or specialist insulin without reducing calories precipitously.
Follow blood gas, lactate, electrolytes, osmolality, renal and liver function, coagulation, creatine kinase and urine output according to phenotype.
Record all natural protein withheld and reintroduce prescribed essential protein within the specialist timeframe to prevent endogenous catabolism.
Monitor disease-specific amino acid, organic acid or acylcarnitine markers and correlate them with clinical rather than isolated numerical recovery.
Before discharge verify emergency-letter access, safe fasting times, glucose-polymer supplies, special medicines and family and school competence.
Special situations
Tachypnoea may be alkalosis
A hyperammonaemic newborn can breathe rapidly from central respiratory stimulation rather than lung disease or metabolic acidosis.
Normal glucose can mislead
Catabolism and toxic metabolite production may continue before blood glucose falls, so energy treatment follows clinical risk.
Ketones are pathway evidence
Their absence during fasting hypoglycaemia is abnormal and points toward insulin effect or fatty-acid oxidation failure.
Protein withdrawal has a clock
Brief cessation reduces substrate, but prolonged deprivation accelerates breakdown of the child's own tissue protein.
Dialysis preparation is treatment
Early calls and access planning save neurological time when ammonia continues rising despite medical scavenging.
Common pitfalls
01
Labelling a sick neonate sepsis only and failing to send ammonia and metabolic samples.
02
Discarding a high ammonia as sampling error without prompt repeat and specialist contact.
03
Waiting for every metabolic result before providing high-energy anti-catabolic treatment.
04
Giving a generic maintenance dextrose rate that cannot suppress catabolism.
05
Withholding protein for several days without metabolic dietetic direction.
06
Using valproate in unexplained hyperammonaemic encephalopathy without considering its metabolic effect.
07
Delaying haemofiltration planning until neurological deterioration is advanced.
08
Assuming a normal newborn screen excludes an inborn error in a symptomatic child.
Hyperammonaemia with respiratory alkalosis and little acidosis suggests a urea-cycle defect; organic acidaemia often has metabolic acidosis, ketosis, raised lactate and secondary ammonia elevation.
Temporarily stop natural protein when hyperammonaemia, maple-syrup urine disease or organic acidaemia is suspected, but use metabolic-team direction and reintroduce essential protein promptly to avoid further catabolism.
Severe or rising ammonia, cerebral oedema, refractory acidosis or toxic metabolites requires immediate ammonia-scavenger or disease-specific therapy and early haemofiltration or haemodialysis planning; do not wait until coma.
Known patients must bring their emergency letter, diagnosis-specific medicines, maximum safe fasting time and glucose-polymer recipe; follow that document rather than a generic fluid plan.
High-anion-gap acidosis with ketosis, lactate or unusual odour can signal an organic acidaemia.
Cardiomyopathy, arrhythmia or rhabdomyolysis during fasting illness suggests an energy-production disorder.
A normal newborn blood-spot result cannot exclude the many metabolic conditions outside the panel or a false-negative screened condition.
Failure to improve after glucose and sepsis treatment requires renewed toxin-removal and metabolic assessment, not diagnostic closure.
05
Urine ketones and organic acids
Why
Capture ketosis and excreted diagnostic metabolites that may remain detectable after blood glucose improves.
Interpretation and limitations
An organic-acid signature can identify the pathway; absent urinary ketones during hypoglycaemia narrows energy defects.
06Hypoglycaemia critical sample
Why
Measure ketones, free fatty acids, insulin, C-peptide, cortisol and growth hormone during a documented low.
Interpretation and limitations
Fuel and hormone relationships distinguish inappropriate insulin, impaired fat oxidation and counter-regulatory failure.
07Genetic and enzyme confirmation
Why
Establish the exact disorder after biochemical stabilisation for prognosis, family testing and targeted therapy.
Interpretation and limitations
Molecular results refine long-term care but should never delay phenotype-directed emergency treatment or detoxification.
2
Move to nasogastric or IV energy when intake is inadequate or airway safety changes and notify the named metabolic centre.
3Monitor diagnosis-specific metabolites and organ risks and do not discharge until normal intake and the safe fasting plan are restored.
03HyperammonaemiaRemove nitrogen before comaAmmonia is significantly elevated, rising or associated with neurological deterioration or cerebral oedema.+
1Repeat a correctly handled sample promptly, stop natural protein temporarily and provide high non-protein energy to reduce endogenous breakdown.
2Start diagnosis-appropriate scavengers, arginine, carglumic acid or cofactors under the metabolic protocol with close electrolytes and acid-base monitoring.
3Involve nephrology and intensive care early for vascular access and haemofiltration or haemodialysis when biochemical or clinical severity requires rapid clearance.
04Recovery and preventionRebuild nutrition and the next emergency planToxic metabolites and physiology improve after acute treatment.+
1Reintroduce controlled essential protein promptly under metabolic dietetic guidance and transition from IV to prescribed enteral intake.
2Identify infection, fasting, medicine or supply trigger and update maximum safe fasting time, emergency recipe and school or travel arrangements.
3Confirm biochemical or genetic diagnosis, counsel family recurrence and schedule neurodevelopmental and organ-specific surveillance.
Key medicines and prescribing safety3 treatments · regimens, roles and cautions+
Provides immediate cerebral fuel and reduces endogenous protein and fat breakdown that feeds the blocked metabolic pathway.
Intravenous glucose for anti-catabolic therapy
Treat documented hypoglycaemia with 10% glucose at the current paediatric emergency bolus dose, then use the age- and weight-specific BIMDG glucose infusion rate needed to suppress catabolism, adding insulin only under metabolic critical-care direction when hyperglycaemia limits delivery.
Monitor glucose, sodium, potassium, lactate and fluid balance closely; maintenance fluid alone may provide inadequate energy and excess free water can worsen cerebral oedema.
Maintains high carbohydrate delivery during illness and prevents fasting-triggered decompensation in selected metabolic disorders.
Glucose-polymer emergency regimen
Give the child's prescribed age-specific concentration and volume frequently by mouth or nasogastric tube when airway and gut are safe; use the current BIMDG recipe and switch to intravenous energy if the target intake is not achieved.
Do not improvise concentration, delay hospital transfer for persistent vomiting or drowsiness, or use enteral feeds when aspiration or ileus is likely.
Creates alternative nitrogen-excretion routes or treats a defined biochemical block while extracorporeal clearance is prepared when required.
Ammonia-scavenger and pathway therapy
Use intravenous sodium benzoate, sodium phenylbutyrate or phenylacetate, arginine, carglumic acid and disease-specific cofactors only at the exact weight-based loading and maintenance doses in the current BIMDG or metabolic-centre protocol.
These high-risk regimens alter sodium, potassium and acid-base balance and require specialist pharmacy preparation; they must not delay dialysis in severe rising hyperammonaemia.