1. Emergency management of
Metabolic Crisis
Dr. Vidyut Bhatia
Pediatric Gastroenterologist
Indraprastha Apollo Hospital, New Delhi
Editor: Celiac Focus
2. 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
3. PROTEIN
GLYCOGEN
FAT
FRUCTOSE
AMINO ACIDS
GALACTOSE
GLUCOSE
FREE FATTY ACIDS
ORGANIC ACIDS
AMMONIA
PYRUVATE
LACTATE
ACETYL CoA
UREA CYCLE
KETONES
UREA
KREBS CYCLE
NADH
ATP
An integrated view of the metabolic pathways
4. 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
5. IEM- Index of Suspicion
Rapid deterioration in an Dietary aversion
otherwise well infant
Family history
Septic appearing infant Severe hyperammonemia,
Failure to thrive metabolic acidosis
Regression in milestones abnl urine/body smell
Recurrent emesis or feeding
difficulty,
alterations in respirations,
lethargy, jaundice, sz,
intractable hiccups
6. “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.”
7. 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
9. Recognize that Smell
Musty or Mousy: Sweaty feet:
PKU isovaleric acidemia or
glutaric acidemia type II
Boiled Cabbage
Cat urine
Tyrosinemia or
hypermethioninemia multiple carboxylase
deficiencies (Biotin
Maple Syrup deficiency)
maple syrup urine
disease
10. 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
11. Emergency Management:
Can be life threatening event requiring
rapid assessment and management
Two primary goals
removal of accumulating metabolites
prevention of catabolism
12. Treatment of the Acutely Sick Child
Maintain ABC
Oxygenation
Hydration
Acid/Base balance
STRIVE TO IDENTIFY PRIMARY METABOLIC
DISORDER
13. 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
14. 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)
15. 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)
16. 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.
17. Diagnostic algorithm
METABOLIC ACIDOSIS
yes no
Ketonuria Ketonuria
yes no yes no
Major hyperlactatemia Maple Syrup Urine Hyperlactatemia Maple Syrup Urine HYPERAMMONEMIA
Disease (MSUD) Disease (MSUD)
yes no yes no yes no
Mitochondrial Organic Hypoglycemia Organic aciduria Hypoglycemia Non-ketonic hyperglycinemia
defect aciduria Pyroglutamic Sulfite oxydase deficiency - XO
aciduria
yes no yes no
Fatty acid oxydation Respiratory Fatty acid oxydation Urea Cycle
Glycogen storage disease chain Variant hyperinsulinism Disorders
Glyconeogenesis defects (glutamate dehydrogenase)
19. 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.
20. Organic Acidemias
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
Isoleucine
Valine
biotin B12
Methionine
Propionyl CoA Methylmalonyl CoA Succinyl CoA
Cholesterol
Odd chain fatty
acids
Krebs
Cycle
leucine Isovaleryl CoA 3MCC HMG CoA Acetyl CoA
Lysine
Acetyl
Tryptophan Glutaryl CoA Crotonyl CoA CoA
*Urine organic acid analysis will show elevation of organic acids
proximal to the enzymatic block; the resulting pattern is
interpreted by the metabolic laboratory
21. 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
22. Consequences
Once ammonia >150 µmol/L can lead to
permanent neurological damage
Requires prompt & aggressive treatment
Withdraw dietary protein
Sodium benzoate/ phenylbutyrate
Haemofiltration/dialysis
24. Fatty acid oxidation
Brain
CPT1/CPT2
Fatty VLCAD LCHAD MCAD SCAD
ketones
acids +
fasting acetyl CoA
Krebs
cycle
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
25. 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
26. 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
27. 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
28. Galactosemia
Dx assisted by Non-glucose reducing
substances in urine
Confirmation by Galactose-1-PO uridyl
transferase activity in RBCs
29. 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
30. 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
