HyperthermiaHyperthermia

Aaron McGuffin, M.D.Aaron McGuffin, M.D.

DefinitionDefinition

►Elevation of core body temperature Elevation of core body temperature above the normal diurnal range of above the normal diurnal range of 36ºC to 37.5ºC due to failure of 36ºC to 37.5ºC due to failure of thermoregulation thermoregulation

►Hyperthermia is Hyperthermia is notnot synonymous with synonymous with the more common sign of fever, which the more common sign of fever, which is induced by is induced by cytokine activationcytokine activation during during inflammationinflammation, and regulated at , and regulated at the level of the the level of the hypothalamushypothalamus

HyperthermiaHyperthermia

►The most important causes of severe The most important causes of severe hyperthermia (greater than 40ºC or hyperthermia (greater than 40ºC or 104ºF) caused by failure of 104ºF) caused by failure of thermoregulation are:thermoregulation are: Heat strokeHeat stroke Neuroleptic malignant syndromeNeuroleptic malignant syndrome Malignant hyperthermia Malignant hyperthermia

PhysiologyPhysiology

► Body temperature is maintained within a Body temperature is maintained within a narrow range by balancing heat load with narrow range by balancing heat load with heat dissipation.heat dissipation.

► Body's heat load results from both metabolic Body's heat load results from both metabolic processes and absorption of heat from the processes and absorption of heat from the environmentenvironment

► As core temperature rises, the As core temperature rises, the preoptic preoptic nucleusnucleus of the of the anterior hypothalamusanterior hypothalamus stimulates stimulates efferent fibers of the ANSefferent fibers of the ANS to to produce produce sweatingsweating and cutaneous and cutaneous vasodilationvasodilation..

PhysiologyPhysiology

► Evaporation is the principal mechanism of heat Evaporation is the principal mechanism of heat loss in a hot environment, but this becomes loss in a hot environment, but this becomes ineffectiveineffective above a relative humidity of 75% above a relative humidity of 75%

► Other methods of heat dissipationOther methods of heat dissipation Radiation- emission of infrared electromagnetic Radiation- emission of infrared electromagnetic

energyenergy Conduction- direct transfer of heat to an adjacent, Conduction- direct transfer of heat to an adjacent,

cooler objectcooler object Convection-direct transfer of heat to convective air Convection-direct transfer of heat to convective air

currentscurrents► These methods cannot efficiently transfer heat These methods cannot efficiently transfer heat

when when environmental temperature exceeds skin environmental temperature exceeds skin temperature.temperature.

PhysiologyPhysiology

► Temperature elevation Temperature elevation ↑ O2 ↑ O2 consumption consumption and metabolic rate and metabolic rate hyperpnea and hyperpnea and tachycardiatachycardia

► Above 42ºC (108ºF), oxidative Above 42ºC (108ºF), oxidative phosphorylation becomes uncoupled, and a phosphorylation becomes uncoupled, and a variety of enzymes cease to function.variety of enzymes cease to function.

► Hepatocytes, vascular endothelium, and Hepatocytes, vascular endothelium, and neural tissueneural tissue are are most sensitivemost sensitive to these to these effects, but all organs may be involved.effects, but all organs may be involved.

► As a result, these patients are at risk of As a result, these patients are at risk of multiorgan system failure.multiorgan system failure.

Heat StrokeHeat Stroke

►Core body temperature > 40.5ºC Core body temperature > 40.5ºC (105ºF) with associated CNS (105ºF) with associated CNS dysfunction in the setting of a large dysfunction in the setting of a large environmental heat load that cannot be environmental heat load that cannot be dissipated dissipated

►Complications include:Complications include:►ARDSARDS►DICDIC►Renal or hepatic failureRenal or hepatic failure►HypoglycemiaHypoglycemia►RhabdomyolysisRhabdomyolysis►Seizures Seizures

Classic (nonexertional) heat Classic (nonexertional) heat strokestroke

► Affects individuals with underlying chronic Affects individuals with underlying chronic medical conditions that either medical conditions that either impair impair thermoregulationthermoregulation or or prevent removal from a prevent removal from a hot environmenthot environment..

► Conditions include:Conditions include: Cardiovascular diseaseCardiovascular disease Neurologic or psychiatric disordersNeurologic or psychiatric disorders ObesityObesity AnhidrosisAnhidrosis Extremes of ageExtremes of age Anticholinergic agents or diuretics Anticholinergic agents or diuretics

Exertional heat stroke Exertional heat stroke ► Occurs in young, otherwise healthy Occurs in young, otherwise healthy

individuals engaged in heavy exercise during individuals engaged in heavy exercise during periods of high ambient temperature and periods of high ambient temperature and humidity humidity

► Findings include cutaneous vasodilation, Findings include cutaneous vasodilation, tachypnea, rales due to noncardiogenic tachypnea, rales due to noncardiogenic pulmonary edema, excessive bleeding due to pulmonary edema, excessive bleeding due to DIC, altered mentation or seizures DIC, altered mentation or seizures

► Labs: coagulopathy, ARF, elevated LFTs due Labs: coagulopathy, ARF, elevated LFTs due to acute hepatic necrosis, respiratory to acute hepatic necrosis, respiratory alkalosis, and a leukocytosis as high as alkalosis, and a leukocytosis as high as 30,000 to 40,000/mm3 30,000 to 40,000/mm3

► One series of 58 patients with heat stroke One series of 58 patients with heat stroke found an acute mortality rate of 21 percent found an acute mortality rate of 21 percent (Ann Intern Med 1998 Aug 1;129(3):173-81) (Ann Intern Med 1998 Aug 1;129(3):173-81)

Malignant Hyperthermia Malignant Hyperthermia ► Rare genetic disorder manifests after tx with anesthetic Rare genetic disorder manifests after tx with anesthetic

agents: succinylcholine and halothaneagents: succinylcholine and halothane► Onset is usually in 1 hour of the administration of anesthesia, Onset is usually in 1 hour of the administration of anesthesia,

rarely delayed up to 10 hoursrarely delayed up to 10 hours► ½ of cases are inherited in as AD; Rest are inherited in ½ of cases are inherited in as AD; Rest are inherited in

different patterns. different patterns. ► Susceptible patients with AD disease have any one of several Susceptible patients with AD disease have any one of several

distinct mutations in the gene for the SKM ryanodine receptor distinct mutations in the gene for the SKM ryanodine receptor (RyR1) which is a homotetrameric Ca++ channel in the (RyR1) which is a homotetrameric Ca++ channel in the sarcoplasmic reticulum of SKMsarcoplasmic reticulum of SKM

► In the presence of anesthetic agents, alterations in the In the presence of anesthetic agents, alterations in the hydrophilic, amino-terminal portion of the ryanodine hydrophilic, amino-terminal portion of the ryanodine receptorreceptor uncontrolled Ca ++ efflux from the SR uncontrolled Ca ++ efflux from the SR tetany, tetany,↑ ↑ SKM SKM metabolism, and heat productionmetabolism, and heat production

► For unclear reasons, overexpression of the wild-type For unclear reasons, overexpression of the wild-type ryanodine receptor does not ablate abnormal myocyte ryanodine receptor does not ablate abnormal myocyte responses to halothane although overexpression of a mutated responses to halothane although overexpression of a mutated ryanodine receptor can induce the malignant hyperthermia ryanodine receptor can induce the malignant hyperthermia phenotype in myocytes from normal individualsphenotype in myocytes from normal individuals

Malignant HyperthermiaMalignant Hyperthermia

► Early clinical findings in malignant hyperthermia Early clinical findings in malignant hyperthermia include muscle rigidity (especially masseter include muscle rigidity (especially masseter stiffness), sinus tachycardia, increased CO2 stiffness), sinus tachycardia, increased CO2 production, and skin cyanosis with mottlingproduction, and skin cyanosis with mottling

► Marked hyperthermia (up to 45ºC [113ºF]) occurs Marked hyperthermia (up to 45ºC [113ºF]) occurs minutes to hours later; core body temperature minutes to hours later; core body temperature tends to rise 1ºC every 5 to 60 minutes. tends to rise 1ºC every 5 to 60 minutes.

► Hypotension, complex dysrhythmias, Hypotension, complex dysrhythmias, rhabdomyolysis, electrolyte abnormalities, DIC and rhabdomyolysis, electrolyte abnormalities, DIC and mixed acidosis accompany the elevated mixed acidosis accompany the elevated temperature.temperature.

► Rarely, biochemically-proven malignant Rarely, biochemically-proven malignant hyperthermia may present solely with hyperthermia may present solely with rhabdomyolysis in the absence of hyperthermiarhabdomyolysis in the absence of hyperthermia

Neuroleptic malignant Neuroleptic malignant syndrome syndrome

► Idiosyncratic reaction to antipsychotic Idiosyncratic reaction to antipsychotic agents.agents.

► IN addition to hyperthermia, NMS is IN addition to hyperthermia, NMS is also characterized by "lead pipe" also characterized by "lead pipe" muscle rigidity, altered mental status, muscle rigidity, altered mental status, choreoathetosis, tremors, and choreoathetosis, tremors, and evidence of autonomic dysfunction, evidence of autonomic dysfunction, such as diaphoresis, labile blood such as diaphoresis, labile blood pressure, and dysrhythmias. pressure, and dysrhythmias.

DIAGNOSTIC EVALUATION DIAGNOSTIC EVALUATION

► Get a rectal temperature; abnormal VS include sinus Get a rectal temperature; abnormal VS include sinus tachycardia, tachypnea, widened pulse pressure, tachycardia, tachypnea, widened pulse pressure, hypotension hypotension

► CXR may demonstrate pulmonary edemaCXR may demonstrate pulmonary edema► EKG may reveal dysrhythmias, conduction EKG may reveal dysrhythmias, conduction

disturbances, nonspecific ST-T wave changes, or disturbances, nonspecific ST-T wave changes, or heat-related myocardial ischemia or infarctionheat-related myocardial ischemia or infarction

► Labs: CBC CCP, Coagulation Studies, creatine kinase, Labs: CBC CCP, Coagulation Studies, creatine kinase, and check for hyperphosphatemia, myoglobinuria and check for hyperphosphatemia, myoglobinuria

► Myoglobinuria should be suspected in a patient who Myoglobinuria should be suspected in a patient who has a brown urine supernatant that is heme-positive, has a brown urine supernatant that is heme-positive, and clear plasma. and clear plasma.

► Toxicologic screening may be indicated if a Toxicologic screening may be indicated if a medication effect is suspected. medication effect is suspected.

► Head CT and lumbar puncture if CNS etiologies Head CT and lumbar puncture if CNS etiologies suspected suspected

DIAGNOSTIC EVALUATIONDIAGNOSTIC EVALUATION

► Diagnosis confirmed by in vitro muscle contracture Diagnosis confirmed by in vitro muscle contracture test following recovery from the acute hyperthermic test following recovery from the acute hyperthermic episode. episode.

► Abnormal augmentation of in vitro muscle contraction Abnormal augmentation of in vitro muscle contraction following treatment with halothane or caffeine is following treatment with halothane or caffeine is diagnostic of the disorder diagnostic of the disorder

► However, this test is expensive, not widely available, However, this test is expensive, not widely available, and frequently not covered by insurance. and frequently not covered by insurance.

► Genetic testing for the more than 40 known mutations Genetic testing for the more than 40 known mutations of the SKM ryanodine receptor (RyR1) can be used in of the SKM ryanodine receptor (RyR1) can be used in conjunction with the in vitro muscle contracture test conjunction with the in vitro muscle contracture test to evaluate individual susceptibility in patients from to evaluate individual susceptibility in patients from families with a history of malignant hyperthermiafamilies with a history of malignant hyperthermia

ManagementManagement►Ensure ABCs, initiate rapid cooling, tx Ensure ABCs, initiate rapid cooling, tx

complicationscomplications

Management Management

ManagementManagement

► CVP monitoring is useful for assessing volume status CVP monitoring is useful for assessing volume status and determining the need for fluid resuscitation and determining the need for fluid resuscitation

► Alpha-adrenergic agonists should be Alpha-adrenergic agonists should be avoidedavoided, since , since the resultant vasoconstriction decreases heat the resultant vasoconstriction decreases heat dissipation. dissipation.

► Continuous core temperature monitoring with a Continuous core temperature monitoring with a rectal or esophageal probe is mandatory, and rectal or esophageal probe is mandatory, and cooling measures should be stopped once a cooling measures should be stopped once a temperature of 39.5ºC (103ºF) has been achieved in temperature of 39.5ºC (103ºF) has been achieved in order to reduce the risk of iatrogenic hypothermiaorder to reduce the risk of iatrogenic hypothermia

► In the case of NMS or malignant hyperthermia, the In the case of NMS or malignant hyperthermia, the presumed causative agent must be discontinued presumed causative agent must be discontinued immediatelyimmediately

ManagementManagement► Cooling measuresCooling measures

Naked patient is sprayed with a mist of lukewarm Naked patient is sprayed with a mist of lukewarm water while air is circulated with large fans. water while air is circulated with large fans. Shivering may be suppressed with intravenous Shivering may be suppressed with intravenous benzodiazepines such as diazepam (5 mg IV) or benzodiazepines such as diazepam (5 mg IV) or lorazepam (1-2 mg IV) or, if NMS is not suspected, lorazepam (1-2 mg IV) or, if NMS is not suspected, with chlorpromazine (25 to 50 mg IV).with chlorpromazine (25 to 50 mg IV).

Immersing the patient in ice water is the most Immersing the patient in ice water is the most effective method of rapid cooling but complicates effective method of rapid cooling but complicates monitoring and accessmonitoring and access

Applying ice packs to the axillae, neck, and groin is Applying ice packs to the axillae, neck, and groin is effective, but is poorly tolerated in the awake effective, but is poorly tolerated in the awake patientpatient

ManagementManagement

► Cooling MeasuresCooling Measures Cold peritoneal lavage results in rapid cooling, but it is an Cold peritoneal lavage results in rapid cooling, but it is an

invasive technique that is contraindicated in pregnant invasive technique that is contraindicated in pregnant patients or those with previous abdominal surgery.patients or those with previous abdominal surgery.

Cold oxygen, cold gastric lavage, cooling blankets, and Cold oxygen, cold gastric lavage, cooling blankets, and cold intravenous fluids may be helpful adjuncts.cold intravenous fluids may be helpful adjuncts.

There is no role for antipyretic agents such as There is no role for antipyretic agents such as acetaminophen or ASA in the management of heat stroke, acetaminophen or ASA in the management of heat stroke, since the underlying mechanism does not involve a change since the underlying mechanism does not involve a change in the hypothalamic set-pointin the hypothalamic set-point

Alcohol sponge baths should be avoided because large Alcohol sponge baths should be avoided because large amounts of the drug may be absorbed through dilated amounts of the drug may be absorbed through dilated cutaneous vessels and produce toxicitycutaneous vessels and produce toxicity

Management:Management: Malignant hyperthermia Malignant hyperthermia

► Dantrolene administration is the mainstay of treatment of Dantrolene administration is the mainstay of treatment of malignant hyperthermia, and should be initiated as soon as the malignant hyperthermia, and should be initiated as soon as the diagnosis is suspected.diagnosis is suspected.

► Since the introduction of dantrolene, the mortality of the fulminant Since the introduction of dantrolene, the mortality of the fulminant syndrome has fallen from close to 70 percent to less than 10 syndrome has fallen from close to 70 percent to less than 10 percent.percent.

► Dantrolene is a nonspecific SKM relaxant that acts by blocking the Dantrolene is a nonspecific SKM relaxant that acts by blocking the release of calcium from the SR release of calcium from the SR decreases the myoplasmic decreases the myoplasmic concentration of free calcium and diminishes the myocyte concentration of free calcium and diminishes the myocyte hypermetabolism that causes clinical symptoms. hypermetabolism that causes clinical symptoms.

► Most effective when given early in the illness (ie, before Most effective when given early in the illness (ie, before hyperthermia occurs), when maximal calcium can be retained hyperthermia occurs), when maximal calcium can be retained within the SRwithin the SR

► A 2 mg/kg IV bolus is given and should be repeated every 5 A 2 mg/kg IV bolus is given and should be repeated every 5 minutes until symptoms abate up to a maximum dose of 10 mg/kg.minutes until symptoms abate up to a maximum dose of 10 mg/kg.

► This may be repeated every 10 to 15 hours. After an initial This may be repeated every 10 to 15 hours. After an initial response, the drug should be continued orally at a dose of 4 to 8 response, the drug should be continued orally at a dose of 4 to 8 mg/kg per day, in four divided doses, for three days.mg/kg per day, in four divided doses, for three days.