Em2-k10 Metabolic Emergencies-new (01)

8/12/2019 Em2-k10 Metabolic Emergencies-new (01)

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EM2-K10 : Metabolic emergencies


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Inborn errors of metabolism (IEM)Hypoglycemia

Hyperglycemia/diabetic ketoacidosisMetabolic acidosisHyponatremia

Adrenal insu ciencyThyrotoxicosis


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Congenital metabolic disorders result from the absence orabnormality of an enzyme or its cofactor, leading to eitheraccumulation 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, increasedprotein intake when switching from breast milk to cows 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 episodesof metabolic decompensation Delay in diagnosis may result in acute metabolic decompen-

sation, progressive neurologic injury, or death

Inborn errors of metabolism (IEM)


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IEM can be grouped into disorders of intermediarymetabolism (classic IEM), disorders of biosynthesis andbreakdown of complex molecules, and disorders ofneurotransmitter metabolism

Many of the disorders of intermediary metabolism can

present with acute life-threatening illness, particularlyorganic acidurias, urea cycle disorders, maple syrup urinedisease, and fatty acid oxidation disorders.

Neurotransmitter defects and related disorders canpresent with severe metabolic encephalopathy.

In contrast, the disorders involving complex moleculestend to progress more slowly and do not typically causeacute metabolic decompensation.

IEM groups


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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 intermediarymetabolism

Amino acid metabolism and transportFatty acid oxidation and ketogenesisCarbohydrate metabolism and transport

Vitamin-related (cobalamin, folate)Peptide metabolismMineral metabolismMitochondrial energy metabolism

Disorders of biosynthesisand breakdown ofcomplex molecules

Purine and pyrimidine metabolismLysosomal storagePeroxisomesIsoprenoid and sterol metabolismBile acid and heme metabolismGlycosylationLipoprotein metabolism

Disorders ofneurotransmittermetabolism

Glycine and serine metabolismPterin and biogenic amine metabolismGamma-aminobutyrate metabolismOther (eg, pyridoxine-dependent or folinic acid-dependent seizures, sulfite oxidase deficiency)


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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


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Complete blood count with differential Arterial blood gas Blood glucose Serum ammonia Electrolytes, blood urea nitrogen (BUN), creatinine, uric

acid Liver function tests: aminotransferases, bilirubin,

prothrombin time Examination of the urine, including color, odor, dipstick,

and presence of ketones

Initial evaluation


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Distinguishing biochemical findings of IEM

Findings

Maplesyrupurine

disease

Organicacide-mias

Ureacycledis.

Dis. ofCO

meta-bolism

F A oxi-dation

dis.

Mito-chon-

drial dis.

Peroxi-somal

dis

Lyso-somal

storagedis.

Metabolic

acidosis ++ - - -

Respiratoryalkalosis

- - + - - - - -

Hyperammonemia

+ ++ - - - -

Hypoglycemia - + + - -

Ketones A/H H A A/H A/L A/H A ALactic 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.


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Management of hypoglycemia, hyperammonemia, andseizures must be initiated promptly to prevent long-termsequelae

Supportive interventions include provision of ventilatorysupport and fluid resuscitation, removal of accumulatingmetabolites, and prevention of catabolism

Selected cofactors may be administered, if indicated,before confirmation of the diagnosis

Management


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Hypoglycemia define as a plasma glucose valueof 40 mg/ dL (2.22 mM) regardless of age

In neonates :


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Pathogenesis

Hypoglycemia is caused by a lower rate of glucoseproduction than that of glucose utilization : Inadequate glucose supply

- Inadequate glycogen stores- Impaired glucose production (ie,

glycogenolysis or gluconeogenesis) Increased glucose utilization primarily due to

hyperinsulinism


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Etiology

Decreasedglucose intake

Fasting, malnutrition, malabsorption

Inborn errors ofmetabolism

Disorders of glycogen metabolism, Disorders ofgluconeogenesis (Fructosemia, galaktosemia)

Endocrinedisorders

Deficiency of the hormones that regulate

glucose homeostasis : cortisol, growthhormone, epinephrine, and glucagon; thyroiddisease

Severe hepaticdysfunction

Fulminan hepatitis, Reye syndrome

Ingestions Alcohol, oral hypoglycemic agents, propanolol,salicylates, quinine

Other causesSepsis, shock, burns, hypothermic infants, Isletcell adenoma, ketotic hypoglycemia


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Clinical manifestationIn infants Nonspecific Irritability, jitteriness, feeding problems,

lethargy, cyanosis, tachypnea, andhypothermia

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, uncharacteristicbehavior, hypothermia, and, in extreme

hypoglycemia, seizure and coma


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Management (1)

Criticalsamples

Blood

Measurement of key substrates: plasmaglucose, FFAs, -hydroxybutyrate, lactate,total and free carnitine, and acylcarnitinesMeasurement of glucoregulatoryhormones: plasma insulin, C-peptide,

cortisol, and growth hormoneOther tests : Serum electrolytes, Liverfunction tests, Ammonia, Toxicologystudies (salicylate, ethanol, sulfonylurea),Metabolic screening for some disorders

Urine

ketones and reducing substances (non-glucose reducing substances suggestsgalactosemia or hereditary fructoseintolerance); toxicology studies, organicacids


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Management (2)

Clinicalmanagement

Glucosetherapy

Conscious and able to drink andswallow : glucose tablets, glucosegel, table sugar, fruit juice, or honeyUnconsciousness and/or unable toswallow : intravenous (IV) dextrose

and SC/IM glucagonDextrose : Initial bolus 0.25 g/kg ofbody weight; maintained, 6 to 9 mg/kgper minute

Glucagon SC/IM 0.03 mg/kg up to a max of 1

mg

Monitoring

Every 30 to 60 minutes until a stableplasma glucose concentration isattained (70-120 mg/dL or 3.9 to6.7 mmol/L)

Thereafter, every two to four hours


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Diabetic ketoacidosis/Hyperglycemia


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Diabetic ketoacidosis (DKA): hyperglycemia (bloodglucose of 200 mg/ dL (11 mmol/L) and metabolicacidosis (venous pH 600 mg/dL), in theabsence of severe metabolic acidosis (serum CO2 >15mmol/L, absent to small ketonemia and ketonuria).

Definition


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Pathogenesis of diabetic ketoacidosis andhyperosmolar hyperglycemic state


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Evaluation: assessment of severity

Degree of dehydration - Patients with DKA areusually more dehydrated than suggested by theclinical examination

Initial laboratory testing should include, at aminimum: serum testing for glucose, electrolytes,creatinine and urea nitrogen, blood gases,hematocrit, hemoglobin A1C, venous pH,and routine urinalysis

Neurologic status: patients with abnormal mentalstatus may have cerebral edema


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Diagnostic criteria for diabetic ketoacidosis (DKA)and hyperosmolar hyperglycemic state (HHS)

DKA

HHS

Mild Moderate Severe Plasma glucose (mg/dL)

(mmol/L) >250 >250 >250 >600

>13.9 >13.9 >13.9 >33.3

Arterial pH 7.25 to 7.30 7.00 to 7.24 7.30

Serum bicarbonate (mEq/L) 15 to 18 10 to 12 Variable

Alteration in sensoria or

mental obtundation Alert

Alert/

drowsy

Stupor/

coma

Stupor/

coma Diabetes Care Vol 29, Issue 12, 2006


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Bedside evaluation of neurological state ofchildren with diabetic ketoacidosis (DKA)

Major criteria

Altered mentation/fluctuating level of consciousnessSustained heart rate deceleration (decline of more than 20 beats per minute)not attributable to improved intravascular volume or sleep state

Age-inappropriate incontinenceMinor criteria

VomitingHeadacheLethargy or being not easily aroused from sleepDiastolic blood pressure >90 mmHg

Age


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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 forpatients with compromised circulation.Hypovolemic shock is a rare occurrence in DKA. Thepatient in shock should be evaluated for other causes ofshock.Following initial fluid resuscitation, replace deficit overthe next 48 hours.This fluid should be given no more rapidly than 1.5 to 2times the maintenance rate during the first 24 hours.Use an isotonic solution for the first 4 to 6 hours, thenswitch to half normal saline solution.Urinary losses should not be replaced

Management (1)


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Electrolytes Sodium: generally low and should rise as fluid deficit,

hyperglycemia, and acidosis are corrected. Failure to risemay be an early sign of cerebral edema.Potassium: patients with DKA have a total bodypotassium deficit (fluids therapy and insulin will lowerpotassium). Added potassium to iv fluid for hypokalemicimmediately. If normokalemic, potassium replacementshould begin with the start of insulin therapy (eg, adding40 meq/L of potassium to the IV solution). Forhyperkalemic, potassium replacement should beinitiated when the serum potassium falls to normal.

Insulin After the initial fluid bolus, begin a continuous insulininfusion at 0.05 to 0.1 units/kg per hour. Mix 50 units ofregular insulin in 50 mL normal saline (such that 1 mL ofthe infusion provides 1 unit of insulin). Do not give aninitial bolus of insulin.

Management (2)


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Glucose Blood glucose falls rapidly during the initial volume

expansion, but after that should not fall faster than 90mg/dL (5 mmol/L) per hour. Add 5 percent dextrosesolution when blood glucose falls to 300 mg/dL (17mmol/L). Add dextrose sooner if level is dropping tooquickly. It may be necessary to use a higherconcentration (10 to 12.5 percent dextrose) to preventhypoglycemia while continuing to infuse insulin tocorrect metabolic acidosis.

Monitoring Record hourly vital signs and neurologic status, as wellas fluid intake (intravenous and oral) and losses.Measure blood glucose, electrolytes, and venous pHhourly for the first three to four hours.Continue to monitor blood glucose hourly.Electrolytes and venous pH may subsequently bemeasured every two hours.

Management (3)


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Metabolic acidosis occurs when there is either a netgain of H+ ions or a net loss of HCO3- ions by thethree following mechanisms : Increased acid generation from an exogenous

source (eg, salicylate ingestion) or endogenousproduction (eg, ketoacidosis and lactic acidosis)

Bicarbonate loss either from the gastrointestinaltract (eg, diarrhea) or kidney (eg, type 2

[proximal] renal tubular acidosis [RTA]) Reduced renal acid excretion (eg, renal failure ortype 1 [distal] RTA)

Metabolic acidosis


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Pediatric causes of metabolic acidosis


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Diagnosis & treatment

The diagnosis of metabolic acidosis is made bylaboratory testing that shows a both a low serumbicarbonate and pH.

The history, physical examination, anion gap, andurine pH are useful aids in determining theunderlying cause of metabolic acidosis.

Although there is controversy regarding the useof sodium bicarbonate in the treatment of acutemetabolic acidosis, its generally recommendbicarbonate therapy to correct severe acidosis inchildren with a pH less than 6.9 to 7.0.


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Hyponatremia

Definition : serum or plasma sodium less than135 meq/L

The most common electrolyte abnormalities

in children Often observed in children on admission to

the hospital Common complication of in-hospital

interventions


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Causes of hyponatremia in children(Based on patient's volume status and renal sodium handling)

Circulatingarterial volume

Urinary sodium concentration25 mEq/L

Decreased

Gastroenteritis Adrenal insufficiencyCystic fibrosis Diuretics - Early effect

Diuretics - Late effect Salt wastingBurnsBleeding

Normal or

increased

Cardiac failure SIADH*Nephrotic syndrome Renal failureCirrhosis 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


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Plasma sodiumlevels Symptoms

>125 meq/L

Less likely to produce any specificsymptoms

Only manifest the symptoms ofunderlying illness

Below 125meq/L

Neurologic symptoms areobserved, beginning with nausea

and malaiseBelow 120meq/L

Headache, lethargy, obtundation,and seizures may occur

Hyponatremia Symptoms


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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 volumestatus of the patient, the presence of severe symptoms,and the chronicity of hyponatremia

The rate of correction does not exceed an increase of 8mEq/L over a 24-hour period (Grade 1A)

Rapid correction can cause osmotic demyelinationsyndrome resulting in diffuse demyelination in the brainand the development of profound irreversible neurologicsymptoms

Treatment


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Adrenal Insufficiency Primary=Addisons disease : adrenal gland

destruction/dysfunction (ie. Auto-immune,hemorrhagic); most common in infants 5-15days old

Secondary=ACTH deficiency (ie.panhypopituitarism or isolated ACTH)

Tertiary or iatrogenic : suppression ofhypothalamic-pituitary-adrenal axis (ie.

chronic steroid use)


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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

tertiary)

Hyponatremia, hyperkalemia, azotemia Major hormonal factor precipitating crisis ismineralcorticoid deficiency, not glucocorticoid


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Critical level of suspicion in all patients withshock

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


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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


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Neonatal thyrotoxicosis (congenital hyperthy-roidism), is usually due to in utero passage ofthyroid-stimulating immunoglobulins from themother 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 antibodiescausing increased thyroid hormone release

Thyrotoxicosis


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Diagnosis is made by measuring neonatal levelsof serum-free thyroxine T4 and TSH shortly afterbirth.

Normal ranges of T4 and TSH concentrations arehigher in neonates than older infants andchildren.

Thyroid function tests may be unreliable in therst few days of life if the mother was takingantithyroid medications.

Diagnosis


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Transient and usually last less than 12 weeks,the duration of which is dependent on thepersistence of maternally transmitted immuno-globulins.

Symptoms include vomiting, diarrhea, poorfeeding and weight loss, sweating, andirritability.

Most infants will have a goiter, and many willalso have exophthalmos, hyperthermia,tachycardia, hepatomegaly, and jaundice.

Although transient, neonatal thyrotoxicosis canbe life-threatening, with a reported mortalityrate of up to 20%, usually from heart failure

Symptoms


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Hyperthyroidism in older infants and children isalmost always due to Graves disease.

Nearly 5% of all patients with hyperthyroidismare less than 15 years old, with the majoritybeing adolescents.

Unlike adults, children with hyperthyroidismusually have an indolent progression ofsymptoms over months, although it may occur

more abruptly.

Hyperthyroidism in older infants and children


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Personality disturbances or motor hyperactivity may be theearliest symptoms, followed by the classic symptoms ofweight 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 andconsists of extreme signs and symptoms of hyper-thyroidism combined with a high fever and altered mentalstatus

It is usually precipitated by infection, trauma, ordehydration

Thyroid storm is life-threatening and treatment should beaggressive and similar to adult management

Symptoms


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Em2-k10 Metabolic Emergencies-new (01)