Metabolic Emergencies

Metabolic Emergencies
Dr James Nurse

Disclaimer Nyhan WL, Kolker S, Hoffman GF. (2017). Emergency Treatment of Inherited Metabolic Disease. In: Hoffman GF, Zschocke J, Nyhan WL Inherited Metabolic Disease - A Clinical Approach. 2nd ed. London: Springer. p Nyhan WL, Kolker S, Hoffman GF. (2017). Emergency Treatment of Inherited Metabolic Disease. In: Hoffman GF, Zschocke J, Nyhan WL Inherited Metabolic Disease - A Clinical Approach. 2nd ed. London: Springer. p

What is metabolic medicine?
AKA: Inherited Metabolic Disease/Inborn Errors of Metabolism Generally result from a single enzyme defect involved in the breakdown, storage or disposal of proteins or glucose Accounts for > 600 distinct disease entities Individually very rare but collective incidence approx 1 in 1000 Around 1000 new cases a year and 200 deaths per annum 40% of those deaths are in children

D A B C What is metabolic medicine? X Y
Production of alternate metabolite may result in toxicity Cofactor X Y A B C Enzyme Enzyme Accumulation of upstream metabolites may result in toxicity Reduction in important metabolite e.g. glucose

Reduced fasting tolerance Disturbed energy metabolism
Acute intoxication Reduced fasting tolerance Disturbed energy metabolism

Aims & Outcomes To review the initial management and investigation of children presenting with possible metabolic decompensation By the end of this session you should: Know when to suspect a metabolic disorder Have a structured approach to metabolic emergencies Acute intoxication Reduced fasting tolerance Disturbed energy metabolism

Recognising a Metabolic Emergency The Neonate
Often non-specific presentation, most commonly in a term infant May have a hour well period Presenting symptoms include: Lethargy & feeding problems Recurrent vomiting Abnormal breathing (typically  RR) Hypotonia Seizures Deterioration with normal infection Ix

Recognising a Metabolic Emergency after the Neonatal Period
Vomiting & lethargy progressing to coma Usually without focal neurology or organ dysfunction Profound acidosis or hypoglycaemia not in keeping with clinical history History may increase concern: Self imposed protein restriction Deterioration after new drug FHx of unexplained death in childhood Consanguineous parents/family background Hart C, Davison JE, Cleary MA Fifteen-minute consultation: Red flags for metabolic disease in routine bloods Arch Dis in Child - Educ Prac Published Online First: 19 May 2018 doi: /archdischild

Likely times of presentation
Neonatal period Weaning Increased oral intake – for example, increased protein load First exposure to a new dietary component, e.g. fructose End of first year Slowdown in growth rate means increased protein catabolism for same protein intake, thus greater pressure on pathways Infection Increased metabolic stress with decreased intake, e.g. D&V Puberty Alterations in growth rate, hormonal milieu Postnatal (i.e. as a mother) Involution of a placenta brings significant protein load, may reveal a previously asymptomatic Urea Cycle Defect Champion M. (2010). An approach to the diagnosis of inherited metabolic disease. Arch Dis Child Educ Pract Ed 95: 40-46

Acute Intoxication

Acute intoxication Basic investigations may herald a metabolic cause:
Disorder leads to accumulation of toxic metabolite, e.g. ammonia (UCDs, OAs), leucine (MSUD), tyrosine Principles of management: Stop ongoing exposure (stop protein for 12–48h) Reversal of catabolism/ Promotion of anabolism Support clearance of toxin Basic investigations may herald a metabolic cause: Acid-base balance, glucose, lactate, ammonia, ketones (2nd line) acylcarnitines, plasma amino acids and urine organic acids (processed under 24 hours) : – –

First-line metabolic investigations
Blood Urine Glucose* Ketones (dipstick)* pH, CO2, bicarb, base deficit* Organic acids (inc Orotic A) Lactate (free flowing)* (Reducing substances) Ammonia (free flowing)* (Amino acids) Amino Acids Acylcarnitines (inc profile, total and free carnitine) LFTs inc clotting screen* Full blood count* Creatine kinase Blood Urine Champion M. (2010). An approach to the diagnosis of inherited metabolic disease. Arch Dis Child Educ Pract Ed 95: 40-46

Baby NK

Baby NK Term infant, born by LSCS weighing 4.5kg
Maternal Graves Disease; off treatment Poor feeding in first 12 hours, unable to latch. EBM offered via syringe At 32 hours: Jittery Developed low grade pyrexia Increased respiratory rate

Progress at local 36h: Assessed by Neonatal Registrar
Jittery but otherwise normal examination IV access and bloods sent Antibiotics started Remained tachypnoeic Chest X-ray – interpreted as normal Raised free T4 - ? significance Ammonia sent at 48 hours: 401 Repeated after 4 hours: 732 36h 42h 48h pH 7.5 7.597 7.58 pCO2 3.06 2.4 2.7 HCO3 22.5 19.2

Patient CP

Patient CP Previously well 16-year-old boy
Worsening agitation & vomiting 2 days after a party; not normal since No history of trauma or drug use In Emergency Department: – intubated and ventilated for low GCS – CT head performed and normal Transferred to ICU, suspected meningo-encephalitis – normal lumbar puncture; slightly high pressure – BP HR, treated for seizures and raised ICP

Patient CP (2) Within 24 hours:
– CT suggestive of  ICP – Pupils fixed and dilated Retrieved to PICU at SGH, re-assessed: – No neurological response off sedatives – MRI: catastrophic brainstem herniation – Ammonia on admission = 3000 µmol/L Extended metabolic testing suggests UCD Formal brain death testing undertaken and organ harvest undertaken at request of parents

Hyperammonaemia as a paradigm of acute intoxication
Ammonia Hyperammonaemia as a paradigm of acute intoxication Weak base 95% NH4+ at physiological pH Sources Deamination of amino acids Gut bacteria

Protein metabolism Protein Growth & repair Breakdown COO- C R H NH3+
Fatty acids Ketones Glucose Urea

Inherited disorders: Urea cycle enzyme defects  Carbamyl phosphate synthetase deficiency (CPS def)  Ornithine carbamyl transferase deficiency (OTC or OCT def)  Argininosuccinate synthetase deficiency (Citrullinaemia, ASS def)  Argininosuccinate lyase deficiency (Arginosuccinic aciduria, ASA or ASL def))  Arginase deficiency  N-acetylglutamate synthetase deficiency (NAGS def) Transport defects of urea cycle intermediates  Lysinuric protein intolerance (LPI)  Hyperammonaemia- hyperornithinaemia-homocitrullinuria syndrome (HHH syndrome)  Citrin deficiency (citrullinaemia type II) Organic acidurias  Propionic acidaemia  Methylmalonic acidaemia  Isovaleric acidaemia and other organic acidaemias BIMDG protocol - Undiagnosed hyperammonaemia © BIMDG Miscellaneous inherited disorders Many metabolic disorders may cause mild- moderate hyperammonaemia. Fatty acid oxidation disorders, congenital lactic acidoses (including pyruvate carboxylase deficiency) and hyperinsulinism- hyperammonaemia (HI-HA - increased glutamate dehydrogenase activity) can all cause hyperammonaemia, although other features usually predominate (e.g. hypoglycaemia) and severe hyperammonaemia is unusual. The Urea Cycle

Management of Hyperammonaemia
Ammonia level (μmol/L) Undiagnosed Case Diagnosed case Above upper limit of normal Exclude sampling error/repeat Stop protein intake Give IV glucose to prevent catabolism ± insulin Same as Undiagnosed case >100 but <250 (in neonate >150 but <250) Same as above Start drug treatment with nitrogen scavengers Consider carnitine, biotin, B12 Consider Carbaglu Start lipid IV 2-3 g/kg to increase calories Start medications and scavengers as per disease specific protocols Prepare for haemofiltration If no rapid drop within 3-6 hours then begin haemofiltration Same as undiagnosed case >500 Commence haemofiltration and all of the above Carbaglu = synthetic N-acetylglutamate Caution with carnitine and lipid in Fatty Oxidation Defects Theoretical risk with carnitine Absolute contraindication for Lipid – only start with specialist input Primum non nocere Alfadhel, M., Al Mutairi, F., Makhseed, N., Al Jasmi, F., Al-Thihli, K., Al-Jishi, E., Al-Sayed, M., Al-Hassnan, Z., Al Murshedi, F., Häberle, J. and Ben-Omran, T. (2016). Guidelines for acute management of hyperammonemia in the Middle East region. Therapeutics and Clinical Risk Management, 12, p.479.

Inherited disorders: Urea cycle enzyme defects  Carbamyl phosphate synthetase deficiency (CPS def)  Ornithine carbamyl transferase deficiency (OTC or OCT def)  Argininosuccinate synthetase deficiency (Citrullinaemia, ASS def)  Argininosuccinate lyase deficiency (Arginosuccinic aciduria, ASA or ASL def))  Arginase deficiency  N-acetylglutamate synthetase deficiency (NAGS def) Transport defects of urea cycle intermediates  Lysinuric protein intolerance (LPI)  Hyperammonaemia- hyperornithinaemia-homocitrullinuria syndrome (HHH syndrome)  Citrin deficiency (citrullinaemia type II) Organic acidurias  Propionic acidaemia  Methylmalonic acidaemia  Isovaleric acidaemia and other organic acidaemias BIMDG protocol - Undiagnosed hyperammonaemia © BIMDG Miscellaneous inherited disorders Many metabolic disorders may cause mild- moderate hyperammonaemia. Fatty acid oxidation disorders, congenital lactic acidoses (including pyruvate carboxylase deficiency) and hyperinsulinism- hyperammonaemia (HI-HA - increased glutamate dehydrogenase activity) can all cause hyperammonaemia, although other features usually predominate (e.g. hypoglycaemia) and severe hyperammonaemia is unusual. The Urea Cycle

Management of Hyperammonaemia
Ammonia level (μmol/L) Undiagnosed Case Diagnosed case Above upper limit of normal Exclude sampling error/repeat Stop protein intake Give IV glucose to prevent catabolism ± insulin Same as Undiagnosed case >100 but <250 (in neonate >150 but <250) Same as above Start drug treatment with nitrogen scavengers Consider carnitine, biotin, B12 Consider Carbaglu Start lipid IV 2-3 g/kg to increase calories Start medications and scavengers as per disease specific protocols Prepare for haemofiltration If no rapid drop within 3-6 hours then begin haemofiltration Same as undiagnosed case >500 Commence haemofiltration and all of the above Carbaglu = synthetic N-acetylglutamate Caution with carnitine and lipid in Fatty Oxidation Defects Theoretical risk with carnitine Absolute contraindication for Lipid – only start with specialist input Primum non nocere Alfadhel, M., Al Mutairi, F., Makhseed, N., Al Jasmi, F., Al-Thihli, K., Al-Jishi, E., Al-Sayed, M., Al-Hassnan, Z., Al Murshedi, F., Häberle, J. and Ben-Omran, T. (2016). Guidelines for acute management of hyperammonemia in the Middle East region. Therapeutics and Clinical Risk Management, 12, p.479.

Management at local (BIMDG)
Bolus glucose (2ml/kg of 10% dextrose); resuscitate with crystalloid as indicated Commence maintenance fluid containing 10% dextrose; replace deficit (1/3 over 6 hours; remainder over 18 hrs) Liaise with SORT +/- metabolic centre Start nitrogen scavengers Fluid resus is only for acutely clapped out child – danger of being done ‘just because on guideline’ Fluids should be no/low salt due to salt content of scavengers Carnitine should NOT be given if there is evidence of a cardiomyopathy, any cardiac arrhythmia or if a long chain fatty acid oxidation disorder is suspected

Loading dose (over 90min) Na content of daily dose (mmol/kg/day)
Management at local (BIMDG) Drug Loading dose (over 90min) Maintenance (over 24h) Max daily dose Na content of daily dose (mmol/kg/day) Sodium benzoate 250 mg/kg 500 mg/kg 3.5 Sodium phenylbutyrate 600 mg/kg 2.8 Arginine 150 mg/kg 300 mg/kg Nil Carnitine* 100 mg/kg Fluids should be no/low sa Carnitine should NOT be given if there is evidence of a cardiomyopathy, any cardiac arrhythmia or if a long chain fatty acid oxidation disorder is suspected. lt due to salt content of scavengers

Phenylacetyl-glutamine
Pharmacological detoxification of ammonia N N Oxo-acid Glutamate NH4+ Phenylbutyrate CoA N N Benzoate CoA Glycine Amino acid 2-Oxo-glutarate Phenylbutyryl-CoA NN Glutamine Benzoyl-CoA Phenylacetyl-CoA N Hippuric acid NN Phenylacetyl-glutamine Benzoate + Glycine  Hippurate (one molecule of nitrogen) Phenlyacetate + Glutamine  Phenylacetylglutamine (two molecules of nitrogen)

Case 3

Case 3 2-day-old, term infant of Bangladeshi extraction
Em LSCS for poor CTG 3rd child, two previous well children Tachypnoeic and pallor on day 3 of life Initial results revealed: - pH: pCO2: Base excess: Glucose: Lactate: 2.5

Retrieved to metabolic centre for further care
Case 3 - continued Ventilated to manage pCO2; minimal support required Cardiovascularly stable Received dextrose at 8mg/kg/min and requird bicarbonate corrections Ammonia: µmol/l - Acute renal impairment Retrieved to metabolic centre for further care

Differential Diagnosis
Hyperammonaemia Differential Diagnosis Symptoms prior to 24 hours Symptoms after 24 hours Premature Full term Metabolic acidosis present No Metabolic Acidosis or Mild Acidosis Urea Cycle Disorders Transient Hyperammonaemia of the Newborn (THAN) Pyruvate Carboxylase Deficiency Fatty Acid Oxidation Defects Organic acidaemias Assess PAA notably Citrulline Normal Absent to trace μM + ASA > 1000 μM no ASA Low/normal Orotic Acid Increased Orotic Acid HHH syndrome CPS1, NAGS OTC Arginosuccinic Aciduria Citrullinaemia Type 2

Other intoxication disorders
Methylmalonic/Propionic aciduria – Lead to massive ketoacidosis – Rehydrate, correct electrolyte imbalance, iv carnitine – Forced diuresis may assist in MMA – Buffering with Sodium bicarbonate may be dangerous Isovaleric acidaemia – Glycine to promote excretion of isovalerylglycine Maple Syrup Urine Disease – Promote anabolism; continue BCAA-free supplement – Supplementary valine and isoleucine required Maintain sodium > 138mmol/L Carnitine allows formation of esters which are preferentially excreted in urine and thus aid intoxification Very large doses may be required Forced diuresis only effective if well hydrated Sodium bicarbonate may be useful in milder acidosis; in more severe cases may be ineffective and risk of cerebral oedema Leucine, isoleucine and valine laid down during formation of proteins Isoleucine lower than leucine therefore will be used up; need to supplement

Reduced Fasting Tolerance

Case 4

Case 4 3-day-old, term infant, normal pregnancy and delivery
Presented with a 24 hour history of: Vomiting Lethargy Rapid breathing Poor perfusion and hepatomegaly

Case 4 - investigations Gas Liver dysfunction pH 7.19 CK: 23,000 U/l
pCO2 3.1 HCO BE Lac 3.2 Glu 0.8 Liver dysfunction CK: 23,000 U/l Ammonia: 145 µmol/l Next bedside test? No ketones (urine or blood)

Permanent Hepatomegaly
Timing Liver size Metabolites Short fast: GSD 1a & b Long fast: FBP, FAO (all with acidosis) Hyperinsulinism Factitious At fast Permanent Hepatomegaly High lactate Hectic, permanent Post prandial GSD III (high CK) GSD VI, IX No acidosis FBP = Fructose-1,6-bisphosphatase deficiency At fast HYPOGLYCAEMIA Ketotic hypoglycaemia Glycogen synthase MCAD Ketolytic defects (with ketoacidosis) Yes Without Hepatomegaly Post prandial Ketosis Hereditary fructose intolerance Hyperinsulism Galactosaemia No Fatty acid oxidation Ketogenesis defects Hyperinsulinism

Long Chain 3-HydroxyAcyl CoA Dehydrogenase deficiency
Acylcarnitine profile Long Chain 3-HydroxyAcyl CoA Dehydrogenase deficiency (LCHADD)

Energy sources during fasting
(Glucose used vs duration of fast)

II: Short to medium fast
Energy sources during fasting (Glucose used vs duration of fast) Phase I: Post-prandial II: Short to medium fast III: Long fast IV: Very long fast Glucose Source Exogenous Glyocgen Gluconeogenesis Gluconeogeneis (liver), Glycogen Gluconeogeneis (Liver & kidney) Consuming tissues All All but liver/muscle Brain, RBCs, medullary kidney Greatest brain nutrient Glucose Ketone bodies

Permanent Hepatomegaly
Timing Liver size Metabolites Short fast: GSD 1a & b Long fast: FBP, FAO (all with acidosis) Hyperinsulinism Factitious At fast Permanent Hepatomegaly High lactate Hectic, permanent Post prandial GSD III (high CK) GSD VI, IX No acidosis FBP = Fructose-1,6-bisphosphatase deficiency At fast HYPOGLYCAEMIA Ketotic hypoglycaemia Glycogen synthase MCAD Ketolytic defects (with ketoacidosis) Yes Without Hepatomegaly Post prandial Ketosis Hereditary fructose intolerance Hyperinsulism Galactosaemia No Fatty acid oxidation Ketogenesis defects Hyperinsulinism

Management of hypoglycaemia
Give glucose 10% 2ml/kg (200 mg/kg) followed by a continuous infusion of 4-6mg/kg/min (maintain normoglycaemia)

Hypoglycaemia suspected If < 3mmol/l investigate
(pallor, anxiety, sweating, weakness, tremor, tachypnoea, nausea, irritability, slurred speech, headache, seizure, coma) Test blood sugar: If < 3mmol/l investigate Investigations (if untreated) Bloods: Glucose Lactate Insulin & C-Peptide 3-hydroxybutyrate Free fatty acids Cortisol & Growth hormone Plasma/blood spot acylcarnitines Plasma amino acids Ammonia Urea & electrolytes Liver function tests Urine: Ketone bodies Organic acids Investigations (if treated) Bloods: Plasma/blood spot acylcarnitines Plasma amino acids Ammonia Urea & electrolytes Liver function tests Urine: Ketone bodies Organic acids Key findings History: - Period of preceding fast? - Intercurrent illness? - Born after 2009, NBS bloodspot - History of sibling death - Consanguineous parents Morning lethargy Rapid response to treatment vs high ongoing sugar needs Developmental delay Examination: Hyperpigmentation Hepatomegaly Hypotonia Dysmorphic features Ghosh, A., Banerjee, I. and Morris, A. (2015). Recognition, assessment and management of hypoglycaemia in childhood. Archives of Disease in Childhood, 101(6), pp

Prior to glucose correction
Investigations Prior to glucose correction – Glucose – Lactate – Insulin and C-peptide – 3-hydroxybutyrate – Free fatty acids – Cortisol – Growth hormone May be taken post Rx – Acylcarnitines – Plasma amino acids – Ammonia – Urea and electrolytes – Liver function tests First urine passed – Ketone bodies – Organic acids

Oral administration of fluids & energy
Age (years) Glucose polymer/maltodextrin solution (%) (kcal/100 ml) Daily amount 0 – 1 10 40 ml/kg 1 – 2 15 60 95 ml/kg 2 – 6 20 80 1200 – 1500 ml 6 – 10 1500 – 2000 ml > 10 25 100 2000 ml Intravenous fluids should be 10% dextrose with saline Higher sugar requirements suggest hyperinsulinism Dixon MA, Leonard JV (1992) Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 67:

Disturbed Energy Metabolism

Disturbed Energy Metabolism
Includes defects of: – pyruvate dehydrogenase complex (PDHC) – the Krebs cycle – the respiratory electron transport chain Typically cause chronic multisystem disease Emergency treatment required for severe acidosis and lactic acidaemia Glucose infusion may lead to an increase in lactic acid

Clinical features Poor fetal weight gain Low Apgars at birth
Hypotonia, poor feeding, tiredness, tachypnoea, abnormal eye movements, seziures, microcephaly Dysmorphic features (PDHC): narrow head, frontal bossing, wide nasal bridge, long filtrum, flared nostrils Disproportionate Lactic Acidosis

Management (medication)
Acidosis: – Sodium bicarbonate (high doses) – up to 20% of Mitochondrial Disorders associated with proximal renal tubular acidosis Lactate: – Dialysis – Dichloroacetate – activates PDHC in brain, liver and muscle Co-factor replacement: – Biotin (Multiple Carboxylase Deficiency) – Riboflavin (Multiple Acyl-CoA Dehydrogenase Deficiency) – Co-enzyme Q10, vitamin E and B vitamin complex – L-Carnitine (if low in plasma or increased esters in urine) Lowering lactate may not improve outcome

Disorders requiring restriction of energy turnover
Management (fluids in infants) Disorders requiring restriction of energy turnover PDHC deficiency  reduce glucose supply: glucose 5-7g/kg/day (monitor lactate) Add fat: 2–3 g/kg/day Test response to Thiamine (3 x 50–100 mg/day) Electron transport chain (OXPHOS) disorders  glucose 10 (–15) g/kg/day** Lowering lactate may not improve outcome

Hyperlactataemia Respiratory chain def. High Pyruvate carboxylase
Permanent with neurological signs Lactate/ Pyruvate Normal or Low Pyruvate deshydrogenase Pyruvate carrier Glycogenesis type III Glycogen synthase Fasting ketotic hypoglycaemia Only in post-prandial phase Hyperlactataemia a series of mitochondrial proteins that transport electrons of hydrogen,released in the Krebs cycle, from acetyl coenzyme A to inhaled oxygen toform H2O: the energy released in the process is conserved as ATP. Saudubray, JM. (2012). Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Berghe G, Walter JH Inborn Metabolic Diseases - Diagnosis and Treatment. 5th ed. London: Springer. p3-54. Neurological signs High: Respiratory chain, Pyruvate carboxylase Lactate/ Pyruvate Low: Pyruvate deshydrogenase Gluconeogenic enzyme defects G Glucose 6 phosphatase Fructose biphosphatase def. Only at fast with hypoglycaemia Fatty acid oxidation Respiratory chain Energetic defects Saudubray, JM. (2012). Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Berghe G, Walter JH Inborn Metabolic Diseases - Diagnosis and Treatment. 5th ed. London: Springer. p3-54.

(pH<7.30 pCO2<30, HCO3-<15)
Metabolic acidosis (pH<7.30 pCO2<30, HCO3-<15) High Ammonia > 100µmol.l Branched chain organic acidurias (MMA, PA, IVA) Sugar > 7mmol/l Diabetes Ketolytic disorders Congenital LA Normal or low Ammonia PC, MCD, KGDH, E3 Respiratory chain defects 3-hydroxybutyric acid or other OA High lactate Ketosis + Normoglycaemia MSUD (late-onset forms) Ketolytic defects Organic acidurias SCAD Normal lactate Gluconeogenesis (FBPase,G6Pase) Glycogen synthase (no hepatomegaly) Respiratory chain defects High lactate (hepatomegaly) Hypoglycaemia MSUD (late-onset forms) MMA, PA, IVA Acetoacetyl-CoA thiolase Adrenal insufficiency Normal lactate

(pH<7.30 pCO2<30, HCO3-<15)
Metabolic acidosis (pH<7.30 pCO2<30, HCO3-<15) Normal glucose (or slightly high) PDH High lactate Fatty acid oxidation defects HMG-CoA lyase FBPase, GsPase Low glucose (hepatomegaly) Ketosis - Renal tubular acidosos I and II Pyroglutamic aciduria Normal lactate Normal glucose Saudubray, JM. (2012). Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Berghe G, Walter JH Inborn Metabolic Diseases - Diagnosis and Treatment. 5th ed. London: Springer. p3-54.

In summary Stop feeds and start 10% dextrose (almost always)
If you suspect a Metabolic Diagnosis remember to involve a specialist centre early on Use the British Inherited Metabolic Disease Group website (accessible directly or via SORT) Early recognition and appropriate management saves lives and significantly reduces long-term morbidity

Thank you

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