Metabolic emergencies

1. Metabolic
Emergencies
Dr abdullah alzahrani

2. INTRODUCTION
• Congenital metabolic disorders result from the absence or
abnormality of an enzyme or its cofactor, leading to either
accumulation or deficiency of a specific metabolite.
• IEM present in one of three ways :
Intoxication , Energy defect or Complex molecule defects
• Metabolic crises occur when there is build-up of toxic metabolites.
• increased catabolism (acute infection; surgery, trauma, or even the
birthing process; fasting)
• increased consumption of a food component (eg, increased protein
intake when switching from breast milk to cow’s milk).

3. INTRODUCTION
• Intoxication : acute , chronic or acid base disturbance
• Acute :
• Vomiting and anorexia or failure to feed , accompanied by dehydration or
shock
• Lethargy that can progress to coma
• Seizures, particularly intractable
• Rapid, deep breathing that can progress to apnea
• hypoglycemia
• Chronic :
• growth delay/FTT, hepatomegaly, cardiomyopathy, spastic diplegia, and
developmental delay or regression
• Example of intoxications : amino acid disorders , UCD, OA, sugar intolerance

4. INTRODUCTION
• Energy defect :
• problem in making energy
• problem with utilizing normal sources of stored energy
• Example of Energy defect : FAOD,GSD, mitochondrial disorders
• Complex molecule defects:
• Chronic , progressive , not present at birth
• present with dysmorphic features , sever bone dysplasia , or
neurological presentation

5. INITIAL EVALUATION
• detection of IEM depends upon a high index of suspicion and
should be considered in patients with certain critical
presentations, such as hypoglycemia or hyperammonemia.
• Patients with life-threatening illness should be evaluated for
other conditions in the differential diagnosis (eg, sepsis,
cardiac disease)
• Blood and urine samples (and CSF with seizures, dystonia, or
focal neurologic signs) should be obtained at the time of the
initial evaluation (as possible) or when symptoms are most
pronounced because laboratory values may be normal when
the patient is well

6. INITIAL EVALUATION
CBC with differential
• Hematologic manifestations of IEM may involve any or all of the cell
lines.
• provide a clue to sepsis, which may be the trigger for a metabolic crisis.
Arterial blood gas
• to detect acid-base disturbances.
• Metabolic acidosis with an increased anion gap is commonly associated
with organic acidemia.
• Respiratory alkalosis is commonly seen in urea cycle disorders as a result
of hyperammonemia
Blood glucose
• Hypoglycemia is typical of disorders of ketogenesis (eg, fatty acid
oxidation disorders), glycogen storage disorders, and disorders of
carbohydrate metabolism.

7. INITIAL EVALUATION
Serum ammonia
• should be obtained from an artery or vein without using a tourniquet,
placed on ice for transport to the laboratory, and analyzed immediately.
• If the plasma ammonia concentration is
>100 micromol/L (1.7 microgram/mL) , the measurement should be
repeated immediately.
• Significant elevations in ammonia
(≥300 micromol/L [5.1 microgram/mL]) are most commonly associated
with urea cycle disorders and certain organic acidemias (particularly
propionic and methylmalonic acidemias).
• An elevated ammonia concentration
(≥120 micromol/L [2.0 microgram/mL] in the newborn and
≥80 micromol/L [1.4 microgram/mL] in older infants and children) is
neurotoxic and must be treated immediately.
• The duration of hyperammonemia, rather than the peak level, is
predictive of poor developmental outcome in newborns.

8. INITIAL EVALUATION
Electrolytes, BUN, creatinine
• to calculate the anion gap. A metabolic acidosis with an
increased anion gap is commonly seen in organic acidemias.
• hyponatremia and hyperkalemia may provide a clue to salt-
wasting
Uric acid
• may be high in patients with GSD.
• It can also be abnormal in patients with more chronic forms of
IEM, with decreased levels seen in patients with defects of
purine metabolism and increased levels in patients with
Lesch-Nyhan disease.

9. INITIAL EVALUATION
urinalysis
• presence or absence of ketones in the urine is helpful in
determining the etiology of hypoglycemia.
• The urine pH is helpful in determining the cause of metabolic
acidosis, urine pH >5 is more suggestive of metabolic acidosis
due to renal tubular acidosis rather than an IEM
• Decreased urine specific gravity in a patient who is vomiting is
suggestive of impaired ability to concentrate the urine, which
is suggestive of renal tubular dysfunction (particularly when it
occurs in conjunction with glycosuria and proteinuria). Renal
tubular dysfunction occurs in a number of IEM

10. INITIAL EVALUATION
urinalysis
• leukocyte esterase or nitrites is suggestive of urinary tract
infection, which may be the precipitant for metabolic crisis, or
the presenting manifestation of an IEM that has an associated
increased risk of sepsis eg, galactosemia
• Children who have nonglucose reducing substances in the urine
may have a carbohydrate intolerance disorder (eg, galactosemia,
hereditary fructose intolerance [HFI]) or an amino acid disorder.
• the absence of reducing substances in the urine does not exclude
these disorders.
• False-positive tests for urine reducing substances in children
may occur in children who have taken penicillins, salicylates,
ascorbic acid

11. INITIAL EVALUATION
Lactate dehydrogenase, aldolase, creatine kinase, and urine myoglobin
• muscle weakness, tenderness, cramping, atrophy, or exercise
intolerance that may indicate presence of rhabdomyolysis (eg,
McArdle disease,VLCAD,CPT II).
Liver function tests (aminotransferases, bilirubin, prothrombin time)
• in patients with coagulopathy, jaundice, or other evidence of
liver dysfunction/failure.
• HFI and galactosemia typically present with liver dysfunction and
coagulopathy.
• Citrin deficiency, transaldolase deficiency, tyrosinemia type I, and
disorders of bile acid biosynthesis may present with cholestatic
jaundice and acute liver failure.

12. INITIAL EVALUATION
If possible, at the time of the initial evaluation, samples also
should be obtained for the specialized tests that may be
necessary depending upon the results of the initial
evaluation
• Quantitative plasma amino acids
• Acylcarnitine profile
• Lactate
• Qualitative urine organic acids
• These samples should be placed in the appropriate tubes
or containers, processed, and stored according to the
requirements of individual clinical laboratories

13. EVALUATION OF SPECIFIC
CRITICAL PRESENTATIONS

14. Hypoglycemia
• Ketosis presents in patients with hypoglycemia and GSD,
these patients also typically have increased plasma
concentrations of lactate, pyruvate, triglycerides, and uric acid.
• Ketosis is also present in patients with hypoglycemia and
organic acidemia or maple syrup urine disease.
• Ketosis is usually absent or inappropriately low in patients
with FAOD and disorders of ketogenesis (such as HMG-CoA
lyase and 3-ketothiolase deficiency) because fatty acids cannot
be converted to ketoacids in the liver.
• immediate management of the infant or child with
hypoglycemia involves obtaining critical samples and
administering parenteral glucose.

15. Hypoglycemia
Initial bolus of glucose
• Dextrose, 0.20 to 0.25 grams/kg of body weight
(maximum single dose, 25 grams).This is usually achieved
with 2.5 mL/kg of 10 percent dextrose solution
• Extravasation of higher concentrations of glucose will
lead to severe tissue damage.The bolus should be
administered slowly (2 to 3 mL/min), regardless of the
patient's age.
• The dextrose is given slowly to avoid acute
hyperglycemia, which can cause rebound hypoglycemia

16. Hypoglycemia
Subsequent infusion
• After the bolus, plasma glucose should be maintained by an
infusion of dextrose at 6 to 9 mg/kg per minute.
• The rate of glucose infusion (mg/kg per minute) can be
calculated as follows:
• Rate of infusion (mg/kg per min) = (Percent dextrose in solution x
10 x rate of infusion [mL per hr]) ÷ (60 x weight [kg])
• Thus, for an infusion of 10 percent dextrose solution:
• 3 mL/kg/hour provides 5 mg/kg per minute
• 5 mL/kg/hour provides approximately 8 mg/kg per minute

17. Hypoglycemia
• During the initial treatment phase, the plasma glucose
should be monitored every 30 to 60 minutes and the
dextrose infusion adjusted accordingly, until a stable
plasma glucose concentration between 70 and
120 mg/dL (3.9 to 6.7 mmol/L) is attained
• Thereafter, plasma glucose should be monitored every
two to four hours.
• Glucagon is effective for initial treatment of
hypoglycemia caused by hyperinsulinemia but may not
be effective for other causes

18. Hyperammonemia
Hyperammonemia
Normal PH or
Alkalosis
Hypoketotic
hypoglycemia
FAOD
normoglycemia
Plasma Amino Acid
Increased citrulline
ASA present
Argininosuccinic
aciduria
Low/absent
citrulline
urine orotidine
orotic acid
Normal / low
CPS
deficiency
high
OTC
deficiency
Increased citrulline
ASA absent
citrullinemia
acidosis
Organic academia
Pyruvate metabolism

19. Hyperammonemia
• Neurologic abnormalities and impaired cognitive
function are significantly correlated with the duration of
hyperammonemia and encephalopathy
• initial approach to treatment consists of the following:
• Rehydrate and maintain good urine output without
overhydration
• Remove nitrogen (ammonia) from the body using medications
and/or hemodialysis
• Stop protein intake and minimize catabolism
• Stimulate anabolism and uptake of nitrogen precursors by
muscle

20. Hyperammonemia
• Glucocorticoids increase protein catabolism and should
not routinely be used.
• Valproic acid decreases urea cycle function and increases
serum ammonia levels and should not be used to treat
seizures
• Mannitol is ineffective in treating cerebral edema caused
by hyperammonemia due to UCDs.

21. Hyperammonemia
sodium phenylacetate and sodium benzoate
• Pharmacologic therapy of hyperammonemia consists of
administration of a combination preparation of sodium
phenylacetate and sodium benzoate
• For patients who weigh ≤20 kg, loading dose of 500 mg/kg
(250 mg/kg of each drug) in a volume of 25 to 35 mL/kg of 10 percent
dextrose solution infused over 90 minutes.
• For patients who weigh >20 kg, dosing is based upon body surface
area.The loading dose is 11 g/m2 (ie, 5.5 g/m2 of each drug).
• The loading dose may be repeated in the rare case that a patient
does not respond to dialysis.
• Drug levels could be monitored in this circumstance to avoid toxicity

22. Hyperammonemia
sodium phenylacetate and sodium benzoate
• Maintenance infusion of sodium phenylacetate-sodium
benzoate (500 mg/kg per 24 hours for patients <20 kg, 11 g/m2 per
24 hours as a continuous infusion for patients >20 kg) is started when
the loading dose is completed.
• Maintenance infusion is continued until oral sodium
phenylbutyrate can be tolerated
• 10 percent dextrose supplemented with potassium acetate (2 to
4 mEq/100 mL), should be given to provide a total of 1 to 1.5 times
daily maintenance fluid requirements.
• The potassium will counteract the hypokalemic effects of the large
sodium load (assuming normal urine output), while the acetate base
will counteract the potential acidosis due to the large chloride load.

23. Hyperammonemia
arginine
• Enzyme deficiencies in the urea cycle (with the exception of
arginase deficiency) prevent the formation of arginine
• arginine hydrochloride as part of the initial management
along with dialysis and sodium phenylacetate-sodium
benzoate. In the absence of a diagnosis of the specific form of
UCD
• patients ≤20 kg, the loading dose is 200 mg/kg dissolved in 25
to 35 mL/kg of 10 percent dextrose solution infused over 90
minutes. For patients >20 kg, the loading dose is 4 g/m2
• maintenance dose is started after the loading dose
• Blood pressure should be monitored since high doses of
intravenous arginine can decrease blood pressure.

24. Hyperammonemia
Hemodialysis
• Hemodialysis should be started as soon as possible after hospital
admission of a patient with severe hyperammonemia
• CAVHD or CVVHD with flow rates >40 to 60 mL/min is optimal.This
technique provides very high flow rates (170 to 200 mL/min) and rapidly
reduces ammonia levels but with greater morbidity associated with
surgical vascular access
• Hemodialysis is stopped when the ammonia concentration has dropped
below 200 micromol/L because it appears to have little effect below this
level.
• However, plasma ammonia may increase again (rebound) because of the
delay in the effect of nitrogen scavenging medications and the ongoing
catabolism that continues to produce waste nitrogen
• Dialysis catheters should be kept in place until ammonia levels have been
stable for at least 24 hours.

25. Take Home Message
• Optimal outcome for children with IEM depends upon
early recognition. Delay in diagnosis may result in acute
metabolic decompensation, progressive neurologic
injury, or death.
• Most important clue to an IEM in the neonate is
deterioration after an initial period of wellbeing. Infants
with IEM are not typically sick immediately at delivery.
• Goal of management include provide of ventilatory
support and fluid resuscitation, removal of accumulating
metabolites, and prevention of catabolism.