Emergency management of Metabolic Crisis Dr. Vidyut Bhatia Pediatric Gastroenterologist Indraprastha Apollo Hospital, New Delhi Editor: Celiac Focus

Inborn Errors of Metabolism

Individually rare, together they are 1:800-5000 incidence

Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation

Don’t be fooled--other diagnoses like sepsis, ICH, pulm. hem. may accompany IEM

Clues to presence of IEM may often be found in FH

PROTEIN GLYCOGEN FAT

AMINO ACIDS FRUCTOSE

GALACTOSE

FREE FATTY ACIDS

AMMONIA

UREA

UREA CYCLE

ORGANIC ACIDS GLUCOSE

PYRUVATE

ACETYL CoA

KREBS CYCLE

NADH

KETONES

ATP

LACTATE

An integrated view of the metabolic pathways

Metabolic Diseases Which Can Present in Crisis

Defects of glucose homeostasis (20)

Defects of amino acids (10)

Defects of fatty or organic acids (20)

Defects of Lactate/Pyruvate (20)

Defects of Peroxisomes

Others

IEM- Index of Suspicion

Rapid deterioration in an otherwise well infant

Septic appearing infant

Failure to thrive

Regression in milestones

Recurrent emesis or feeding difficulty,

alterations in respirations, lethargy, jaundice, sz, intractable hiccups

Dietary aversion Family history

Severe hyperammonemia, metabolic acidosis abnl urine/body smell

“Waiting until sepsis and other more common causes of illness are ruled out before initiating a specific diagnostic evaluation is inadvisable, as is indiscriminate

study of all ill newborns for metabolic disorders.”

History and Antecedent Events

Catabolic state induction (sepsis, fasting, dehydration)

Protein intake

Change or addition of PO proteins, carbs, etc… in formula

Consanguinity

FHx of SIDS, autism, devl delay

Assessment:

Vitals Level of alertness Abnl activity/mvmts CV- perfusion Dysmorphology, hair, eyes-cornea Abdo- HS megaly Neuro- DTRs, tone, etc Skin- bruise, pigment, color

Recognize that Smell

Musty or Mousy:

PKU

Boiled Cabbage

Tyrosinemia or hypermethioninemia

Maple Syrup

maple syrup urine disease

Sweaty feet:

isovaleric acidemia or glutaric acidemia type II

Cat urine

multiple carboxylase deficiencies (Biotin deficiency)

Laboratory Assessment of Neonates Suspected of Having an Inborn Error of Metabolism Routine Studies Special Studies Blood lactate and pyruvate Complete blood count and differential Plasma amino acids Plasma ammonia Plasma carnitine Plasma glucose Urine amino acids Plasma electrolytes and blood pH Urine organic acids Urine ketones Urine-reducing substances

Emergency Management:

Can be life threatening event requiring rapid assessment and management

Two primary goals

removal of accumulating metabolites

prevention of catabolism

Treatment of the Acutely Sick Child Maintain ABC

Oxygenation Hydration Acid/Base balance

STRIVE TO IDENTIFY PRIMARY METABOLIC DISORDER

Emergency Management

NPO

D5-D10 1-1.5 x maint

Correct hypoglycemia

Correct hypoglycemia IV dextrose bolus, 25%, 0.25-0.5 g/kg/dose (1-2 mL/kg); not to exceed 25 g/dose

Dextrose 10-15% IV @ 8-10 mg/kg/min

Add insulin, 0.2-0.3 IU/kg, as needed

Acidosis and electrolyte abnormalities

The pH and dose at which bicarbonate should be administered are controversial

pH <7.0-7.2, dose 0.35-0.5 mEq/kg/h up to 1-2 mEq/kg/h

For intractable acidosis, consider hemodialysis

Dialysis, lactulose if High/toxic NH4 (nl is <35µmol/L)

Some quick supplements:

Carnitine: IV/PO 100 mg/kg/d

Sodium Benzoate, Phenylacetate for Hyperammonemia

IV: 0.25 g/kg bolus over 24 h, then infusion of 0.25 g/kg over 24 h

Mega-vitamin therapy:

Vitamin B12 (1 mg) should be given im (B12 responsive form of methylmalonic academia)

Biotin (10 mg) should be given orally or by nasogastric tube, (multiple carboxylase deficiency)

Patient is stabilized Now what?

Broad DDx

You can group into KEY features

Can focus on initial labs = Hyperammonia, hypoglycemia, metabolic acidosis.

Can focus on Prominent neurologic features

Can focus on Dysmorphic features

If these don’t exactly fit, resort back to categories of IEMs and Neurodegenerative Disorders.

Diagnostic algorithm

METABOLIC ACIDOSIS

HYPERAMMONEMIA

Ketonuria Ketonuria

Hyperlactatemia

Hypoglycemia

Major hyperlactatemia Maple Syrup Urine Disease (MSUD)

Maple Syrup Urine Disease (MSUD)

Hypoglycemia Organic 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

Quick References:

MA: *metabolic acidosis

NH4:

Glu:

Dz: *Non-ketotic Hyperglycine

*Urea Cycle defects

*Fatty Acid Oxs *OAemia

*OAemia *OAemia

*OAemia *Glycogen Strg dfc *Amino Aciduris

*Carb Metabolism dfc

Organic Acidemias:

*Acidotic with high Gap

*Urine Ketones high

*High to nl Ammonia

Often present first 2-7 days of life after dietary protein introduced.

Drunk appearance in infant.

*May have low WBC and Plts.

Check serum AAs/OAs, Urine AAs/OAs, CSF OAs/AAs.

Organic Acidemias

Isoleucine Valine Methionine Cholesterol Odd chain fatty acids

leucine Isovaleryl CoA HMG CoA Acetyl CoA

Krebs Cycle

Methylmalonyl CoA Propionyl CoA Succinyl CoA biotin B12

Lysine Tryptophan Glutaryl CoA Crotonyl CoA

3MCC

Acetyl CoA

Organic acids are intermediates in the catabolic pathways to break down amino acids, lipids and other compounds to acetyl CoA and succinyl CoA which are entry points into the Kreb cycle

*Urine organic acid analysis will show elevation of organic acids proximal to the enzymatic block; the resulting pattern is interpreted by the metabolic laboratory

Urea Cycle Defects

Symptom free period and then emesis->lethargy-->>COMA

Key features: High Ammonia, low BUN Possible Lactic acidosis *Absence of ketonuria* Nl to mild low Glucose

**Treat high ammonia, infuse glucose, send plasma AAs/OAs, urine orotic acid, and plasma citrulline.

Infusion of 6ml/kg 10% Arginine HCl over 90 min may help

Consequences

Once ammonia >150 µmol/L can lead to permanent neurological damage

Requires prompt & aggressive treatment Withdraw dietary protein

Sodium benzoate/ phenylbutyrate

Haemofiltration/dialysis

Urea cycle disease versus organic acidemias

lethargy/coma

vomiting

hyperammonemia

metabolic ketoacidosis

primary respiratory alkalosis

UCD OA

+ +/-

+

+

+

+ + +

-

-

+

Fatty acids

fasting

ketones

acetyl CoA

Krebs cycle

VLCAD LCHAD MCAD SCAD

CPT1/CPT2

+

Brain

Fatty acid oxidation

Distinguishing feature of FAOD is hypoketotic hypoglycemia MCAD deficiency most common and has a 25% risk of death with first episode LCHAD, VLCAD and carnitine uptake disorder are variably associated with, hepatomegaly, liver disease, hypertrophic cardiomyopathy and potential arrythmias

Liver disease

A metabolic liver disease should be suspected if there is one or more of the following:

persistent unconjugated jaundice

hepatocelluar dysfunction

hypoglycemia without other liver dysfunction

Liver disease

Hepatocellular dysfunction Disorders of amino acid metabolism

Tyrosinemia I Disorders of carbohydrate metabolism

Galactosemia Hereditary Fructose Intolerance Glycogen Storage Disease type IV

Lysosomal storage disorders Niemann Pick Disease

Galactosemia

Galactokinase deficiency--less common

Galactose-1-P uridyl transferase (GALT) deficiency- causes classic galactosemia

Gal-1- P is toxic

Clinical

Presents classically as a sick newborn with vomiting diarrhea, jaundice, progressive liver and renal disease, E.coli sepsis, progressive bilateral cataracts

Galactosemia

Dx assisted by Non-glucose reducing substances in urine

Confirmation by Galactose-1-PO uridyl transferase activity in RBCs

Lastly: Non-ketotic Hyperglycinemia

Unique entity in that Glucose, NH4, pH are all normal

4 types with varying ages of onset, however, classic form is Neonatal with onset in 1st week of life.

Will present just like the other devastating IEMs. Lethargy, emesis, hypotonia, seizures, etc…

Uncontrolled hiccups.

Dx with no urine ketones, and Elevated Glycine.

No effective Rx. Will require diet restriction

The Metabolically ill Child

If you Don’t know you Wont think

If You Don't Think You Wont Look

If You Don't Look You Wont Find

If You Don't Find You Can’t Treat