EM2-K10 : Metabolic emergencies

Inborn errors of metabolism (IEM)
Hyperglycemia/diabetic ketoacidosis
Metabolic acidosis
Adrenal insufficiency
● 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
● Metabolic crises occur when there is build-up of toxic metabolites
● Triggers include factors that cause increased catabolism (acute
infection; surgery, trauma, or even the birthing process; fasting)
or increased consumption of a food component (eg, increased
protein intake when switching from breast milk to cow’s milk).
● Acute metabolic decompensation typically occurs after a period
of apparent well-being.
● Neonate is deterioration after an initial period of well-being
● Older infants and children may present with recurrent episodes
of metabolic decompensation
● Delay in diagnosis may result in acute metabolic decompen-
sation, progressive neurologic injury, or death
Inborn errors of metabolism (IEM)
● IEM can be grouped into disorders of intermediary
metabolism (classic IEM), disorders of biosynthesis and
breakdown of complex molecules, and disorders of
neurotransmitter metabolism
● Many of the disorders of intermediary metabolism can
present with acute life-threatening illness, particularly
organic acidurias, urea cycle disorders, maple syrup urine
disease, and fatty acid oxidation disorders.
● Neurotransmitter defects and related disorders can
present with severe metabolic encephalopathy.
● In contrast, the disorders involving complex molecules
tend to progress more slowly and do not typically cause
acute metabolic decompensation.
IEM groups
Source: Hoffman GF, Nyhan WL, Zschocke J, et al. Inherited metabolic diseases, Lippincott Williams & Wilkins,
Philadelphia 2002.
Types of inborn errors of metabolism
Disorders of intermediary
Amino acid metabolism and transport
Fatty acid oxidation and ketogenesis
Carbohydrate metabolism and transport
Vitamin-related (cobalamin, folate)
Peptide metabolism
Mineral metabolism
Mitochondrial energy metabolism
Disorders of biosynthesis
and breakdown of
complex molecules
Purine and pyrimidine metabolism
Lysosomal storage
Isoprenoid and sterol metabolism
Bile acid and heme metabolism
Lipoprotein metabolism
Disorders of
Glycine and serine metabolism
Pterin and biogenic amine metabolism
Gamma-aminobutyrate metabolism
Other (eg, pyridoxine-dependent or folinic acid-
dependent seizures, sulfite oxidase deficiency)
● Vomiting and anorexia or failure to feed
● Lethargy that can progress to coma
● Seizures, particularly intractable
● Rapid, deep breathing that can progress to apnea
● Hypothermia
● An acute life threatening event (ALTE) or sudden infant
death syndrome (SIDS)
● Patients can also present with an acid-base disorder,
hyperammonemia, or hypoglycemia
Clinical manifestations
● Complete blood count with differential
● Arterial blood gas
● Blood glucose
● Serum ammonia
● Electrolytes, blood urea nitrogen (BUN), creatinine, uric
● Liver function tests: aminotransferases, bilirubin,
prothrombin time
● Examination of the urine, including color, odor, dipstick,
and presence of ketones
Initial evaluation
Distinguishing biochemical findings of IEM
Dis. of
F A oxi-
drial dis.
± ++ - ± ± ± - -
- - + - - - - -
± + ++ - ± - - -
Hypoglycemia ± ± - + + ± - -
Ketones A/H H A A/H A/L A/H A A
Lactic acidosis ± ± - + ± ++ - -
Adapted from: Weiner DL. Metabolic Emergencies. In: Textbook of Pediatric Emergency Medicine, 5th ed, Fleisher GR, Ludwig S,
Henretig FM (Eds), Lippincott, Williams & Wilkins, Philadelphia 2006. p.1193.
● Management of hypoglycemia, hyperammonemia, and
seizures must be initiated promptly to prevent long-term
● Supportive interventions include provision of ventilatory
support and fluid resuscitation, removal of accumulating
metabolites, and prevention of catabolism
● Selected cofactors may be administered, if indicated,
before confirmation of the diagnosis
● Hypoglycemia define as a plasma glucose value
of ≤40 mg/dL (2.22 mM) regardless of age
● In neonates : <40 mg/dL (2.2 mmol/L) during
the first 24 hours of life and <50 mg/dL (2.8
mmol/L) after 24 hours of age
● Others: thresholds of plasma glucose = 36
mg/dL (2 mmol/L) in asymptomatic infants, and
= 45 mg/dL (2.5 mmol/L) in symptomatic
Hypoglycemia is caused by a lower rate of glucose
production than that of glucose utilization :
• Inadequate glucose supply
- Inadequate glycogen stores
- Impaired glucose production (ie,
glycogenolysis or gluconeogenesis)
• Increased glucose utilization primarily due to
glucose intake
Fasting, malnutrition, malabsorption
Inborn errors of
Disorders of glycogen metabolism, Disorders of
gluconeogenesis (Fructosemia, galaktosemia)
Deficiency of the hormones that regulate
glucose homeostasis : cortisol, growth
hormone, epinephrine, and glucagon; thyroid
Severe hepatic
Fulminan hepatitis, Reye syndrome
Alcohol, oral hypoglycemic agents, propanolol,
salicylates, quinine
Other causes
Sepsis, shock, burns, hypothermic infants, Islet
cell adenoma, ketotic hypoglycemia
Clinical manifestation
In infants
● Nonspecific
● Irritability, jitteriness, feeding problems,
lethargy, cyanosis, tachypnea, and
In children and adults
● Autonomic response (early manifestations) :
hypoglycemia and include sweating, weakness,
tachycardia, tremor, and feelings of nervousness
and/or hunger
● Neuroglycopenia (prolonged hypoglycemia) :
lethargy, irritability, confusion, uncharacteristic
behavior, hypothermia, and, in extreme
hypoglycemia, seizure and coma
Management (1)
Measurement of key substrates: plasma
glucose, FFAs, ß-hydroxybutyrate, lactate,
total and free carnitine, and acylcarnitines
Measurement of glucoregulatory
hormones: plasma insulin, C-peptide,
cortisol, and growth hormone
Other tests : Serum electrolytes, Liver
function tests, Ammonia, Toxicology
studies (salicylate, ethanol, sulfonylurea),
Metabolic screening for some disorders
ketones and reducing substances (non-
glucose reducing substances suggests
galactosemia or hereditary fructose
intolerance); toxicology studies, organic
Management (2)
Conscious and able to drink and
swallow : glucose tablets, glucose
gel, table sugar, fruit juice, or honey
Unconsciousness and/or unable to
swallow : intravenous (IV) dextrose
and SC/IM glucagon
Dextrose : Initial bolus 0.25 g/kg of
body weight; maintained, 6 to 9 mg/kg
per minute
SC/IM 0.03 mg/kg up to a max of 1
Every 30 to 60 minutes until a stable
plasma glucose concentration is
attained (70-120 mg/dL or 3.9 to
6.7 mmol/L)
Thereafter, every two to four hours
Diabetic ketoacidosis/Hyperglycemia
● Diabetic ketoacidosis (DKA): hyperglycemia (blood
glucose of ≥200 mg/dL (11 mmol/L) and metabolic
acidosis (venous pH <7.30 and/or serum bicarbonate
<15 meq/L), resulting in hyperosmolality and volume
● Hyperosmolar hyperglycemic state (HHS) is a
hyperglycemia emergency which is distinguished from
classic DKA by marked hyperosmolality (effective
osmolality of >320 mOsm/L) due to severe
hyperglycemia (plasma glucose >600 mg/dL), in the
absence of severe metabolic acidosis (serum CO2 >15
mmol/L, absent to small ketonemia and ketonuria).
● DKA and HHS are part of a spectrum, representing the metabolic
consequences of insulin deficiency, glucagon excess, and
counterregulatory hormonal responses to stressful triggers in
patients with diabetes.
● DKA is more common in younger patients with type 1 diabetes,
though it can occur in type 2 diabetes.
● DKA is the leading cause of morbidity and mortality in children
with type 1 diabetes mellitus, also can occur in children with type
2 diabetes mellitus
● HHS occurs less frequently, and is associated with higher
mortality, representing underlying comorbidity.
● Hyperglycemia results from impaired glucose utilization,
increased gluconeogenesis and increased glycogenolysis; glucose
concentrations are most often lower in DKA compared with HHS.
● Ketoacidosis results from lipolysis, with synthesis of ketones from
free fatty acids in the liver mitochondria.
● Insulin levels in HHS are insufficient to allow appropriate glucose
utilization, but are adequate to prevent lipolysis and subsequent
Pathogenesis of diabetic ketoacidosis and
hyperosmolar hyperglycemic state
Evaluation: assessment of severity
● Degree of dehydration - Patients with DKA are
usually more dehydrated than suggested by the
clinical examination
● Initial laboratory testing should include, at a
minimum: serum testing for glucose, electrolytes,
creatinine and urea nitrogen, blood gases,
hematocrit, hemoglobin A1C, venous pH,
and routine urinalysis
● Neurologic status: patients with abnormal mental
status may have cerebral edema
Diagnostic criteria for diabetic ketoacidosis (DKA)
and hyperosmolar hyperglycemic state (HHS)

Mild Moderate Severe
Plasma glucose (mg/dL)
>250 >250 >250 >600
>13.9 >13.9 >13.9 >33.3
Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30
Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18
Urine ketones* Positive Positive Positive Small
Serum ketones -
Nitroprusside reaction
Serum ketones - Enzymatic
assay of beta
hydroxybutyrate (normal
range <0.6 mmol/L)
Positive Positive Positive Small
0.6 to 2.0
2.0 to 5.0
Effective serum osmolality
Variable Variable Variable >320
Anion gap >10 >12 >12 Variable
Alteration in sensoria or
mental obtundation
Diabetes Care Vol 29, Issue 12, 2006
Bedside evaluation of neurological state of
children with diabetic ketoacidosis (DKA)
Major criteria
Altered mentation/fluctuating level of consciousness
Sustained heart rate deceleration (decline of more than 20 beats per minute)
not attributable to improved intravascular volume or sleep state
Age-inappropriate incontinence
Minor criteria
Lethargy or being not easily aroused from sleep
Diastolic blood pressure >90 mmHg
Age <5 years
Diagnostic criteria
Abnormal motor or verbal response to pain
Decorticate or decerebrate posture
Cranial nerve palsy (especially III, IV, and VI)
Abnormal neurogenic respiratory pattern (eg, grunting, tachypnea, Cheyne-
Stokes respiration, apneusis)
Signs that occur before treatment should not be considered in the diagnosis of the cerebral edema. Cerebral edema is
diagnosed if any of the diagnostic criteria is present. Cerebral edema is also likely if two major criteria OR one major and
two minor criteria are present
Fluids Initial bolus of 10 to 20 mL/kg of an isotonic solution
should be given over one hour.
A second bolus may be infused over the next hour for
patients with compromised circulation.
Hypovolemic shock is a rare occurrence in DKA. The
patient in shock should be evaluated for other causes of
Following initial fluid resuscitation, replace deficit over
the next 48 hours.
This fluid should be given no more rapidly than 1.5 to 2
times the maintenance rate during the first 24 hours.
Use an isotonic solution for the first 4 to 6 hours, then
switch to half normal saline solution.
Urinary losses should not be replaced
Management (1)
Electrolytes Sodium: generally low and should rise as fluid deficit,
hyperglycemia, and acidosis are corrected. Failure to rise
may be an early sign of cerebral edema.
Potassium: patients with DKA have a total body
potassium deficit (fluids therapy and insulin will lower
potassium). Added potassium to iv fluid for hypokalemic
immediately. If normokalemic, potassium replacement
should begin with the start of insulin therapy (eg, adding
40 meq/L of potassium to the IV solution). For
hyperkalemic, potassium replacement should be
initiated when the serum potassium falls to normal.
Insulin After the initial fluid bolus, begin a continuous insulin
infusion at 0.05 to 0.1 units/kg per hour. Mix 50 units of
regular insulin in 50 mL normal saline (such that 1 mL of
the infusion provides 1 unit of insulin). Do not give an
initial bolus of insulin.
Management (2)
Glucose Blood glucose falls rapidly during the initial volume
expansion, but after that should not fall faster than 90
mg/dL (5 mmol/L) per hour. Add 5 percent dextrose
solution when blood glucose falls to 300 mg/dL (17
mmol/L). Add dextrose sooner if level is dropping too
quickly. It may be necessary to use a higher
concentration (10 to 12.5 percent dextrose) to prevent
hypoglycemia while continuing to infuse insulin to
correct metabolic acidosis.
Monitoring Record hourly vital signs and neurologic status, as well
as fluid intake (intravenous and oral) and losses.
Measure blood glucose, electrolytes, and venous pH
hourly for the first three to four hours.
Continue to monitor blood glucose hourly.
Electrolytes and venous pH may subsequently be
measured every two hours.
Management (3)
Metabolic acidosis occurs when there is either a net
gain of H+ ions or a net loss of HCO3- ions by the
three following mechanisms :
● Increased acid generation from an exogenous
source (eg, salicylate ingestion) or endogenous
production (eg, ketoacidosis and lactic acidosis)
● Bicarbonate loss either from the gastrointestinal
tract (eg, diarrhea) or kidney (eg, type 2
[proximal] renal tubular acidosis [RTA])
● Reduced renal acid excretion (eg, renal failure or
type 1 [distal] RTA)
Metabolic acidosis
Pediatric causes of metabolic acidosis
Pediatric causes of metabolic acidosis
Pediatric causes of metabolic acidosis
Diagnosis & treatment
● The diagnosis of metabolic acidosis is made by
laboratory testing that shows a both a low serum
bicarbonate and pH.
● The history, physical examination, anion gap, and
urine pH are useful aids in determining the
underlying cause of metabolic acidosis.
● Although there is controversy regarding the use
of sodium bicarbonate in the treatment of acute
metabolic acidosis, its generally recommend
bicarbonate therapy to correct severe acidosis in
children with a pH less than 6.9 to 7.0.
● Definition : serum or plasma sodium less than
135 meq/L
● The most common electrolyte abnormalities
in children
● Often observed in children on admission to
the hospital
● Common complication of in-hospital
Causes of hyponatremia in children
(Based on patient's volume status and renal sodium handling)
arterial volume
Urinary sodium concentration
<25 mEq/L >25 mEq/L
Gastroenteritis Adrenal insufficiency
Cystic fibrosis Diuretics - Early effect
Diuretics - Late effect Salt wasting
Normal or
Cardiac failure SIADH*
Nephrotic syndrome Renal failure
Cirrhosis Water intoxication
Adapted from: Somers MJG. Fluid and electrolyte therapy in children. In: Pediatric Nephrology, 6th ed,
Avner ED, Harmon WH, Niaudet P, Yoshikawa N (Eds), Springer-Verlag, Berlin 2009
*SIADH : syndrome of inappropriate antidiuretic hormone
Plasma sodium
>125 meq/L
Less likely to produce any specific
Only manifest the symptoms of
underlying illness
Below 125
Neurologic symptoms are
observed, beginning with nausea
and malaise
Below 120
Headache, lethargy, obtundation,
and seizures may occur
Hyponatremia Symptoms
● Fluid restriction
● Administration of sodium chloride
● Treatment of the underlying etiology
● Management are based on the magnitude and cause of the
sodium deficit, the rate of sodium decline, the volume
status of the patient, the presence of severe symptoms,
and the chronicity of hyponatremia
● The rate of correction does not exceed an increase of 8
mEq/L over a 24-hour period (Grade 1A)
● Rapid correction can cause osmotic demyelination
syndrome resulting in diffuse demyelination in the brain
and the development of profound irreversible neurologic
Adrenal Insufficiency
● Primary=Addison’s disease : adrenal gland
destruction/dysfunction (ie. Auto-immune,
hemorrhagic); most common in infants 5-15
days old
● Secondary=ACTH deficiency (ie.
panhypopituitarism or isolated ACTH)
● “Tertiary” or “iatrogenic” : suppression of
hypothalamic-pituitary-adrenal axis (ie.
chronic steroid use)
Clinical manifestations of
Adrenal Insufficiency
● Dehydration, hypotension, shock out of
proportion to severity of illness
● Nausea, vomiting, abdominal pain, weakness,
tiredness, fatigue, anorexia
● Unexplained fever
● Hypoglycemia (more common in children and
● Hyponatremia, hyperkalemia, azotemia
● Major hormonal factor precipitating crisis is
mineralcorticoid deficiency, not glucocorticoid
● Critical level of suspicion in all patients with
● Demonstration of inappropriately low cortisol
secretion: basal morning level vs. random
“stress” level
● Determine cortisol and ACTH secretion:
 ACTH,  cortisol  primary;
 ACTH,  cortisol  secondary or tertiary
Diagnosis of Adrenal Insufficiency
● Do not wait for confirmatory labs
● Fluid resuscitation - isotonic crystalloid
● Treat hypoglycemia
● Glucocorticoid replacement - hydrocortisone in
stress doses - 25-50 mg/m2 (1-2 mg/kg) IV
● Consider mineralocorticoid (Florinef®)
Treatment of Adrenal Insufficiency
● Neonatal thyrotoxicosis (congenital hyperthy-
roidism), is usually due to in utero passage of
thyroid-stimulating immunoglobulins from the
mother to fetus.
● Incidence : 1 case per 4000 to 50,000 live births
● Most cases are due to maternal Graves’ disease,
an autoimmune disorder that produces thyroid-
stimulating hormone (TSH) receptor antibodies
causing increased thyroid hormone release
● Diagnosis is made by measuring neonatal levels
of serum-free thyroxine T4 and TSH shortly after
● Normal ranges of T4 and TSH concentrations are
higher in neonates than older infants and
● Thyroid function tests may be unreliable in the
first few days of life if the mother was taking
antithyroid medications.
● Transient and usually last less than 12 weeks,
the duration of which is dependent on the
persistence of maternally transmitted immuno-
● Symptoms include vomiting, diarrhea, poor
feeding and weight loss, sweating, and
● Most infants will have a goiter, and many will
also have exophthalmos, hyperthermia,
tachycardia, hepatomegaly, and jaundice.
● Although transient, neonatal thyrotoxicosis can
be life-threatening, with a reported mortality
rate of up to 20%, usually from heart failure
● Hyperthyroidism in older infants and children is
almost always due to Graves’ disease.
● Nearly 5% of all patients with hyperthyroidism
are less than 15 years old, with the majority
being adolescents.
● Unlike adults, children with hyperthyroidism
usually have an indolent progression of
symptoms over months, although it may occur
more abruptly.
Hyperthyroidism in older infants and children
● Personality disturbances or motor hyperactivity may be the
earliest symptoms, followed by the classic symptoms of
weight loss, heat intolerance, diaphoresis, palpitations,
diarrhea, and amenorrhea.
● A goiter is present in nearly 100% of cases, and exo-
phthalmos, tachycardia, and hypertension are common
● Thyroid storm can occur in the pediatric population and
consists of extreme signs and symptoms of hyper-
thyroidism combined with a high fever and altered mental
● It is usually precipitated by infection, trauma, or
● Thyroid storm is life-threatening and treatment should be
aggressive and similar to adult management
● Propanolol (Beta-adrenergic blocker) 0.01 mg/kg/dose
intravenously and titrated to clinical effect; oral 2 mg/kg/d
in three to four divided doses
● Thyroid hormone synthesis can be blocked using propyl-
thiouracil, 5 to 10 mg/kg/d, or methimazole, 0.5 to 1
mg/kg/d, both in three divided oral doses.
● Iodine can be given in the form of Lugol’s solution (8 mg
iodine/drop), 1 to 3 drops daily.
● Iodine should be started at least 1 hour after administering
an anti-thyroid drug like propylthiouracil to avoid
increasing thyroid gland stores before the anti-thyroid
effect occurs.
● Glucocorticoid treatment with hydrocortisone or prednisone
may also be helpful in severe cases, because it inhibits
thyroid hormone release and decreases peripheral
conversion of T 4 to T3