METABOLIC EMERGENCIES IN THE NEONATE

1. METABOLIC EMERGENCIES IN THE NEONATE N. Guffon, Edouard Herriot Hospital, Pediatrics, Lyon, France U. Simeoni, Timone University Hospital, Neonatology, Marseille, France J.B. Gouyon, University Hospital, Neonatology, Dijon, France

2. Index

3. When to � think metabolic � ( 1 )

4. When to � think metabolic � ( 2 )

5. Immediate investigations(parallel to screening for sepsis) Blood: Ammonemia, Bicarbonates, Glucose, Transaminases, Prothrombin time, Lactic acid, Uric acid Urine: Ketonuria (colorimetric bedside test), unusual odour or colour, pH

6. Which emergency measures need to be undertaken? ( 1 ) Within 24 to 48 hours of presentation, i.e. before the diagnosis of a specific metabolic disease and the respective treatment are established. Scenario 1: No acidosis, no ketonuria, hyperammonaemia ? suspected UCD � High caloric, protein-free nutrition, preferentially through continuous enteral feeding (100-130 kcal/kg/day, 65-70% carbohydrates) � Insulin for reinforcement of anabolism (dose: 0.02 - 0.1 Units/kg/h); Check regularly for glycaemia and readjust the dose if needed � Ammonaps� (Sodium Phenylbutyrate) through nasogastric tube: 250-600 mg/kg/day in 4 doses � Sodium Benzoate iv: 200-500 mg/kg/day in 4 doses � Arginine iv: 100-150 mg/kg/day in 4 doses

7. Which emergency measures need to be undertaken? ( 2 ) Scenario 2: Acidosis and/or ketonuria, with or without hyperammonaemia ? suspected Organic aciduria or MSUD (Maple Syrup Urine Disease) � High caloric, protein free nutrition (as mentioned) � Insulin (as mentioned) � Hydroxocobalamine, 1-2 mg/day, IV � Biotine, 10-20 mg/day, IV or oral � Thiamine 10-50 mg/day, IV or oral in 1-2 doses � Riboflavine 20-50 mg/day, IV or oral in 1-2 doses � Carnitine 100-400 mg/kg/day, IV in 4 doses In any case: an emergency toxin removal may be needed. Prepare for toxin removal procedures.

8. Which emergency measures need to be undertaken? ( 3 ) Note: Bicarbonate infusion for correction of acidosis is NOT recommended; only in renal tubular acidosis or in pyroglutamic aciduria! If no improvement after 4-6 hours of treatment then start toxin removal procedure, such as: � Peritoneal dialysis � Continuous Hemodialysis/Hemodiafiltration Note: Hemodialysis is shown to be the most effective method (Gouyon et al 1994, Ogier de Baulny 2002, Sch�fer 1999) however, the choice for a particular method may depend on local availability and experience.

9. Diagnostic algorithm

10. Specific investigations(with the aid of a metabolic specialist) From initial samples: � Blood: Amino acids, Acyl carnitine profile � Urine: Organic acids, Oroticuria Main diagnostic pathways: � Urea Cycle Disorders: Plasma amino acids, oroticuria; then specific enzymatic activity � Organic aciduria: Urinary organic acids; then specific enzymatic activity � Fatty acid oxidation: blood carnitine and acylcarnitine profile, urinary organic acids then specific enzyme activity � Respiratory chain disorders: very high lactatemia then specific enzyme activity, very poor prognosis eventually post mortem samples (see below) Postmortem cases: In the absence of a specific orientation towards a diagnostic pathway the following samples need to be taken (in addition to blood and urine) : � skin biopsy (in saline solution at RT) � muscle and liver biopsy (freeze immediately at �80�C)

11. Case examples ( 1 ) Case 1 Child born at 37 weeks of gestation, birthweight 2450 g, consanguineous parents Day 1: episode of cyanosis while breast feeding Day 2: poor feeding Day 3: oliguria, trembling, slight hypotonia Day 4: generalized seizure, progressing lethargy and hypotonia, abnormal movements of the lower limbs Day 5: coma Blood ammonia: 500 �mol/l Emergency measures: peritoneal dialysis, sodium benzoate, arginine hydrochloride, high caloric nasogastric feeding without protein

12. Case examples ( 2 ) Case 1 (cont.) Further investigations: low citrulline, ornithine, arginine and isoleucine, normal organic acids Carbamylglutamate given at day 25 because of recurrent ammonaemia (CPS or NAGS deficiency?) Enzyme test for enzyme activity showed decreased NAGS Function Diagnosis: NAGS deficiency Treatment: Carbaglu� (ongoing) (Guffon et al 1995) Comment: in this case screening for metabolic diseases especially hyperammonemia would have been indicated at day 2, parallel to septic screening.

13. Case examples ( 3 ) Case 2 Child born at 39 weeks of gestation, birth weight 3250g, no consanguinity 1st hospitalisation at day 3: admission with poor feeding, weight loss (16%), intravenous rehydratation then discharged after 24 h At home: poor feeding, no weight gain, attempts of feeding with different milk formulas 2nd hospitalisation at day 17: poor feeding, no weight gain since birth, diagnosis of low urinary infection (104 E Coli) : Antibiotics, no screening for ketonuria At home: persistent poor feeding and no weight gain, patient sleeps a lot 3rd hospitalisation at 1.5 months: poor feeding, weight 3 600 g, vomiting, infectious screening negative, normal abdominal X ray and ultrasound, improvement with glucose infusion. After reintroduction of milk: vomiting, drowsiness, moaning, altered general condition, transfered with the diagnosis of intestinal occlusion.

14. Case examples ( 4 ) Case 2 (cont.) At arrival: hypothermia (36�C), bad general condition, drowsiness,a reactivity, no eye contact, huge axial and peripheral hypotonia, polypnea, normal visceral exam Metabolic acidosis (HCO3-: 13 mmol/l), ketonuria ++, hyperammonaemia 349 �mol/l, leuconeutropaenia suspicion of organic aciduria emergency care: continuous free protein, high caloric nasogastric feeding IV carnitine 350 mg x 4/day IV vitamine B12 : 1 mg/day IV biotine 10 mg/day IV insulin Diagnosis: methylmalonic aciduria (mut-) (plasma methyl malonic acid (MMA) 846 �mol/l, urinary MMA 38 245 �mol/l) Good outcome