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METABOLIC EMERGENCIES IN THE NEONATEN. Guffon, Edouard Herriot Hospital, Pediatrics, Lyon, France
U. Simeoni, Timone University Hospital, Neonatology, Marseille, France
J.B. Gouyon, University Hospital, Neonatology, Dijon, France
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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
E
MERGENCY
POSTEMERG
ENCY
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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)
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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)
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Immediate investigations(parallel to screening for sepsis)
Blood: Ammonemia, Bicarbonates, Glucose, Transaminases, Prothrombin time, Lactic acid, Uric acidUrine: Ketonuria (colorimetric bedside test), unusual odour or colour, pH
Note:Ketonuria is always an indicator for a me tabolic disease in the ne wborn.Increased Uric acid is indicative for organic aciduria
Thrombopenia 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 plasmafrozen at -20C, if not immediately analysed
Urine: First miction (store at -20C)
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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
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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.
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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, Schfer 1999)
however, the choice for a particular method may depend on local availability and experience.
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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
Pyroglutamicaciduria
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
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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 80C)
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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
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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.
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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%), intravenousrehydratation 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 screeningnegative, normal abdominal X ray and ultrasound, improvement with glucose infusion.
After reintroduction of milk: vomiting, drowsiness, moaning, altered general condition, transferedwith the diagnosis of intestinal occlusion.
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Case examples ( 4 )
Case 2 (cont.)
At arrival: hypothermia (36C), 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
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Blau N et al (2003) Simple test in urine and blood. In: Physicians 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 Pedia tr 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.
References and further reading
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