239_metabolik hastalıklar (1)

7/29/2019 239_metabolik hastalklar (1)

1/17

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


2/17

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


3/17

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



4/17

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)



5/17

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)


6/17

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


7/17

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.


8/17

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.


9/17

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


10/17

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)


11/17

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


12/17

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.


13/17

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.


14/17

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


15/17

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


16/17

Other documents on this topic are avai lable from Orphan Europe Headquarter at:

FRANCE

ORPHAN EUROPESARL

Immeuble Le Wilson

70, avenue du Gnral de Gaulle

92058 PARIS LA DEFENSE

FRANCE

Tel.: +33 (0)1 47 73 64 58

Fax: +33 (0)1 49 06 00 04

e.mail: [email protected]

www.orphan-europe.com

Or one of its local affiliates:

UNITED KINGDOM ITALY

ORPHAN EUROPE (UK) Ltd. ORPHAN EUROPE (Italy) Srl.

Isis House, 43 Station Road Via Cellini, 11

Henley-on-Thames 20090 SEGRATE (MILANO)

OXFORDSHIRE RG9 1AT ITALY

UNITED KINGDOM Tel.:+ 39 02 26 95 01 39

Tel.: +44 (0) 1491 414 333 Fax: + 39 02 26 95 36 74Fax: +44 (0) 1491 414 443 e.mail: [email protected]

e.mail: [email protected] www.orphan-europe.com



17/17

SPAIN PORTUGAL GERMANY

ORPHAN EUROPE S.L. ORPHAN EUROPE (Germany) Gmbh

Gran Via de les Corts Catalanes, 649 Max-Planck-Strasse 6

Despacho n1 63128 DIETZENBACH

08010 BARCELONA GERMANYSPAIN Tel.: + 49 (0) 60 74 81 21 60

Tel.: + 34 93 342 51 20 Fax : + 49 (0) 60 74 81 21 66

Fax: + 34 93 270 10 50 e.mail: [email protected]



POLAND NORDIC COUNTRIES

ORPHAN EUROPE (Germany) Gmbh ORPHAN EUROPE AB

Przedstawicielstwo w Polsce Banrgatan 37Ul. Czeresniowa 98 S 115 22 STOCKHOLM

02 456 WARZAWA SWEDEN

POLAND Tel.: + 46 8 545 80 230

Tel.: + 48 22 863 86 01 Fax: + 46 8 660 5078

Fax: + 48 22 863 58 96 e.mail: [email protected]



BENELUXORPHAN EUROPE

King Albert I Avenue 48 bus 3

1740 WEMMEL

BELGIUM


Documents

239_metabolik hastalıklar (1)