management of iem

8/2/2019 Management of IEM

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Dr.Lakshmi.L


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Treatment Initial Emergency management

Definitive


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Emergency managementInitial ED treatment does not require knowledge of the

specific metabolic disease or even disease category.

1. Establishment of ABC

2. Correction of acute metabolic derangements


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Emergency managementAs In any critically ill child establish a stable

airway, breathing, and circulation

Metabolic correction includes:

Correction of Hydration

Correction of biochemical abnormalities Metabolic acidosis

Hypoglycemia

Hyperammonemia


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Metabolicderangements

Accumulation

of toxicmetabolites

Loss ofsubstrate

mixed


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Metabolicderangements

Accumulation

of toxicmetabolites

Loss ofsubstrate

mixed

correction ofmetabolicabnormalities

-Elimination of

toxic metabolites-prevention offurther formationof toxicmetabolites-cofactor

administration

Provision ofadequate substrate


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Goals of the initial treatment for patients with an inborn error of metabolism

correction of metabolic abnormalities, and

Elimination of toxic metabolites

prevention of further formation of toxic metabolites Administration of Adequate calories

Treatment of precipitating factors when possible

Institute co factor therapy

Even the apparently stable patient with mild symptoms maydeteriorate rapidly with progression to death within hours.

With appropriate therapy, patients may completely recoverwithout sequelae.


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Correction of hypoglycemia

Hypoglycemia is one of the common manifestation of

many IEMs. Every attack of hypoglycemia is detrimental to the

growing brain.

Further more One of the goals in IEM management is

to prevent catabolism and establish anabolic state So Correction of hypoglycemia is paramount

important in newborn with IEM


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Hypoglycemia in Galactocemia

GSD

Gluconeogenic defects OA

FAO deffects

Ketogenesis defects

Fructose-1,6-diphosphatase deficiency

Hereditary fructose intolerance


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Correction of hypoglycemia Hypoglycemia corrected by IV dextrose bolus, 10%

dextrose in newborn, 25%dextrose in older infants

0.25-0.5 g/kg/dose (1-2 mL/kg); not to exceed 25 g/dose, and

followed by continuous IV administration of dextrose.

For all patients in whom an IEM cannot be ruled out, givedextrose 10-15% IV at a rate high enough (1 to 1.5maintenance) to prevent catabolism (8-10 mg/kg/min).

A target glucose of 120 170 mg/dl is maintained If necessary Add insulin 0.2-0.3 IU/kg, as needed to

maintain normoglycemia.


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Correction of dehydration This enables us to achieve adequate renal perfusion

and elimination of toxic metabolites

Shock if present is corrected with normal saline Dehydration with 5DNS

Hypotonic fluids are avoided in view of developmentof cerebral edema


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Treatment of acute acidosis

Acidosis in IEM Could beorganic acidemia

congenital lactic acidosis


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Organic acid acidosis Defects in Organic acid metebolism

Fatty acid oxidation disorders

Defects in ketone metabolism Ketothiolase deficiency

Succinyl-CoA: 3-ketoacid-CoA transferase deficiency

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency


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Primary Lactic acidosis Primary lactic acidoses

Pyruvate dehydrogenase complex deficiency

Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxykinase deficiency

Mitochondrial respiratory/electron transport chaindefects


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Treatment of acidosispH 7.35-7.457.1 7.35, asymptomatic- frequent review of the metabolic

parameterspH 7.1 deteriorating Sodium bicarbonate starting with half correction (base deficit

*weight*0.3)/2 Administered slowly(0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)) Review frequently Monitor potassium

When potassium is low and patient symptomatic potassiumcorrection given (1 mEq/kg/h)

Intractable acidosis needs hemodialysis


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Organic acidemia Kept nil oral

Iv glucose

Supportive care L-Carnitine: 100mg/kg/day iv or oral

Vitamin cocktail

Biotin 10mg/day oral

Vitamin b12 1-2mg/day im

Thiamine 300mg/day iv


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Management of congenital lactic

acidosis Supportive care

L-carnitine: 50-100 mg/kg orally

Vitamin cocktail Thiamine: up to 300 mg/day in 4 divided doses.

Riboflavin: 100 mg/day in 4 divided doses.

Biotin 10 mg/day. (Biotin responsive Multiple

carboxylase deficiency may present with unexplainedlactic acidosis)

Add co-enzyme Q: 5-15 mg/kg/day


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Hyperammonemia Urea cycle disorders

THAN

Congenital lactic acidosis Organic acidemias

FAO defects


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Treatment of hyper ammonemia

Normal blood ammonia levels 10-40 mcmols/l Significant hyperammonemia is life threatening and must be

treated immediately upon diagnosis.1. Stop all feeds2. Supportive care3. Give adequate glucose/iv lipids to provide adequate calories

and prevent catabolism4. Administration of sodium phenylbutyrate and sodium

benzoate(alternate pathway for nitrogen excretion)

5. Arginine in hyperammonemia without acidosis(urea cycledefects except arginase deficiency), an infusion of 6 mL/kg of10% arginine HCL (0.6 g/kg) can be given intravenously over90 minutes.

6. L-carnitine-200mg/kg/day


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Sodium benzoate (ivor oral)

250 mg/kg loadingdose

250-400mg/kg/dayin 4 div doses


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Sodiumphenylacetate

LD-250mg/kg

250-500mg/kg/day


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Hemodialysis

For ammonia greater than 500-600 mcg/dL,

if comatose or ventilator-dependent evidence of cerebral Edema

Levels >300 mcg/dl after ammonul treatment

Two to 3 days of therapy is usually necessary. The goalof HD is to achieve a plasma ammonia concentrationof


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If hemodialysis is not readily available, peritoneal dialysis(< 10% as effective as hemodialysis) or double volumeexchange transfusion (even less effective) can be

performed while arrangements are made to transport toa center where hemodialysis is possible, as long as thisdoes not delay transfer.


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Refractory seizures -suspected

metabolic etiology If patient persists to have seizures despite 2 or 3

antiepileptic drugs in adequate doses,

consider trial of pyridoxine 100 mg intravenously.

give trial of biotin 10 mg/day and folinic acid 5mg twicedaily (folinic acid responsive seizures).

Trial of pyridoxal phosphate 10 mg/kg/dose X 2 doses isalso recommended, however this is not available inIndia.

glucose transporter defect- responds to the ketogenicdiet


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Further Inpatient Care Once initial stabilization attained and toxic

metabolites have been normalized For amino and organic acidopathies and urea cycle defects,

protein intake should be restricted to 40-50% ofrecommended daily allowance (RDA).

Lipids, 2-3 g/kg/d as 20% intralipid, can be given to increasecaloric intake, but they are contraindicated for certain fattyacid oxidation defects.

For patients able to tolerate enteral feeding, protein-restrictedpreparations may be given.

With definitive diagnosis, specific dietary regimens, availablefor most inborn errors of metabolism should be initiated.


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Definitive treatment Dietary Restriction

Supplement deficient products

Stimulate alternate pathway Supply vitamin co-factor

Transplantation (organ or bone marrow)

Enzyme replacement therapy

Gene therapy


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Long term treatment of IEM Medical therapy specific for the inborn error of

metabolism diagnosed will need to be continued,usually for life.

Long-term, routine follow-up screening should beprovided for potential disease complications


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Dietary treatment Strict adherence to dietary and pharmacologic

regimen is recommended for patients diagnosed withan inborn error of metabolism.


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Galactosemia

lactose-restricteddiet for their entirelives

Glycogen storage disorders

The mainstay of therapy isfrequent feedings and

restriction of lactose andsucrose


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Elimination ofdietary fructose andsucrose

HF

intolerance

Glucoseadministration

L-carnitine suppleFatty acidoxidation

defects


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homocystinuria PKU

MSUD

indigenous diets basedon aminoacid contentof the diet


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Enzyme replacement ERT is now commercially available for some

lysosomal storage disorders.

However, these disorders do not manifest in thenewborn period, an exception being

Pompes disease (GSD Type II) which may presentin the newborn period and for which ERT is now

available


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COFACTOR REPLACEMENT

THERAPY The catalytic properties of many enzymes depend on

the participation of non protein prosthetic groups,such as vitamins and minerals, as obligatorycofactors. The following co-factors may be beneficialin certain IEM


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Methylmalononic acidemia, homocystinuria, Vitamin B12

Holocarboxylase synthetase deficiency, Biotinase deficiency, biotin

Mitochondrial disorders, PDH def thiamin

Homocystinuria, xanthurenic aciduria, primary hyperoxaluria,Pyridoxin responsive fits, hyperornithemia

Pyridoxine,Pyridoxalphosphate

Hereditary orotic aciduria, Methionine synthase deficiency,

Cerebral folate transporter deficiency, hereditary folatemalabsorption,Kearns-Sayre syndrom

Folinic acid

Glutaric aciduria Type I, Type II, mild variants of ETF, ETFDH,complex I deficiency

Riboflavin


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Organ transplantation Hematopoietic stem cell transplantation

Hepatocyte transplantation


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Gene therapy The genetically defective function will be restored by

transfer of a normal gene into somatic cells.

The therapeutic potential and safety of gene therapyhas been explored in cultured cells and experimentalanimals,

but therapeutic clinical trials have not yet been

proposed or performed in humans


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Prevention Genetic counselling

Prenatal screening


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Prognosis Prognosis varies based on individual inborn error of

metabolism (IEM) and may differ for different forms ofa particular IEM.

A high index of suspicion is critical for early diagnosisand treatment of IEM.

Rapid treatment may be life saving and often results in

full recovery.


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Patient Education Provide education regarding disease and patient care

(manifestations, course of disease, treatment,psychosocial support) as appropriate.

Provide genetic counseling to discuss recurrence risks,screening of other family members, and prenataldiagnosis.

Provide information regarding support groups.

National Organization of Rare Diseases (NORD) candirect families to resources for more than 1000 IEMs.Professional and peer support groups exist for manyIEMs.


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conclusionDont think of IEM as rare, exotic and untreatable

disorders.

Think of IEM in sick newborns in parallel with othercommon conditions

Even if the chances of survival appear less, everyattempt must be made to reach a diagnosis so that

parents can be guided for future pregnancy


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management of iem

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