Transcript METABOLIC DISEASES IN THE NEONATE

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
Index
EMERGENCY
When to « think metabolic »
Immediate investigations
POST EMERGENCY
Which emergency measures need to be undertaken?
Diagnostic algorithm
Specific investigations
Case examples
(Saudubray 2002, Saudubray & Ogier de Baulny 1995)
When to « think metabolic » ( 1 )
Initial symptoms:
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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 )
Additional factors
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initial symptom free interval
consanguinity
family history (previous neonatal deaths, possibly unexplained)
deterioration despite symptomatic therapy (possibly unexplained)
Note:
symptoms are usually non specific,
metabolic disease may be excluded when obvious cause is known
Careful!
Metabolic diseases are often associated with infections!
(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 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 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
yes
Ketonuria
Ketonuria
yes
Major hyperlactatemia
yes
Mitochondrial
defect
no
Organic
aciduria
no
no
Maple Syrup Urine
Disease (MSUD)
yes
Hyperlactatemia
yes
Hypoglycemia
yes
Fatty acid oxydation
Glycogen storage disease
Glyconeogenesis defects
no
Maple Syrup Urine
Disease (MSUD)
Organic aciduria
Pyroglutamic
aciduria
no
Respiratory
chain
no
HYPERAMMONEMIA
yes
no
Hypoglycemia
yes
Fatty acid oxydation
Variant hyperinsulinism
(glutamate dehydrogenase)
Non-ketonic hyperglycinemia
Sulfite oxydase deficiency - XO
no
Urea Cycle
Disorders
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, 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.
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 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 µmol/l, urinary MMA 38 245 µmol/l)
Good outcome
References and further reading
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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