METABOLIC EMERGENCIES IN THE NEONATE

N. Guffon, Edouard Herriot Hospital, Pediatrics, Lyon, FranceU. Simeoni, Timone University Hospital, Neonatology, Marseille, France

J.B. Gouyon, University Hospital, Neonatology, Dijon, France

Index

(Saudubray 2002, Saudubray & Ogier de Baulny 1995)

When to « think metabolic »

Immediate investigations

Which emergency measures need to be undertaken?

Diagnostic algorithm

Specific investigations

Case examples

EM

ER

GEN

CY

PO

ST

EM

ER

GEN

CY

When to « think metabolic » ( 1 )

Initial symptoms:

– lethargy (or “just not well”)– refusal to feed, poor sucking,vomiting– poor weight gain– polypnoea– hypothermia– axial hypotonia– limb hypotonia– abnormal movements (boxing,

pedalling,tremor, ...)– hepatomegaly

With possible progression to:

altered consciousness, seizures, coma, multivisceral failure

(Saudubray 2002, Saudubray & Ogier de Baulny 1995)

When to « think metabolic » ( 2 )

Note:

symptoms are usually non specific, metabolic disease may be excluded when obvious cause is known

Careful!Metabolic diseases are often associated with infections!

Additional factors

– initial symptom free interval – consanguinity– family history (previous neonatal deaths, possibly

unexplained)– deterioration despite symptomatic therapy (possibly

unexplained)

(Saudubray 2002, Saudubray & Ogier de Baulny 1995)

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

Note: Ketonuria is always an indicator for a metabolic disease in the newborn.Increased Uric acid is indicative for organic aciduriaThrombopenia and Neutropenia are criteria for severity in organic aciduria(an increased urine pH with acidosis, without Ketonuria is suggestive of renal tubular acidosis)

Supplementary samples to be taken before starting emergency therapy for specific investigations:

Blood: 4-5 ml blood, sampled on lithium heparinate, centrifuge rapidly, store plasma

frozen at -20°C, if not immediately analysed

Urine: First miction (store at -20°C)

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

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.

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, Schäfer 1999)however, the choice for a particular method may depend on local availability and

experience.

Diagnostic algorithm

METABOLIC ACIDOSIS

HYPERAMMONEMIA

Ketonuria Ketonuria

Hyperlactatemia

Hypoglycemia

Major hyperlactatemia Maple Syrup Urine Disease (MSUD)

Maple Syrup Urine Disease (MSUD)

HypoglycemiaOrganic aciduria

Organic aciduria Pyroglutamic

aciduria

Non-ketonic hyperglycinemia Sulfite oxydase deficiency - XO

Urea Cycle Disorders

Respiratory chain

Fatty acid oxydation Variant hyperinsulinism

(glutamate dehydrogenase)

Fatty acid oxydation Glycogen storage disease

Glyconeogenesis defects

Mitochondrial defect

no

no

no no

no

no no

no

yes

yes

yes

yes

yes

yes

yes yes

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)

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 µmol/l

Emergency measures: peritoneal dialysis, sodium benzoate, arginine hydrochloride, high caloric nasogastric feeding without protein

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.

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, diagnosisof 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.

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

µmol/l, leuconeutropaenia

suspicion of organic aciduria

emergency care: continuous free protein, high caloric nasogastric feedingIV carnitine 350 mg x 4/dayIV vitamine B12 : 1 mg/dayIV biotine 10 mg/dayIV insulin

Diagnosis: methylmalonic aciduria (mut-)(plasma methyl malonic acid (MMA) 846 µmol/l, urinary MMA 38 245 µmol/l)

Good outcome

Blau N et al (2003) Simple test in urine and blood. In: Physician’s guide to the laboratory diagnosis of metabolic diseases. Blau N, Duran M, Blaskovics ME, Gibson KM Editors. Springer Verlag, Berlin Heidelberg, 3-10.Guffon N. et al (1995): A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis 18(1): 61-5.Gouyon JB et al (1994): Removal of branched-chain amino acids by peritoneal dialysis, continuous arterivenous hemofiltration, and continuous arterivenous hemodialysis in rabbits: implications for maple syrup urine disease treatment; Ped Res 35: 357-61.Leonard JV (1985): The early detection and management of inborn errors presenting acutely in the neonatal period. Eur J Pediatr 143: 253-7. Ogier de Baulny H (2002): Management and emergency treatments of neonates with a suspicion of inborn errors of metabolism. Semin Neonatol 7: 17-26. Saudubray JM et al (1995): Clinical approach to inherited metabolic diseases. In: Inborn metabolic diseases. Fernandez J, Saudubray JM, van den Berghe G Editors. Springer Verlag, Berlin Heidelberg, 3-39.Saudubray JM et al (2002): Clinical approach to inherited metabolic disorders in neonates : an overview. Semin Neonatol 7: 3-15.

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