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MALIGNANT HYPERTHERMIA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Malignant hyperthermia (MH) is a syndrome that is triggered by volatile anesthetic agents and depolarizing muscle relaxants. It is a sudden pharmacogenetic hypermetabolic crisis involving uncontrolled calcium release from skeletal muscle that causes potentially fatal consequences. The predisposition for the development of MH is an inherited autosomal dominant trait.

Specific Substances

    A) DEPOLARIZING MUSCLE RELAXANTS
    1) Succinylcholine
    2) Succinylcholine bromide
    3) Decamethonium
    4) Suxamethonium
    VOLATILE INHALATION ANESTHETICS
    1) Desflurane
    2) Enflurane
    3) Halothane
    4) Isoflurane
    5) Methoxyflurane
    6) Sevoflurane
    7) Chloroform
    8) Cyclopropane
    9) Ether
    OTHER AGENTS
    1) Ondansetron (probable-association in susceptible individuals)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) GENERAL INFORMATION: Malignant hyperthermia (MH) is a syndrome that is triggered by volatile anesthetic agents (most commonly halothane) and depolarizing muscle relaxants typically used during surgery and procedures requiring general anesthesia. The predisposition for the development of MH is an inherited autosomal dominant trait.
    B) TOXICOLOGY: MH occurs when susceptible individuals are exposed to triggering agents resulting in an increase in intracellular calcium from the sarcoplasmic reticulum, activation of the sympathetic nervous system, and catecholamine release. The increased intracellular calcium results in persistent muscle contraction due to the continuous interaction between actin and myosin. Biochemical pathways are simultaneously triggered in an attempt to resequester excess calcium, but ultimately lead to breakdown of adenosine triphosphate (ATP), lactic acidosis, hypercarbia, and hyperthermia. Hyperthermia in MH results primarily from increased muscle activity exceeding the body's capacity to dissipate the generated heat. "Awake" malignant hyperthermia-like reaction worsened by succinylcholine has been reported in a child who presented with muscle rigidity and hyperthermia unrelated to anesthesia.
    C) EPIDEMIOLOGY: The estimated incidence of MH in North America and Europe is 1:15,000 anesthetic administration events for children and adolescents and 1:50,000 to 1:150,000 events for adults. The incidence of MH has also been reported to range from 1:200 to 1:250,000 depending on the geographic location. However, the true figure is difficult to ascertain as the majority of susceptible individuals are completely asymptomatic until exposed to triggering drugs or conditions. Furthermore, the development of MH is dependent upon the dose and duration of administration of the anesthetic.
    D) WITH POISONING/EXPOSURE
    1) Rapid elevation of the core temperature is a common finding in patients with MH, but it may be absent. Body temperature can increase at a rate of 0.5 degrees C to 2 degrees C every 5 to 10 minutes and may reach or exceed 40 degrees C very rapidly. Temperature increase results from persistent muscle contraction. Patients may reach temperatures above 46 degrees C in 20 minutes and progress to severe acidosis, shock, and ventricular fibrillation.
    2) EARLY SIGNS: Masseter spasm/muscle rigor (trismus), increased end-tidal CO2, unexplained tachycardia, an increase in core temperature, unstable blood pressure, tachypnea (if not paralyzed with muscle relaxants), flushed skin, metabolic acidosis, hyperkalemia, and hypermagnesemia can occur.
    3) INTERMEDIATE SIGNS: Cardiac dysrhythmias, supraventricular tachycardias, ventricular dysrhythmias, dark blood in operative field, cyanosis, mottled skin, diaphoresis, hypertension, hypercapnia, hypoxemia, elevation in blood lactate and pyruvate, and decreased HCO3 may develop.
    4) LATE SIGNS/COMPLICATIONS: Hypoxemia, hypotension, hyperkalemia, hypermagnesemia, rhabdomyolysis, seizures, cerebral edema, cardiovascular collapse, disseminated intravascular coagulopathy, hyperthermia, massive skeletal muscle swelling, pulmonary edema, and acute renal failure may be observed.
    5) ABORTIVE MH: Patients present with metabolic acidosis, increased creatine kinase and dysrhythmias; however, severe hyperthermia does not develop.

Laboratory Monitoring

    A) An unexplained increase in end-tidal carbon dioxide is the most sensitive indicator of possible MH.
    B) Monitor core temperature, arterial blood gases, ECG, vital signs, electrolytes, glucose, CK, coagulation studies, hepatic enzymes, renal function, lactate, and urine output.
    C) CAFFEINE-HALOTHANE CONTRACTURE TEST (known in EUROPE as IN VITRO CONTRACTURE TEST) - The only recognized laboratory test to diagnose MH.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) MANAGEMENT
    1) Terminate the surgery as soon as possible. Immediately begin hyperventilation with 100% oxygen. All triggering agents should be discontinued. Switch the vaporizer off. Monitor core temperature, arterial blood gases, ECG, vital signs, urine output, electrolytes, CK, coagulation studies, lactate, liver enzymes, and renal function. Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions.
    B) DECONTAMINATION
    1) The only decontamination necessary is to stop the exposure.
    C) AIRWAY MANAGEMENT
    1) The airway will already be secured in the majority of malignant hyperthermia cases. If not, they may need to be secured due to altered mental status, muscle contraction inhibiting respiration, or as a result of large doses of benzodiazepines used in the treatment of malignant hyperthermia. Avoid using volatile anesthetic agents or depolarizing muscle relaxants for intubation or sedation management.
    D) RHABDOMYOLYSIS
    1) Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be needed to maintain urine output. Urinary alkalinization is NOT routinely recommended. Vigorous fluid replacement with 0.9% saline is necessary even if there is no evidence of dehydration. Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 2 to 3 mL/kg/hr. In severe cases, 500 mL of fluid per hour may be required for the first several days. Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    E) HYPERTHERMIA
    1) Treat hyperthermia aggressively. The best method for cooling the body in patients with malignant hyperthermia is controversial. Direct cooling by immersion of the body in cold water may enhance the conduction of heat from the body, but also may interfere with resuscitative measures. Evaporative cooling by spraying cool water directly on the skin and directing fans at the patient can rapidly decrease temperature and will allow for concurrent resuscitative measures. Other methods that may be effective for cooling include ice packs to the groin, axilla and neck, cooling blankets, extracorporeal partial bypass, and cold intravenous fluids. Cooling measures should be discontinued when the core body temperature reaches 38 degrees C to 38.8 degrees C to prevent hypothermia. Antipyretics are not useful because of their lack of effect on excessive heat production produced by the intense hypermetabolic skeletal muscle reaction.
    F) PSYCHOMOTOR AGITATION
    1) Treat with intravenous benzodiazepines; large doses may be needed.
    G) HYPERKALEMIA
    1) Treat hyperkalemia using standard treatment measures (intravenous sodium bicarbonate, calcium, insulin and dextrose, inhaled albuterol).
    H) CONDUCTION DISORDER OF THE HEART
    1) Treat cardiac dysrhythmias per standard ACLS guidelines, however, avoid the use of calcium channel blocker due to a possible drug interaction with dantrolene (the antidote for malignant hyperthermia).
    I) ANTIDOTE
    1) If malignant hyperthermia is suspected, administer dantrolene by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached. Sodium dantrolene is an effective and specific treatment for an acute malignant hyperthermia. Dantrolene acts by increasing the contraction activation threshold voltage at the sarcoplasmic reticulum involved in calcium release, thus limiting the amount of calcium available for muscle contraction. Dantrolene should be immediately administered intravenously and maintained until tachycardia, muscle rigidity, increased end-tidal carbon dioxide, hyperthermia, and any other manifestation of malignant hyperthermia are controlled. Some references advocate that dantrolene should be administered for an additional 24 to 72 hours after the acute episode to prevent recurrence of malignant hyperthermia symptoms. NOTE: Cardiovascular collapse in association with hyperkalemia has been reported in patients treated with calcium channel blockers while receiving dantrolene. Calcium channel blockers should not be used in the management of malignant hyperthermia symptoms when patients are treated with dantrolene due to potential drug interaction.
    2) For POST CRISIS FOLLOW-UP OF malignant hyperthermia, dantrolene capsules, 4 to 8 mg/kg/day in 4 divided doses for 1 to 3 days. This may be increased as the clinical situation indicates. When oral dantrolene administration is not practical, intravenous dantrolene (starting with 1 mg/kg) may be used to prevent or attenuate the recurrence of malignant hyperthermia. Dosing is the same for adults and children.
    J) ACIDOSIS
    1) Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg.
    K) ENHANCED ELIMINATION PROCEDURE
    1) Dialysis is only indicated for the treatment of severe rhabdomyolysis or hyperkalemia that may result from malignant hyperthermia.
    L) PATIENT DISPOSITION
    1) ADMISSION CRITERIA: All patients with suspected malignant hyperthermia should be admitted to an intensive care unit until all signs and symptoms have resolved for a minimum of 24 hours.
    2) CONSULT CRITERIA: An anesthesiologist or toxicologist should be consulted in all cases of suspected malignant hyperthermia.
    M) PITFALLS
    1) Failure to recognize malignant hyperthermia is the greatest pitfall. The presence of sinus tachycardia, hypertension, and tachypnea in patients with malignant hyperthermia may be misinterpreted as inadequate anesthesia.
    N) TOXICOKINETICS
    1) ONSET: The malignant hyperthermia crisis may begin as a fulminant crisis once the triggering agent is administered (within 10 minutes) or it may start several hours after administration of the triggering agent. Postoperative malignant hyperthermia episodes may occur in the immediate postoperative period or (rarely) several days later.
    O) PREDISPOSING CONDITIONS
    1) GENETICS: Susceptibility to malignant hyperthermia in humans has an autosomal dominant transmission via the ryanodine receptor gene RYR1 located on chromosome 19 (19q13.1). The RYR1 gene is responsible for encoding the skeletal muscle sarcoplasmic reticulum calcium-release channel and a genetic defect at one of these receptors appears to occur in persons with malignant hyperthermia.
    2) PHYSIOLOGIC CHARACTERISTICS: A short, stocky build; bulky muscles; muscular hypertrophy; strabismus; hernias; club foot; pectus carinatum; joint hypermobility; and spontaneous dislocation.
    3) PHYSIOLOGIC CONDITIONS: Myotonia congenita; chronic muscle cramps; exercise-induced rhabdomyolysis/myoglobinuria; Duchenne muscular dystrophy (X-linked disorder); Becker muscular dystrophy, osteogenesis imperfecta, arthrogryposis, kyphoscoliosis, King-Denborough syndrome, and previous incidence of neuroleptic malignant syndrome associated with the use of antipsychotic medications.
    P) DIFFERENTIAL DIAGNOSIS
    1) The following should be ruled out: inadequate anesthesia or analgesia; inappropriate breathing circuit, fresh gas flow or ventilation; infection or sepsis; tourniquet ischemia; anaphylaxis; pheochromocytoma; thyroid storm; cerebral ischemia; neuroleptic malignant syndrome, poisoning by sympathomimetic drug, ecstacy or other dangerous recreational agents, serotonin syndrome, anticholinergic agent toxicity, strychnine, salicylates, heat stroke, meningoencephalitis, tetanus, cerebral anoxia, or other muscle diseases. Clonus, shivering, tremor, and hyperreflexia are typically present in serotonin syndrome but are absent in malignant hyperthermia.

Range Of Toxicity

    A) TOXICITY: No specific toxic dose exists. In untreated patients, mortality rate may be as high as 65% to 70%, primarily due to ventricular dysrhythmias. The longer the duration of anesthesia, the higher the mortality secondary to cardiac arrest. Decreasing fatality rates may be due to the improved awareness and education of anesthesia providers, more rapid diagnosis, and earlier and more aggressive treatment. Maximum temperature correlates with mortality.

Clinical Effects

Summary Of Exposure

    A) GENERAL INFORMATION: Malignant hyperthermia (MH) is a syndrome that is triggered by volatile anesthetic agents (most commonly halothane) and depolarizing muscle relaxants typically used during surgery and procedures requiring general anesthesia. The predisposition for the development of MH is an inherited autosomal dominant trait.
    B) TOXICOLOGY: MH occurs when susceptible individuals are exposed to triggering agents resulting in an increase in intracellular calcium from the sarcoplasmic reticulum, activation of the sympathetic nervous system, and catecholamine release. The increased intracellular calcium results in persistent muscle contraction due to the continuous interaction between actin and myosin. Biochemical pathways are simultaneously triggered in an attempt to resequester excess calcium, but ultimately lead to breakdown of adenosine triphosphate (ATP), lactic acidosis, hypercarbia, and hyperthermia. Hyperthermia in MH results primarily from increased muscle activity exceeding the body's capacity to dissipate the generated heat. "Awake" malignant hyperthermia-like reaction worsened by succinylcholine has been reported in a child who presented with muscle rigidity and hyperthermia unrelated to anesthesia.
    C) EPIDEMIOLOGY: The estimated incidence of MH in North America and Europe is 1:15,000 anesthetic administration events for children and adolescents and 1:50,000 to 1:150,000 events for adults. The incidence of MH has also been reported to range from 1:200 to 1:250,000 depending on the geographic location. However, the true figure is difficult to ascertain as the majority of susceptible individuals are completely asymptomatic until exposed to triggering drugs or conditions. Furthermore, the development of MH is dependent upon the dose and duration of administration of the anesthetic.
    D) WITH POISONING/EXPOSURE
    1) Rapid elevation of the core temperature is a common finding in patients with MH, but it may be absent. Body temperature can increase at a rate of 0.5 degrees C to 2 degrees C every 5 to 10 minutes and may reach or exceed 40 degrees C very rapidly. Temperature increase results from persistent muscle contraction. Patients may reach temperatures above 46 degrees C in 20 minutes and progress to severe acidosis, shock, and ventricular fibrillation.
    2) EARLY SIGNS: Masseter spasm/muscle rigor (trismus), increased end-tidal CO2, unexplained tachycardia, an increase in core temperature, unstable blood pressure, tachypnea (if not paralyzed with muscle relaxants), flushed skin, metabolic acidosis, hyperkalemia, and hypermagnesemia can occur.
    3) INTERMEDIATE SIGNS: Cardiac dysrhythmias, supraventricular tachycardias, ventricular dysrhythmias, dark blood in operative field, cyanosis, mottled skin, diaphoresis, hypertension, hypercapnia, hypoxemia, elevation in blood lactate and pyruvate, and decreased HCO3 may develop.
    4) LATE SIGNS/COMPLICATIONS: Hypoxemia, hypotension, hyperkalemia, hypermagnesemia, rhabdomyolysis, seizures, cerebral edema, cardiovascular collapse, disseminated intravascular coagulopathy, hyperthermia, massive skeletal muscle swelling, pulmonary edema, and acute renal failure may be observed.
    5) ABORTIVE MH: Patients present with metabolic acidosis, increased creatine kinase and dysrhythmias; however, severe hyperthermia does not develop.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Rapid elevation of the core temperature (Schuster et al, 2014; Lavezzi et al, 2013; Rusyniak & Sprague, 2005; Ali et al, 2003; Hadad et al, 2003) is a late finding in patients with malignant hyperthermia (MH), but it may be absent (Ali et al, 2003).
    2) Increased body temperature, at a rate of 0.5 degrees C to 2.0 degrees C every 5 to 10 minutes, is usually observed and may reach or exceed 40 degrees C very rapidly (Fortunato-Phillips, 2000).
    3) In MH, central thermoregulation appears to be normal, and the temperature increase results from persistent muscle contraction. With a rate of temperature increase of 1 degrees C every 5 minutes, patients may reach temperatures above 46 degrees C in 20 minutes and progress to severe acidosis, shock, and ventricular fibrillation (Ali et al, 2003).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Unexplained sinus tachycardia, ventricular dysrhythmias, ventricular fibrillation and asystole have been reported (Lavezzi et al, 2013; Kozack & MacIntyre, 2001; Fortunato-Phillips, 2000; Lindholm et al, 2000; Martin & Vane, 2000; Isselbacher et al, 1994).
    b) An unexplained cardiac dysrhythmias or cardiac arrest may be the initial presentation of malignant hyperthermia (Denborough, 1998).
    c) In untreated patients, mortality rate is 65% to 70%, which is often due to ventricular dysrhythmias (Kozack & MacIntyre, 2001).
    d) CASE REPORT: Kleopa et al (2000) reported an unusual case of hyperkalemic cardiac arrest and rhabdomyolysis in an 18-year-old man with a history of muscular dystrophy, after a 6-hour orthognathic procedure using isoflurane and rocuronium (Kleopa et al, 2000).
    B) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Severe tachycardia (Lavezzi et al, 2013; Rusyniak & Sprague, 2005; Hadad et al, 2003; Denborough, 1998) is an early finding in malignant hyperthermia (MH) occurring within 30 minutes of the induction of anesthesia. Tachycardia is present in almost all patents with MH, resulting from an increase in catecholamine release (Ali et al, 2003).
    b) CASE REPORT: A case of malignant hyperthermia has been reported in a 10-year-old patient receiving desflurane for maintenance anesthesia. Ten to 15 minutes after receiving desflurane, the heart rate increased to 165 beats per minute, and body temperature increased to 40 degrees C. Therapy for the reaction was initiated, and included 220 mg of dantrolene bolus followed by a 12-hour infusion. No further reaction was noted (Fu et al, 1996).
    C) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension followed by unstable hypotension has been reported (Kozack & MacIntyre, 2001; Fortunato-Phillips, 2000; Lindholm et al, 2000; Martin & Vane, 2000; Isselbacher et al, 1994).
    b) Signs of intraoperative malignant hyperthermia (MH), such as hypertension, tachycardia, and tachypnea, may be erroneously interpreted as evidence of insufficient anesthetic depth. Hypertension is usually not pronounced in the early phases of MH (Ali et al, 2003).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH POISONING/EXPOSURE
    a) Increased end-tidal CO2 (double or even triple the baseline) is often the first sign of an incipient MH crisis. Tachypnea (if not paralyzed with muscle relaxants), hypoxemia, cyanosis, and respiratory acidosis may be observed (increased PaCO2, decreased pH, decreased PaO2) (Schuster et al, 2014; Ali et al, 2003; Hopkins, 2000; Kozack & MacIntyre, 2001; Martin & Vane, 2000; Kleopa et al, 2000; Lindholm et al, 2000; Fortunato-Phillips, 2000; Isselbacher et al, 1994).
    b) Pulmonary edema may develop later in the reaction (Kozack & MacIntyre, 2001; Isselbacher et al, 1994).
    c) CASE REPORT: Generalized muscle rigidity and hypercapnia occurred in a 2-year-old girl who received halothane without succinylcholine. Her postoperative creatine kinase was 18,046 U/L. The patient was thought to have experienced an aborted episode of malignant hyperthermia. The authors recommend that patients who exhibit generalized muscle rigidity after halothane inhalation should be treated as malignant-hyperthermia-susceptible (Medina & Mayhew, 1998). In abortive MH, the patient presents with metabolic acidosis, increased creatine kinase and dysrhythmias; however, no deadly high fever develops (Martin & Vane, 2000).
    d) CASE REPORT: Rhabdomyolysis developed in a 40-year-old man undergoing cardiopulmonary bypass after receiving 2 doses of enoximone. The patient did not receive any inhalation anesthetics or succinylcholine during the procedure. Elevated CK (9,348 Units/liter) and serum myoglobin (8,887 micrograms/liter) concentrations along with increased partial pressure of carbon dioxide (48 mmHg) during mechanical ventilation led to suspicions of malignant hyperthermia, and dantrolene was administered. Rectal temperatures remained normal during this time. Serum muscle enzyme concentrations returned to normal, and the patient recovered (Riess et al, 2001).
    1) Five months postoperatively, in vitro contracture testing of the patient's muscle specimens confirmed the presence of enoximone-sensitive, MH-susceptible muscle fascicles. DNA genotyping and mutation detection screening of the patient's ryanodine receptor gene revealed a G7297A mutation which has been associated with susceptibility to MH (Riess et al, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may develop later in the reaction (Lavezzi et al, 2013; Kozack & MacIntyre, 2001; Martin & Vane, 2000; Isselbacher et al, 1994).
    B) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) Cerebral edema may develop later in the reaction (Kozack & MacIntyre, 2001; Isselbacher et al, 1994).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) MYOGLOBINURIA
    1) WITH POISONING/EXPOSURE
    a) Myoglobinuria is common. Acute oliguric renal failure may develop secondarily in patients with severe MH (Fortunato-Phillips, 2000).
    b) Myoglobinuria may present as dark or cola-colored urine (Martin & Vane, 2000).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure may be a late complication (Kozack & MacIntyre, 2001; Isselbacher et al, 1994).
    C) OLIGURIA
    1) WITH POISONING/EXPOSURE
    a) Oliguria is a late finding in malignant hyperthermia (Hopkins, 2000).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Combined metabolic and respiratory acidosis may be observed (Schuster et al, 2014; Kozack & MacIntyre, 2001; Fortunato-Phillips, 2000; Martin & Vane, 2000; Kleopa et al, 2000; Isselbacher et al, 1994).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Decreased platelets may be observed in MH crisis (Fortunato-Phillips, 2000).
    B) BLOOD COAGULATION PATHWAY FINDING
    1) WITH POISONING/EXPOSURE
    a) Coagulopathy may be observed, generally associated with severe hyperthermia (Lindholm et al, 2000; Fortunato-Phillips, 2000).
    C) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) Disseminated intravascular coagulation may be a late complication, generally in patients who develop severe hyperthermia (Kozack & MacIntyre, 2001; Martin & Vane, 2000; Isselbacher et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISORDER OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Erythematous flush, peripheral mottling, central cyanosis, and diaphoresis have been seen (Ali et al, 2003; Fortunato-Phillips, 2000; Martin & Vane, 2000).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MASSETER SPASM
    1) WITH POISONING/EXPOSURE
    a) Masseter spasm/muscle rigidity (trismus) is considered an early sign, it may be prolonged ore may resolve spontaneously within 5 minutes (Hopkins, 2000; Kozack & MacIntyre, 2001; Fortunato-Phillips, 2000; Martin & Vane, 2000; Isselbacher et al, 1994).
    b) Sustained jaw rigidity or masseter spasm after succinylcholine (Rusyniak & Sprague, 2005; Hadad et al, 2003; Ali et al, 2003) resulting in difficult intubation may be the first sign of malignant hyperthermia (MH) (Hadad et al, 2003).
    c) Adults experience masseter spasm less often than children (Martin & Vane, 2000). Masseter muscle spasm, jaw rigidity or trismus may be present in 1% of children induced with inhalation agents followed by succinylcholine (Ali et al, 2003).
    B) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis may occur due to the sustained skeletal muscle contraction and its accompanying hypermetabolic state (Schuster et al, 2014; Kozack & MacIntyre, 2001). It may be detected by increased levels of serum creatine kinase and LDH, and myoglobinuria, and may lead to hyperkalemia, acute renal failure or (rarely) compartment syndrome (Kozack & MacIntyre, 2001; Kleopa et al, 2000; Fortunato-Phillips, 2000; Martin & Vane, 2000; Lindholm et al, 2000; Johnson et al, 1999; Isselbacher et al, 1994).
    b) CASE REPORT: In a 35-year-old bodybuilder, maximal plasma concentrations of myoglobin (278,000 mcg/L) and creatinine kinase (106,800 International Units/L) occurred within 24 hours after surgery. Continuous veno-venous hemofiltration was used for 28 consecutive days. Although the patient denied the use of any anabolic drugs or dietary supplements, increased muscle mass and potentially greater susceptibility of hypertrophic skeletal muscle cells may have contributed to the massive rhabdomyolysis (Schenk et al, 2001).
    c) Massive skeletal muscle swelling may be a late complication (Isselbacher et al, 1994).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Increased glucose levels may be observed (Fortunato-Phillips, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) An unexplained increase in end-tidal carbon dioxide is the most sensitive indicator of possible MH.
    B) Monitor core temperature, arterial blood gases, ECG, vital signs, electrolytes, glucose, CK, coagulation studies, hepatic enzymes, renal function, lactate, and urine output.
    C) CAFFEINE-HALOTHANE CONTRACTURE TEST (known in EUROPE as IN VITRO CONTRACTURE TEST) - The only recognized laboratory test to diagnose MH.
    4.1.2) SERUM/BLOOD
    A) BIOCHEMISTRY
    1) An unexplained increase in end-tidal carbon dioxide is the most sensitive indicator of possible MH (Ali et al, 2003). Monitor end-tidal CO2, oxygen saturation, hepatic enzymes, glucose, renal function, CK, coagulation studies and urinalysis; status checks are recommended at frequent intervals (Ali et al, 2003; Fortunato-Phillips, 2000).
    2) TEMPERATURE - Heat production at a rate of 0.5 degrees C to 2.0 degrees C every 5 to 10 minutes; may reach or exceed 40 degrees C very rapidly (Fortunato-Phillips, 2000). Monitor core temperature continuously.
    3) CK - CK levels in serum increase rapidly above 200 Units/L and can reach levels of 20,000 Units/L or higher (Fortunato-Phillips, 2000).
    4) ELECTROLYTES - Serum electrolytes should be obtained to assess for hypercalcemia, hyperkalemia, hyperphosphatemia as muscle breakdown progresses (Ali et al, 2003; Vanholder et al, 2000; Denborough, 1998).
    5) ACID/BASE BALANCE - Obtain arterial and venous blood gases to assess for metabolic and respiratory acidosis resulting from the hypermetabolic state. Metabolic acidosis may be related to an acute intracellular inorganic phosphate deficiency (Hopkins, 2000) or may be seen as a complication of rhabdomyolysis (Vanholder et al, 2000).
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) CAFFEINE-HALOTHANE CONTRACTURE TEST (KNOWN IN EUROPE AS IN VITRO CONTRACTURE TEST)
    1) The only recognized laboratory test to diagnose MH (Kozack & MacIntyre, 2001).
    2) To perform the caffeine-halothane contracture test (CHCT), also known as the in vitro muscle biopsy contracture test (IVCT), approximately 2 grams of muscle are obtained from the vastus lateralis or vastus medialis muscle and are dissected into strips. Six muscle strips are tied with sutures at both ends and mounted into baths of caffeine and halothane. One end of the suture is connected to a stationary hook, while the other end is connected to a force transducer. In vitro, halothane is a triggering anesthetic, and caffeine causes muscle contraction (Ali et al, 2003; Rosenberg et al, 2002; Kozack & MacIntyre, 2001).
    3) The North American CHCT protocol consists of adding halothane 3% to the gas flow of 3 baths using an in-line vaporizer, while caffeine is incrementally added to the other 3 baths. The development of a muscle contracture is the diagnostic end point. The test must be concluded within 5 hours of the muscle biopsy (Ali et al, 2003; Rosenberg et al, 2002).
    4) The availability of the CHCT is limited to only 6 medical centers in the United States and 2 in Canada (Malignant Hyperthermia Association of the United States, 2005; Litman & Rosenberg, 2005).
    5) About 30% of the specimens from a muscle biopsy may respond differently during testing. Equivocal results for the MH CHCT may be present in 10% to 15% of patients. Creating a standard protocol for all laboratories is difficult because of the degenerating nature of the test material. Given the low specificity of the CHCT test and the low MH prevalence (1 in 50,000), the test has limited usefulness as a screening tool for MH. However, experts agree that it is preferable to classify a person as MH-susceptible when in doubt than to exclude the diagnosis in a person with MH (Rosenberg et al, 2002).
    a) SENSITIVITY - Both the North American and the European malignant hyperthermia (MH) caffeine-halothane contracture test (CHCT) protocols have a sensitivity of 97% to 99% for MH (Litman & Rosenberg, 2005; Rosenberg et al, 2002).
    b) SPECIFICITY - The specificity of the European CHCT protocol is 90% for MH, while the specificity of the North American protocol is approximately 80% to 85% (Rosenberg et al, 2002).
    6) In another study, these tests were proved to be highly reliable (a sensitivity of 97% to 99% and a specificity of up to 93.6%). The risk of a false negative result is less than 1% for the European and 3% for the North American protocol. The risk of a false positive result is 7% for the European and 22% for the North American protocol (Baur et al, 2000).
    7) FALSE-POSITIVE RESULTS - Patients with muscle disorders associated with increased intracellular calcium, such as muscular dystrophy, may have a false-positive caffeine-halothane contracture test (CHCT) for malignant hyperthermia (MH). The false-positive rate for the CHCT test has been reported to range from 10% to 15% (Rosenberg et al, 2002).
    8) CAFFEINE-HALOTHANE CONTRACTURE TEST - This test has 2 classifications (Kozack & MacIntyre, 2001):
    a) Malignant hyperthermia susceptibility (MHS) - An abnormal response to caffeine or halothane, or a combination of caffeine and halothane.
    b) Malignant hyperthermia normal (MHN) - A normal response in both caffeine and halothane.
    9) IN VITRO CONTRACTURE TEST - Has 3 classifications (Kozack & MacIntyre, 2001):
    a) Malignant hyperthermia susceptibility (MHS) - An abnormal response is observed in each of 2 separate baths of caffeine and halothane.
    b) Malignant hyperthermia equivocal (MHE) - When muscle fibers contract abnormally to either caffeine or halothane, but not both.
    c) Malignant hyperthermia normal (MHN) - When no abnormal responses are observed.
    10) A multicenter study evaluated the usefulness of an in vitro contracture test (IVCT) with a new test substance (4-chloro-m-cresol (4-CmC), a ryanodine receptor-specific agonist) for a better definition of MH susceptibility. Diagnosis made by the standard IVCT was compared with the results of this 4-CmC test on muscle specimens of 202 individuals. It was suggested that this may offer a more accurate test (fewer patients classified at MH equivocal) when combined with the halothane and/or caffeine tests (Baur et al, 2000). Further study is needed.
    b) GENE MUTATION ANALYSIS
    1) Sample cells for genetic mutation analysis may be obtained from buccal cells, WBCs, muscle cells, or other tissues (Litman & Rosenberg, 2005).
    2) INDICATION - RYR analysis is usually recommended in individuals with a positive CHCT result, relatives of patients with established MH susceptibility by CHCT or RYR mutation, or individuals or their families who have not had a CHCT performed who have a history of a highly suspicious MH episode (masseter muscle rigidity, high temperature or rhabdomyolysis associated with general anesthesia), or heat stroke with a family history of MH susceptibility(Litman & Rosenberg, 2005)
    3) Identification of mutations in the gene encoding the calcium-release channel in skeletal muscle (ryanodine receptor [RYR]) appears to be associated with malignant hyperthermia (MH) susceptibility (Ali et al, 2003).
    4) The North American mutation analysis protocol screens for 17 of the most common mutations associated with RYR, and allows for the identification of up to 25% of individuals with MH susceptibility (Litman & Rosenberg, 2005).
    5) In family members of probands with a known mutation, screening for a specific mutation can considerably lower the cost of the screening. However, for relatives of probands with a suspected MH episode without identified causative mutations, a caffeine-halothane contracture test (CHCT) is recommended (Litman & Rosenberg, 2005; Girard et al, 2004).
    6) LIMITATIONS: The presence of genetic heterogeneity for MH, and the high cost and the low specificity of the test limits its use as a diagnostic tool for MH susceptibility (Litman & Rosenberg, 2005; Hopkins, 2000).
    a) Given the variable phenotype expression of MH, some individuals with known MH susceptibility may not present with MH symptoms when exposed to triggering agents. Additionally, some individuals with known MH susceptibility by genetic testing may have a negative CHCT. Discordance between the genotype and phenotype tests, assessed by a European multicenter study with 500 unrelated patients, was present in 10% of individuals or 2.6% of families evaluated for MH susceptibility (Litman & Rosenberg, 2005).
    7) The sensitivity of genetic mutation testing for malignant hyperthermia (MH) has been reported to be 25% (Litman & Rosenberg, 2005).
    8) Relatives of probands with a known mutation in which a mutation is identified during screening are considered MH susceptible. However, MH susceptibility in relatives of a proband cannot be ruled out by the absence of a causative mutation (Litman & Rosenberg, 2005).
    c) SERUM CREATINE KINASE LEVELS - Determined by a simple blood test. No longer considered the diagnostic test of choice; lack of accuracy and the occurrence of both false positive and false negative results. Elevated resting creatine kinase levels are seen in only 70% of individuals susceptible to MH. In addition, these levels may be elevated in individuals who are not susceptible to MH as a result of muscle injury unrelated to MH (Kozack & MacIntyre, 2001).
    d) PHOSPHORUS MAGNETIC RESONANCE SPECTROSCOPY (31P-MRS) combined with a standardized exercise protocol - Currently investigated. Detects metabolic abnormalities in the skeletal muscle of individuals with MH (Kozack & MacIntyre, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) All patients with suspected malignant hyperthermia should be admitted to an intensive care unit until all signs and symptoms have resolved for a minimum of 24 hours.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) An anesthesiologist or toxicologist should be consulted in all cases of suspected malignant hyperthermia.

Monitoring

    A) An unexplained increase in end-tidal carbon dioxide is the most sensitive indicator of possible MH.
    B) Monitor core temperature, arterial blood gases, ECG, vital signs, electrolytes, glucose, CK, coagulation studies, hepatic enzymes, renal function, lactate, and urine output.
    C) CAFFEINE-HALOTHANE CONTRACTURE TEST (known in EUROPE as IN VITRO CONTRACTURE TEST) - The only recognized laboratory test to diagnose MH.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) Terminate the surgery as soon as possible. Immediately begin hyperventilation with 100% oxygen. All triggering agents should be discontinued. Switch the vaporizer off. Monitor core temperature, arterial blood gases, ECG, vital signs, urine output, electrolytes, CK, coagulation studies, and renal function. Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions.
    2) Although several sources recommend that the entire anesthesia system should be changed, it is no longer required to change the breathing circuit, CO2 absorbant (soda lime canister), and anesthesia machine (i Gardi et al, 2001; Martin & Vane, 2000; Fortunato-Phillips, 2000; Isselbacher et al, 1994).
    3) DANTROLENE: Administer dantrolene by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.
    B) MONITORING OF PATIENT
    1) An unexplained increase in end-tidal carbon dioxide is the most sensitive indicator of possible malignant hyperthermia.
    2) Monitor core body temperature, arterial blood gases, ECG, vital signs, electrolytes, glucose, CK, clotting factors, lactate, liver enzymes and renal function and urine output.
    C) DANTROLENE
    1) Sodium dantrolene is an effective and specific treatment for an acute malignant hyperthermia crisis (Rusyniak & Sprague, 2005; Ali et al, 2003). Dantrolene acts by increasing the contraction activation threshold voltage at the sarcoplasmic reticulum involved in calcium release, thus limiting the amount of calcium available for muscle contraction (Rusyniak & Sprague, 2005; Hadad et al, 2003; Ali et al, 2003).
    2) Dantrolene should be immediately administered intravenously and maintained until tachycardia, muscle rigidity, increased end-tidal carbon dioxide, hyperthermia, and any other manifestations of malignant hyperthermia are controlled (Hadad et al, 2003). Dantrolene should be administered for an additional 24 to 72 hours after the acute episode to prevent recurrence of malignant hyperthermia symptoms (Rusyniak & Sprague, 2005).
    3) PRECAUTION: Cardiovascular collapse in association with hyperkalemia has been reported in patients treated with calcium channel blockers while receiving dantrolene. Calcium channel blockers should not be used in the management of malignant hyperthermia symptoms when patients are treated with dantrolene (Prod Info DANTRIUM(R) IV injection, 2007).
    a) VERAPAMIL: Concomitant administration of verapamil and dantrolene in a 60-year-old man resulted in hyperkalemia and hyperglycemia, with peak potassium and glucose levels of 7.1 mmol/L and 351 mg/dL, respectively, 2.5 hours post-dantrolene administration, and myocardial depression, with cardiac output decreased to 3.0 L/min and a cardiac index of 1.4 (baseline 4.5 L/min and 2.1, respectively). The patient recovered with supportive care. Six months later, the patient received nifedipine and dantrolene concurrently without the development of significant hyperkalemia or myocardial depression (Rubin & Zablocki, 1987).
    4) INTRAVENOUS
    a) The minimum initial recommended dose for malignant hyperthermia is 1 milligram/kilogram by continuous rapid intravenous push. If symptoms persist or reappear, the dose may be repeated, to a cumulative dose of 10 milligrams/kilogram. Dosing is the same for adults and children (Prod Info DANTRIUM(R) IV injection, 2007).
    b) For the PROPHYLAXIS OF malignant hyperthermia, intravenous dantrolene 2.5 milligrams/kilogram beginning approximately 1-1/4 hours before anticipated anesthesia and infused over approximately 1 hour is recommended. Additional dantrolene during the surgery may be needed. Dosing is the same for adults and children (Prod Info DANTRIUM(R) IV injection, 2007).
    c) For POST CRISIS FOLLOW-UP OF malignant hyperthermia, dantrolene capsules, 4 to 8 milligrams/kilogram/day in 4 divided doses for 1 to 3 days. This may be increased as the clinical situation indicates. When oral dantrolene administration is not practical, intravenous dantrolene (starting with 1 mg/kg) may be used to prevent or attenuate the recurrence of malignant hyperthermia. Dosing is the same for adults and children (Prod Info DANTRIUM(R) IV injection, 2007).
    5) ORAL
    a) For the PROPHYLAXIS OF malignant hyperthermia, dantrolene 4 to 8 milligrams/kilogram/day in 3 or 4 divided doses for 1 or 2 days prior to surgery is recommended. The last dose should be administered approximately 3 to 4 hours before scheduled surgery with a minimum of water. Dosing is the same for adults and children (Prod Info DANTRIUM(R) IV injection, 2007).
    b) For POST CRISIS FOLLOW-UP OF malignant hyperthermia, oral dantrolene 4 to 8 milligrams/kilogram/day in four divided doses, for a 1- to 3-day period is recommended to prevent recurrence of the manifestations of malignant hyperthermia. Dosing is the same for adults and children (Prod Info DANTRIUM(R) IV injection, 2007).
    D) METABOLIC ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    E) RHABDOMYOLYSIS
    1) Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be needed to maintain urine output. Urinary alkalinization is NOT routinely recommended. Vigorous fluid replacement with 0.9% saline is necessary even if there is no evidence of dehydration. Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 2 to 3 mL/kg/hr. In severe cases, 500 mL of fluid per hour may be required for the first several days. Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    2) Furosemide or mannitol has been used to maintain diuresis, and prevent renal failure secondary to myoglobinuria (Fortunato-Phillips, 2000; Martin & Vane, 2000; Isselbacher et al, 1994).
    F) HYPERKALEMIA
    1) Treat hyperkalemia using standard treatment measures (intravenous sodium bicarbonate, calcium, insulin and dextrose, inhaled albuterol).
    2) Treat severe hyperkalemia (associated dysrhythmias, QRS widening) aggressively. Monitor ECG continuously during and after therapy.
    3) Sodium bicarbonate: Adult or Child: 1-2 milliequivalents/kilogram IV bolus.
    4) Insulin/dextrose: Adult: 5 to 10 units regular insulin IV bolus with 100 mL of D50 IV immediately; monitor serum glucose every 30 minutes. Child: 0.5 to 1 gram/kilogram dextrose as D25 or D10 IV followed by 1 unit of regular insulin for every 4 grams of dextrose infused; monitor serum glucose every 30 minutes.
    G) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Accelerate evaporative heat loss by keeping patient's skin wet with cool water and placing fans in the room. Administer cool oxygen and intravenous fluids. Use ice packs and cooling blankets. Lower the temperature in the room. If malignant hyperthermia develops intraoperatively and the abdominal cavity is open it may be lavaged with cool 0.9% saline. Monitor core temperature continuously if possible or at least every 30 minutes until below 38 degrees centigrade.
    a) The best method for cooling the body in patients with malignant hyperthermia is controversial. Direct cooling by immersion of the body in cold water may enhance the conduction of heat from the body, but also may interfere with resuscitative measures. Ice packs to the groin, axillae, and the neck may be a less cumbersome method (Hadad et al, 2003).
    b) Evaporative cooling by spraying water directly on the skin may be beneficial and will allow for concurrent resuscitative measures. Other methods that may be effective for cooling include cooling blankets, extracorporeal partial bypass, iced peritoneal lavage (Hadad et al, 2003), and cold intravenous fluids (Ali et al, 2003).
    c) Cooling measures should be discontinued when the core body temperature reaches 38°C to 38.8°C to prevent hypothermia (Hadad et al, 2003; Ali et al, 2003).
    d) Antipyretics are not useful because of their lack of effect on excessive heat production produced by the intense hypermetabolic skeletal muscle reaction (Hadad et al, 2003).
    H) CONDUCTION DISORDER OF THE HEART
    1) Correct hyperkalemia, aggressively treat hyperthermia and correct hypotension, administer oxygen, and correct severe acidosis. Institute continuous cardiac monitoring and obtain an ECG. Antidysrhythmics may be necessary in addition to these measures in some cases. Unstable rhythms require cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    I) PSYCHOMOTOR AGITATION
    1) Sedatives (eg, benzodiazepines) should be used for severe agitation and during the cooling period (Hadad et al, 2003).
    a) INDICATION
    1) If patient is severely agitated, sedate with IV benzodiazepines.
    b) DIAZEPAM DOSE
    1) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    2) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) LORAZEPAM DOSE
    1) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    2) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    d) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    J) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    6) A case of unsuspected fulminant malignant hyperthermia complicated by life-threatening hyperkalemia and massive rhabdomyolysis in a bodybuilder was managed successfully by early institution of continuous veno-venous hemofiltration (CVVH). Early institution of CVVH results in a rapid reduction of the circulating free myoglobin (Schenk et al, 2001).

Abstracts

Case Reports

    A) ADULT
    1) SEVOFLURANE: A 59-year-old hospitalized man with persistent lumbalgia was admitted to the ICU because of increasing dyspnea and tachypnea. Following tracheal intubation, he was sedated with propofol and sufentanil infusion and a chest radiography showed bilateral pulmonary infiltration, suggestive of influenza pneumonia. He received moxifloxacin, piperacillin/tazobactam, and oseltamivir, but on day 4, more sedation was required. An anesthetic conserving device for additional sevoflurane sedation was installed. Hemodynamic instability developed after 5 hours of sevoflurane administration. His vital signs included an arterial blood pressure of 78/44 mmHg, a heart rate of 110 beats/min, and a temperature of 39.6 degrees C which increased rapidly to 40.7 degrees C within 30 minutes. Laboratory results revealed severe acidosis (pH 7.17, pCO2 70.4 mmHg, pO2 104 mmHg, base excess 9.8, lactate 0.6 mmol/L), and acute rhabdomyolysis with significantly elevated creatine kinase (3455 Units/L) and myoglobin (4197 mcg/L). Following the discontinuation of sevoflurane and treatment with IV dantrolene (225 mg), his condition gradually improved and he had an uneventful clinical course. He was successfully extubated on day 17. He underwent muscle biopsy and in vitro contracture testing 9 months later which confirmed the patient's malignant hyperthermia susceptibility (Schuster et al, 2014).
    B) PEDIATRIC
    1) "AWAKE" MALIGNANT HYPERTHERMIA: Awake malignant hyperthermia-like reaction worsened by succinylcholine has been reported in a child who presented with muscle rigidity and hyperthermia unrelated to anesthesia (Lavezzi et al, 2013).
    a) CASE REPORT: A 6-year-old boy presented with lower extremity rigidity, trismus, fever, tachycardia, and seizures after 10 minutes of playing outside in a splash pool on a hot, humid day. Despite aggressive supportive therapy, his condition worsened and succinylcholine was administered to place an endotracheal tube. At this time, he developed cardiac arrest, but resuscitation efforts were unsuccessful and he died 1 hour after presentation to the ED. The cause of death was determined to be malignant hyperthermia, based on the presence of muscle rigidity with extremely high temperature and adverse response to succinylcholine. An earlier report revealed that the patient, his father, and 2 of his siblings had lumbar lordosis, but no history of malignant hyperthermia, heat intolerance, or exercise intolerance was found. A novel RYR1 variant, Gly4820Arg, was found in exon 100 using a postmortem liver specimen. The child's family members were also screened and the same RYR1 variant was found in the father and 2 siblings. A muscle biopsy and caffeine-halothane contracture test (CHCT) of the father revealed positive results for malignant hyperthermia. Histology analysis of the father's muscle sample showed central core disease (CCD) (Lavezzi et al, 2013).

Range Of Toxicity

Summary

    A) TOXICITY: No specific toxic dose exists. In untreated patients, mortality rate may be as high as 65% to 70%, primarily due to ventricular dysrhythmias. The longer the duration of anesthesia, the higher the mortality secondary to cardiac arrest. Decreasing fatality rates may be due to the improved awareness and education of anesthesia providers, more rapid diagnosis, and earlier and more aggressive treatment. Maximum temperature correlates with mortality.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) In untreated patients, mortality rate is 65% to 70%, which is often due to ventricular dysrhythmias (Kozack & MacIntyre, 2001). A positive correlation between maximum temperature level and mortality was recorded in 89 patients who developed malignant hyperthermia following administration of 94 anesthetics. The longer the duration of anesthesia, the higher the mortality secondary to cardiac arrest (Britt & Kalow, 1970).
    2) Decreasing incidence may be due to the improved awareness and education of anesthesia providers, more rapid diagnosis, and earlier and more aggressive treatment (Martin & Vane, 2000).

References

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