Critical Care Medicine

Malignant Hyperthermia and Related Conditions

Malignant hyperthermia and related conditions

Synonym

Malignant Hyperpyrexia, MH

Related conditions

There are no known related conditions, but there are many potentially confusing mimics, which we will discuss in the context of the differential diagnosis.

1. Description of the problem

Clinical vignette

The best way to approach the diagnosis of malignant hyperthermia is through a clinical vignette, which follows: As a CCM physician, you receive an admission directly from the operating room, where a patient has had a general anesthetic for the open reduction and internal fixation of a femur fracture and a right frontal burr hole to reduce a small subdural collection of blood that was the result of a head-on car collision that left the patient unconscious.

The patient was intubated in the field, and preoperative CT scanning of the head, neck, thorax, abdomen and lower extremities revealed a small amount of subdural blood, a few non-displaced rib fractures with no hemo/pneumothorax, a normal abdomen and the right femur fracture. The neck has been cleared by neurosurgery. The age and sex of the patient is immaterial.

You receive a report that during the surgery, the patient's vital signs had been stable, but in the last 10 minutes of the surgery, the heart rate and blood pressure had been slowly rising despite the anesthesiologist's rather liberal administration of narcotics.

Intraoperative temperatures had been maintained around 36°C through the use of a forced air warming blanket, but during the last 10 minutes of the surgery, the temperature had been slowly rising, with the last recorded temperature before leaving the operating room now 38.5°C. The forced air warmer had been turned off when the patient's temperature had reached 36.5°C.

In the operating room, ventilation was controlled, with the patient pharmacologically paralyzed using non-depolarizing skeletal muscle relaxant, but the patient had initially been intubated in the field using succinylcholine. The EMT did not note any difficulty during the intubation. The patient is brought to the intensive care unit intubated and the first end-tidal carbon dioxide measurement is 55 mm Hg.

You and the anesthesiologist begin to discuss the possible reasons for this constellation of findings, and it is suggested that this might be malignant hyperthermia (MH).

What every clinician needs to know

MH is a rare pharmacogenetic sensitivity of skeletal muscle to volatile anesthetics and depolarizing muscle relaxants such as succinylcholine (and only to these agents - not to any of the intravenous agents or local anesthetics presently or previously in clinical use) that results in autonomic activation, hypermetabolism that results in a mixed respiratory-metabolic acidosis, truncal or total body rigidity in a significant number of patients, masseter muscle spasm (trismus = "jaws of steel") in some patients in response to the depolarizing effects of succinylcholine, hyperthermia (may be a late sign) and rhabdomyolysis. Gene mutations that confer MH susceptibility have been identified in three genes, although there are undoubtedly two or more other genes that can confer susceptibility:

  1. RyR1, the gene for the ryanodine receptor type 1, the skeletal muscle primary calcium release channel of sarcoplasmic reticulum that normally functions in excitation contraction coupling (50-70% of MH susceptible families).

  2. CACN1S, the gene for the skeletal muscle L-type, voltage dependent calcium channel in transverse tubules that is the voltage sensor in excitation-contraction coupling (~1% of families). This channel is also known as the skeletal muscle dihydropyridine receptor (DHPRs), and the mutations are in the alpha-1s subunit.

  3. STAC3, a gene responsible for skeletal muscle myotube fusion in development, that was identified as the causative gene in Native American Myopathy and resultant MH susceptibility (see below, very restricted populations).

Clinical features

The hallmark of a full blown episode of MH is runaway metabolism and a rate of production of CO2 that is difficult if not impossible to control with increasing minute ventilation. In the awake patient this will manifest as severe hyperventilation, with the breaths rapid and deep. In the mechanically ventilated patient, MH will result in the physician or respiratory therapist constantly increasing minute ventilation that is unable to compensate for the continuing rise in end-tidal CO2. The combination of extremely high temperatures (as high as 42-43°C), severe acidosis (pH<7), and the hyperkalemia that results both from acid buffering and rhabdomyolysis, results in autonomic and cardiovascular instability and arrhythmias, renal failure from myoglobin precipitation in proximal tubules, and eventual death in virtually all untreated patients. Fortunately, there is specific pharmacologic therapy for MH in the form of the drug dantrolene (see below).

Not all the signs and symptoms of MH enumerated above have to occur in the patient experiencing an MH episode. Hence, the symptomatic expression of the syndrome is variable (see below). This problem contributes to the difficulty of making the diagnosis of an MH episode.

While not pathognomonic, the sine qua non of a full blown MH episode, however, is the mixed respiratory-metabolic acidosis in the setting of general anesthesia with volatile anesthetics, whether succinylcholine is used or not, and in the presence a rising end-tidal CO2 that cannot be controlled with increasing minute ventilation. MH may occur intraoperatively and for some undetermined time that is generally thought to be less than 12 hours postoperatively, though the vast majority of cases occur within an hour postoperatively. No cases of postoperative MH initiating later than 12 hours postoperatively have been described.

MH is transmitted in an autosomal dominant fashion within families, but has both incomplete penetrance and variable expressivity.

In this instance, incomplete penetrance means that just because you have the genetic trait does not mean you will get MH on the first exposure to volatile anesthetics (indeed the North American Malignant Hyperthermia Registry knows of a patient that did not trigger until the 30th anesthetic - clearly an outlier); variable expressivity means that a susceptible individual may present with a symptom pattern varying from smoldering to explosive.

Furthermore, MH may present due to a sporadic mutation, i.e., when there is no family history of MH, or of unexplained perioperative deaths accompanied by hyperthermia. To make things more difficult, there is no known pathognomonic sign of MH susceptibility in the non-anesthetized patient, who functions completely normally as far as we know, and is generally without evidence of myopathic symptoms. Approximately 50% of patients who present with perioperative MH have had previous, uneventful general anesthetics.

There are now three known rare skeletal myopathies, however, with proven high concordance with MH susceptibility: central core disease (CCD), King-Denborough syndrome, and Native American Myopathy (NAM). NAM was recently described as an autosomal recessive myopathy in the Lumbee Indian population of North Carolina, but this author has seen twins from a Somali immigrant population in the United States with the exact same myopathic constellation. Some myologists believe that multiminicore disease (MMD) is a myopathic precursor to CCD and consider MMD patients as MH susceptible (MHS).

Two other myopathies, Nemaline Rod Myopathy and Congenital Neuromuscular Disease with Uniform Type 1 Fiber (CNMDU1), both associated with RyR1 mutations, have been reported to be concordant with MH suscpetibility.

No other myopathies, including the muscular dystrophies and the myotonias, are known to have concordance with MH susceptibility, though inadvertent use of Succinylcholine can induce hyperkalemic cardiac arrest in the former and total body rigidity in the latter, bringing such patients to the attention of critical care staff. While the vast majority of MH susceptible patients do not exhibit myopathic signs, some may have elevated creatine kinase levels at rest.

2. Emergency management

Emergency management steps

  1. Stop offending agent, ventilate with 100% O2, monitor patient with standard ASA monitors and arterial line invasive monitoring.

  2. Call for help.

  3. Infuse dantrolene.

  4. Follow ABG, electrolytes, CBC, coagulation profile and CK/myoglobin levels. Treat acidosis and electrolyte abnormalities according to standard protocols.

  5. Watch for the development of arrhythmias, treat according to ACLS protocols.

  6. Cool patient judiciously.

  7. Follow for signs of rhabdomyolysis and treat appropriately.

  8. Follow for signs of recrudescence.

Management points not to be missed

The management of an episode of MH should include the following:

If intraoperatively

Stop the offending agent (remove the vaporizers) and ventilate with 100% O2. Notify the surgeon and other operating room personnel that you suspect MH, and that the surgery must be concluded as quickly as possible. High flow oxygen should be used to flush out the anesthesia machine, and activated charcoal filters should be placed on both the inspiratory and expiratory limbs of the anesthesia circuit.

If postoperatively

Notify Health Care Team of your suspicion of MH. Have the MH cart brought from the nearest anesthetizing location STAT. Assess whether patient needs to be reintubated.

Then for all intra- and postoperative MH episodes continue as follows:

  1. Call for help and the MH cart: this is a code-like situation, and you will need extra personnel to assist. CALL the MH Hotline, run by the Malignant Hyperthermia Association of the United States (MHAUS), at 1-800-644-9737 for assistance with the differential diagnosis and treatment. Hotline consultants are available 24/7 × 365.

  2. Begin dantrolene administration, 2.5 mg/kg until symptoms disappear, then give 1 mg/kg every 6 hours for 24 hours to prevent recrudescence. Dantrolene is very hydrophobic and classically was packaged in crystalline form with NaOH and mannitol to increase solubility, with only 20 mg per vial. To solubilize dantrolene, you will need sterile water (warmed will improve solubility).

  3. Many patients need as much as 10 mg/kg to truncate an episode of MH and some need more. There is no upper limit to how much dantrolene you can give in the acute treatment of MH, or how rapidly you can push the dose. If you believe that the patient has MH, KEEP GIVING DANTROLENE at 2.5 mg/kg until signs and symptoms reverse, even if you need >20 mg/kg. The major side effect of dantrolene is weakness, but at this point the patient is intubated anyway and being mechanically ventilated. Other potential side effects have to do with the caustic nature of dantrolene: phlebitis and skin sloughing if dantrolene extravasates. Therefore, large vein access is recommended for dantrolene infusion.

  4. Follow acidosis and potential for hyperkalemia with serial ABGs and electrolytes and treat according to accepted critical care guidelines. Calcium in the form of chloride or gluconate may be given acutely in the treatment of hyperkalemia, as there is no evidence that it exacerbates the MH episode.

  5. Follow CBC and coagulation parameters, as DIC may occur, especially in patients whose temperatures are ≥42°C.

  6. Follow urine, serum myoglobin and CPK levels for evidence of rhabdomyolysis. If this occurs, forced diuresis will likely be necessary. Alkalinization of urine may be necessary, but the usefulness of this in preventing myoglobin precipitation in the kidneys has recently been called into question. Remember that dantrolene preparations contain mannitol, so that extra mannitol is not necessary. Forcing further diuresis can be accomplished with furosemide or diuretics with similar characteristics (potassium wasting).

  7. Cool the patient if temperature is dangerously high. Gastric or bladder lavage with iced saline is NO LONGER recommended. IV infusion of cooled saline, while of potential efficacy, also has its dangers. What is recommended now is to cool the patient either with an active external cooling blanket and/or pack the body in ice. You MUST measure core temperature and stop active cooling when temperatures reach ~ 37-38°C. Overcooling to temperatures in the range of 34°C,which are easily reached with active cooling, can be very dangerous and induce ventricular fibrillation, especially in the face of uncontrolled acidosis. As with EHI, it is recommended to cover the patient with a sheet wetted with tepid water and then use a large fan to blow air over the patient, cooling the patient by evaporative heat loss.

  8. MH can recrudesce, so ICU monitoring is mandatory even after the MH episode is reversed. A checklist to assist management is available from MHAUS (www.mhaus.org), and should be posted in every operative suite and attached to the MH crash cart.

3. Diagnosis

Diagnostic criteria and tests

There are no specific tests that can confirm MH in the acute phase. It is a constellation of findings in the setting of a general anesthetic with volatile anesthetics. Succinylcholine will often worsen the presentation of MH, but MH can happen in its absence. There are now >3 cases in the literature showing that MH can occur with Succinylcholine alone, in the absence of volatile anesthetics. This author is aware of a manuscript in preparation that is reviewing cases of MH from a national database that purports significant numbers cases that derive from use of succinylcholine in the absence of volatile anesthetics.

As mentioned above, rising temperatures, autonomic activation, rising CO2 levels despite increasing of minute ventilation and a mixed respiratory-metabolic acidosis constitute the constellation of findings in the perioperative period that suggests a diagnosis of MH. If there is a positive family history of MH, than your diagnostic suspicion should rise. Rising CO2 may precede tachycardia or vice-versa. One does not have to get all signs and symptoms together.

Clinical pearl: palpate large muscle groups. In florid MH, muscle may be hot to touch before core temperature has risen, and it may be rigid ("hard as a board") even in the presence of non-depolarizing skeletal muscle relaxants. In MH, contractures, not contractions, occur. The former is the result of a persistent overload of myoplasmic Ca2+, the latter the result of both dysregulated release of sarcoplasmic reticulum Ca2+ and entry of extracellular Ca2+.

Other possible diagnoses

Unfortunately for the clinician, even if a number of the above constellation of signs present themselves in the perioperative period, there are a number of causes - iatrogenic, endogenous, and pharmacological - that could cause a number or all of the signs of MH. One must be careful not to misdiagnose for fear of not treating the right entity. The differential diagnosis includes the following:

Iatrogenic

Right mainstem intubation, inadequate ventilation, a stuck anesthesia machine expiratory valve, or over-active CO2 insufflation during laparoscopy accompanied by rapid venous uptake can all cause a rising CO2. Ensure that there is no active CO2 delivery system on your anesthesia machine, and if there is, that this is not accidentally flowing. Severe elevations in CO2 can cause autonomic activation, with tachycardia and hypertension. It should not cause high fevers.

Endogenous

  1. Sepsis: severe infections can cause tachycardia, severe metabolic acidosis and very high temperatures, but CO2 generally does not rise unless the patient has concomitant obstructive lung disease or respiratory mechanical factors are concomitantly dysfunctional.

  2. Thyroid storm: tremendous outpouring of autonomic stimuli and metabolic activation, giving severe hypertension and tachycardia, rising temperatures and metabolic acidosis. No respiratory component that can't be compensated for.

  3. Hypothalamic stroke: disrupts temperature regulatory nuclei and can lead to runaway fevers as high as in MH. Seizures, not present in MH, may result. No acidosis formally accompanies this event.

  4. Pheochromocytoma: characterized by unusually strong autonomic stimulation, with severe tachycardia and hypertension and occasionally accompanied by fevers.

Other drug-related hyperthermic syndromes

Neuroleptic malignant syndrome (NMS)

Neuroleptic malignany syndrome (NMS) occurs in ~0.02% of patients treated with neuroleptic drugs that block the activity of brain dopamine, with haloperidol being the classic but not the only offender. Any drug that has dopamine blocking activity, whether a classical neuroleptic drug or not, has the potential for causing NMS. It is important to note that apart from haloperidol used in treating postoperative delirium or agitation, other drugs used in perioperative settings, such as metoclopramide, promethazine, and prochlorperazine, have neuroleptic properties and have been implicated in cases of NMS.

Most cases of NMS occur within 1-2 weeks after triggering drugs are started. The usual course is for symptoms to develop over a few days, but it can occur within hours of administration. Concomitant exhaustion, dehydration, agitation or catatonia imparts a higher risk of NMS in patients on these drugs.

Typical signs of NMS are hyperthermia, muscle rigidity with tremors, altered consciousness and changes in vital signs. Laboratory abnormalities include creatine kinase elevations, acidosis and hypoxia. Like MH, there are no pathognomonic signs of NMS, so context is everything, but unlike MH, in NMS patients with reduced consciousness and suppressed respiratory drive, it is possible to control the mixed respiratory-metabolic acidosis with mechanical ventilation. In addition, a critical differentiating point from MH is that the centrally driven, generalized rigidity of NMS can be reversed with depolarizing skeletal muscle relaxants.

In-vitro muscle contracture tests for MH susceptibility in NMS patients have uniformly been negative, so there is no crossover sensitivity. Genetic testing has not consistently identified causative mutations in the genes associated with MH in these patients. They are considered different disorders.

Early diagnosis, discontinuation of offending drug(s), and supportive care are the mainstay of treatment. Although the mortality rate has declined due to better recognition, the syndrome is still potentially fatal in approximately 5% to 10% of cases if not diagnosed in time. Once triggering drugs are withheld, signs and symptoms generally resolve in 1-2 weeks, although symptoms may last longer if long-acting drugs have been used. A few patients develop a residual catatonic and Parkinsonian state that can last much longer, and this condition may be responsive to electroconvulsive therapy (ECT).

Benzodiazepines, dopamine agonists, dantrolene, and ECT have all been advocated in the treatment of NMS based on numerous clinical case reports and series, but advantages over supportive care alone have not been established. Rigorous studies have not been performed, likely due to the rarity of the syndrome, and the fact that the syndrome usually dissipates once the offending drug is stopped. For more information, see the Neuroleptic Malignant Syndrome Information Service website at www.nmsis.org.

Parkinsonism-Hyperthermia Syndrome (PHS)

People with Parkinson's disease (PD) and related Lewy-body disorders are at risk for severe fluctuations in muscle tone, resulting in rigidity, bradykinesia and other symptoms. These can be effectively controlled by drugs like levodopa, which increase dopamine in the brain. This control begins to wane after several years of treatment.

PHS is a syndrome that is nearly identical in its presentation to NMS and MH if anti-PD medications are stopped, or during "off" episodes, when the drugs inexplicably lose their effectiveness. Sometimes this syndrome has been iatrogenically induced perioperatively when patients were told to stop their medications, especially levodopa, prior to surgery for any of a variety of reasons, and were not restarted on their preoperative medications soon enough postoperatively.

Reports suggest that PHS may occur in 2-3% of PD patients after drug cessation. Like NMS, symptoms develop a few hours to a few days after drug cessation.

Treatment consists of supportive and intensive medical and nursing care, as well as restarting discontinued dopamine medications as soon as possible. If a syndrome that looks like PHS has developed in an individual who has not discontinued his dopamine medications, other sources of the symptoms have to be sought, including NMS or MH, if the situation is appropriate.

There are reports that dantrolene, in addition to reintroducing dopamine agonists, has been effective in treating PHS, although rigorous trials have not been done to determine efficacy. Acute cessation of anti-PD drugs should be avoided.

As in NMS, the underlying cause of PHS is a sudden reduction in brain dopaminergic activity: in NMS, because of anti-dopaminergic neuroleptic drugs, and in PHS, because of the intrinsic lack of dopamine revealed by the sudden cessation of dopaminergic drugs.

Serotonin syndrome (SS)

This syndrome usually results when two or more drugs that raise serotonin levels in the brain are taken concomitantly, but it also occurs following single drug exposure or overdose.

While all drugs that increase brain serotonin levels have been implicated as causing SS, the ones most often associated with severe or fatal cases of SS are the monoamine oxidase inhibitors (MAOIs) when they are used in combination with other drugs that raise serotonin levels (antidepressants, certain opiods that potentiate serotonergic activity: meperidine, tramadol, dextromethorphan and fentanyl). Morphine and its congeners have not been implicated in this interaction and are a reasonable choice for pain control in the context of concurrent serotonergic treatment.

Other drugs that increase serotonin activity and may cause SS include anti-migraine drugs (triptans) and the antibiotic, linezolid. Certain drugs used in the hospital setting, as well as over–the-counter drugs and supplements, have clandestine MAOI activity and may produce severe instances of serotonin syndrome when used inadvertently in combination with serotonergic drugs. These include

  1. The antibiotic linezolid

  2. Methylene blue, a dye that is used during parathyroid surgery, sentinel node surgery, or, rarely, to reverse methemoglobinemia

  3. Some drugs or supplements derived from herbal products (i.e., St. John’s wort)

Serotonergic mechanisms also have been specifically implicated in toxic reactions following abuse of 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) and other similarly acting drugs of abuse (see annotated reference below).

Selective serotonin reuptake inhibitors (SSRIs) are responsible for SS in 0.5-0.9 cases per 1000 patient months of treatment, which will rise to 14-16% in cases of overdose. In one large database study, the incidence of SS among patients prescribed serotonergic agents ranged between 0.07% and 0.09%.

The onset of symptoms is usually abrupt and clinical symptoms range from mild to a full-blown hypermetabolic syndrome that is indistinguishable from NMS and MH. Most often, a patient with SS, usually elderly, develops agitation and confusion, with elevated vital signs and GI symptoms. Symptoms of SS are based on a triad of cognitive-behavioral, neuromuscular, and autonomic abnormalities, which include alterations in consciousness and mood, restlessness, agitation, tremor, myoclonus, hyperreflexia, gait incoordination and muscular rigidity, and autonomic abnormalities that include tachycardia, blood pressure fluctuations, sweating, shivering, tachypnea, salivation, pupillary dilation, and hyperthermia.GI symptoms may occur, as well, and include diarrhea, incontinence, nausea, and vomiting.

Serotonin syndrome is usually self-limited and resolves rapidly, but it can be sustained and fatal in severe cases of hyperthermia associated most often with the use of MAOIs. Treatment of SS involves stopping all medications that increase serotonin, and providing supportive medical care. Sedation with benzodiazepines may be useful for controlling agitation and for correcting mild increases in heart rate and blood pressure. Based on anecdotal clinical reports, moderate cases appear to benefit from administration of serotonin 5-HT-2A antagonists such as cyproheptadine. Antipsychotics with serotonergic antagonist properties have been suggested as well, but they may add the confounding autonomic, neurologic, and thermoregulatory effects of dopamine blockade. A few cases of severe SS with extreme temperatures seemed to benefit from dantrolene administration.

Baclofen withdrawal

Baclofen is a drug used to treat the severe muscle spasticity that usually results following severe nervous system injury. There are several reports of NMS-like features emerging in patients withdrawn from baclofen, a drug that enhances the effects of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, in the brain and spinal cord, resulting in reduced spasticity.

Baclofen is increasingly being used in intrathecal infusions to treat the spasticity in children with cerebral palsy, dystonia and spinal cord injuries. MH- and NMS-like hyperthermic syndromes have been reported in patients when the infusion pumps fail and treatment is not reinstituted quickly enough.

Episodes consisting of hyperthermia, skeletal muscle rigidity, mental status changes, autonomic changes, respiratory distress, rhabdomyolysis and coagulation problems have been reported in patients withdrawn from either oral or intrathecal baclofen. Besides supportive care, treatment has included reinstitution of baclofen therapy. Occasionally, dantrolene has been used, as well, but this drug only relieves the rigidity associated with the syndrome, not the other more debilitating and dangerous symptoms.

Stimulants

People who take large doses of amphetamines, whether purposely or inadvertently, develop sweating, pupillary changes, tachycardia, hyperactivity and confusion, which may progress to hyperthermia, delirium, seizures, arrhythmias, shock, renal failure, coagulation disorders and death. Because of the prevalence of abuse of these drugs, awareness of amphetamine toxicity is imperative. There is also increasing concern about similar hyperthermic reactions to the use of cathinones ("bath salts"), compounds derived from the khat plant.

Stimulant-induced hyperthermia reflects increased heat production in skeletal muscle which results from generalized autonomic stimulation, hyperactivity, agitation and/or seizures. Evidence of rhabdomyolysis in the form of elevated CK levels occurs as well. Some patients develop an NMS- or MH-like syndrome with extreme muscle rigidity.

MDMA (ecstasy) and other methylenedioxy forms of amphetamine are receiving increasing attention in connection with the metabolic consequences of their abuse. While they are forms of amphetamine, they have about one-tenth the stimulant effects of the parent drug, but also possess hallucinogenic properties. MDMA also is a potent releaser of serotonin as well as a potent inhibitor of its uptake, so its toxicity may be related to SS.

MDMA toxicity has been associated with the entire range of NMS- and MH-like symptoms in clinical case reports, including muscle rigidity and breakdown, autonomic stimulation leading to renal or respiratory failure, coagulation disorders and in some cases death.

Hyperthermic MDMA crises have been associated with overexertion in hot settings during "rave" dances, suggesting that stimulant-driven dehydration and exertional heatstroke may play a role in its toxicity. Treatment of these hyperthermic MDMA crises is supportive: ventilatory assistance, cooling measures, anticonvulsants and fluid replacement are recommended. The use of dantrolene has been beneficial in a few cases but remains unproven and controversial.

Hyperthermic crises are often cited in fatal cocaineintoxication. In addition to hyperthermia, these intoxications are often associated with seizures, agitation, mutism, rhabdomyolysis, and renal, respiratory and/or cardiovascular failure.

The temperature rise in cases of cocaine intoxication are likely the result of increased heat production of skeletal muscle from autonomic activation, increased activity and seizures, compounded by cocaine-induced vasoconstriction, reduced skin blood flow, and resultant decreased thermal radiation and cooling.

Patients with rhabdomyolysis after cocaine intoxication typically present with agitation and muscle aches, and most develop hyperthermia. Death is most likely to occur in patients with rhabdomyolysis who develop acute renal failure, liver dysfunction/failure and blood coagulation disorders.

Some have noted a resemblance between cocaine intoxication and NMS. There are differences, however. Cocaine abuse induced-hyperthermia is associated with high ambient temperatures and often in the absence of muscle rigidity, while NMS occurs simply as a result of neurolept toxicity, without need for environmental contributions.

Systemic hyperthermia is commonly preceded or accompanied by an agitated delirium in cocaine intoxication, while in NMS, mentation is usually characterized by withdrawal and catatonia. Both cocaine and amphetamines regulate a central peptide responsible for catabolic effects and increasing energy expenditure in all cells of the body, with a tendency for inducing hyperthermia.

No literature exists as to the potential for neuroleptics to induce the same peptide. Clearly, multiple mechanisms are at work in drug toxicities and the potential for many points of metabolic and pathophysiological overlap between them exists.

Hallucinogens

Phencyclidine (PCP, "angel dust")continues to be used as a drug of abuse and has diverse effects on behavior and neurological function, including depressant, stimulant, hallucinogenic and analgesic effects. Signs of PCP intoxication are dose related.

At low doses, patients may show staggering gait, slurred speech, numbness of the extremities, sweating, muscle rigidity and catatonia. At higher doses, anesthesia, stupor and coma may result, accompanied by tachycardia, hypertension, salivating, sweating, hyperthermia, muscle rigidity and convulsions 72-96 hours after ingestion.

Rhabdomyolysis, occasionally associated with renal failure, is the most common serious medical complication of acute PCP toxicity. Ketamine, an anesthetic that is a chemical cousin of PCP, also has been associated with elevated temperatures during anesthesia, but it is not a known trigger for MH. Ketamine has recently been proposed as a rapid experimental treatment for depression, so that we may see more instances of adverse reactions to and abuse of this agent.

Similarly, lysergic acid diethylamide (LSD),a psychomimetic drug with effects similar to serotonin, produces hyperthermia along with other effects on the autonomic nervous system. Patients may develop psychosis, catatonic stupor, hyperactivity or rigidity, rhabdomyolysis and sympathetic activation, leading to hyperthermia, coagulation disorders, respiratory arrest and coma.

Although the hyperthermia in these cases may result from extreme exertion, the potential significance of serotonin mechanisms in the brain underlying hyperthermic drug reactions should not be overlooked.

Central anticholinergic syndrome (CAS)

There are many drugs and compounds in the environment that block both central and peripheral cholinergic transmission and induce CAS. The clinical picture of CAS is identical with that of paradigmatic atropine-induced cholinergic intoxication: agitation with seizures, restlessness, hyperthermia, hallucinations, disorientation, stupor, coma and respiratory depression.

Medically useful drugs that have been implicated in CAS include the above mentioned atropine, scopolamine, phenothiazines, butyrophenones, tricyclic antidepressants, ketamine, etomidate, H-2 blocking agents such as cimetidine, and antihistamines such as diphenhydramine.

Intentional or unintentional intoxication with hallucinogenic plants (i.e., Datura stramonium [jimson weed]) or mushrooms (i.e., Amanita muscaria) can cause CAS due to intrinsically anticholinergic tropane alkaloids.

Several cases of CAS have been reported following Chinese herbal tea consumption.

Symptoms are of both CNS and PNS toxicity: "Red as a beet, dry as a bone, blind as a bat, mad as a hatter and hot as a hare." The mnemonic refers to the symptoms of flushing, dry skin and mucous membranes, mydriasis with loss of accommodation, altered mental status and fever. Ataxia, disorientation, short-term memory loss, confusion, hallucinations, psychosis, agitated delirium, seizures, coma, respiratory failure and CV collapse may also be part of the spectrum of presenting signs.

Notably, patients may present with tachycardia and hypertension, decreased intestinal peristalsis and functional ileus, urinary retention, tremulousness and myoclonus. In the anesthetized patient with CAS, very few of these symptoms other than hyperthermia, tachycardia, hypertension and CV instability will be present, giving rise to the suspicion of MH.

Mitochondrial uncoupling agents and other toxins

There are many reports in the literature of hyperthermia caused by the ingestion, either accidentally or intentionally during attempted suicide, of drugs and toxins from classes not listed above. For example, salicylates are a common cause of poisoning and, when taken in large doses, interfere with energy metabolism by uncoupling of mitochondrial oxidative phosphorylation.

Although patients with salicylate poisoning present most often with hyperventilation (a characteristic of awake MH), tinnitus and gastrointestinal irritation, severe cases may resemble MH with elevated temperature, rhabdomyolysis, metabolic acidosis and unstable vital signs. This can lead to pulmonary and cerebral edema, hypotension, seizures, hypoxia, hypoglycemia and cardiopulmonary arrest.

The diagnosis is suspected by history and confirmed by finding ASA pill fragments in gastric lavage and performing blood salicylate levels. Treatment consists of supportive intensive care, gastric lavage, alkalinization of the urine and hemodialysis to remove the blood salicylate.

Another environmental toxin that is a mitochondrial energy uncoupler is dinitrophenol (DNP). This compound is a staple in the chemical manufacturing industry and has been used in the processing of dyes, wood preservatives, explosives and as a pesticide. It was even used as a dietary weight loss supplement in the 1930s, but was soon banned from foodstuffs due to its rapidly recognized toxicity.

In recent years, however, it has again become available through unregulated mail-order websites, with resulting increases in reported cases of poisoning. Like salicylates, DNP can cause an MH-like syndrome with hyperthermia, muscle rigidity and breakdown, acidosis, and a shock-like state leading to multiple organ failure and death. Treatment is supportive intensive care, and while some have recommended the use of dantrolene, there is little evidence for its efficacy.

Coda - With all the above drug-related, hyperthermic syndromes, there is no evidence of crossover sensitivity to the development of MH. Conversely, there is no evidence of MH susceptible individuals being more sensitive to the hyperthermic effects of any of the drugs/toxins listed above.

Environmental

Exertional heat illness (EHI), with or without rhabdomyolysis

Heat stroke, as it is commonly called, is a potentially fatal disorder characterized by extremes of core temperature (>40.5°C) induced by internal metabolic production (as in severe exercise) usually associated with high environmental temperatures and conditions that favor core body heat retention rather than heat dissipation.

As a result, normal body thermostatic mechanisms are unable to maintain normal body temperature, and lead to a series of pathophysiological events that culminate in severe metabolic acidosis, multiorgan failure, coma and death. Treatment is supportive, and iced-water baths are the most effective method of body cooling. The earlier the diagnosis and the institution of treatment, the lower the morbidity.

There has been some literature that claims there is a relationship between EHI and MH susceptibility. Indeed, there is literature that there is a high rate of EHI-MH susceptibility overlap in military recruits in whom there tends to be a high rate of EHI, especially during basic training. Moreover, there have been a number of recent case reports of EHI that may have been episodes of MH in MH susceptible individuals, as well as scientific reports of EHI-MH syndrome overlap in the MH-mutant RyR1 knock-in mouse model.

Treatment of EHI should always be directed at cooling and hydration in order to prevent secondary organ dysfunction, but it should be noted that there is likely a small degree of overlap between those who are MH susceptible and those who experience EHI. Treatment with dantrolene, while likely ineffective in pure EHI, may be lifesaving in those with MH susceptibility who get EHI, in that this entity may be heat-induced, awake MH.

Unfortunately, unless you know a priori that your patient is MH susceptible or comes from a family that carries a history of MH susceptibility, you have no way of making a definitive diagnosis during therapeutic attempts. There is no real downside to giving dantrolene empirically in cases of EHI that seem refractory to cooling and hydration measures, just in case this case is one in which EHI and MH overlap, and the former has triggered the latter.

(A good slide show on the treatment of EHI is available on Medscape at http://reference.medscape.com/features/slideshow/heat-illness?src=nl_slide.) Indeed, the mouse models of MH are also very sensitive to the development of EHI, which responds to dantrolene.

Confirmatory tests

Unfortunately, there are no easily available tests that can confirm that a patient is suffering an episode of MH. There is a retrospective grading scale developed by Larach et al. (see references below) that is designed to determine the likelihood of an event having been MH, and while it was developed using expert opinion, it remains the most useful clinical grading scale available to assist with diagnostics.

There are two available laboratory tests that can potentially confirm MH susceptibility. The first is the pharmacological evaluation of strips of live muscle from a skeletal muscle biopsy known in North America as the Caffeine-Halothane Contracture Test (CHCT), and in Europe, with a slightly modified approach, known as the In-Vitro Contracture Test (IVCT). Both of these tests are performed on freshly harvested muscle, and the specimens cannot, therefore, be sent to a tesing center by mail, nor can the tests be performed on material that was frozen or preserved.

Unfortunately, there are only five extant laboratory sites in the North America. that perform the CHCT. This test is invasive and expensive (it is not always covered by insurance), and it is often hard to get to a laboratory that does it. For more information on the specifics of these tests and on locations where these tests are performed, see www.mhaus.org in North America, and www.emhg.org for Europe.

The second test is a genetic test that looks for causative mutations in the genes known to confer susceptibility to MN: RyR1, CACN1S and STAC3. RyR1 is the site of variants in about 50-70% of patients experiencing MH episodes, and only about 25-30% have known causative mutations. Indeed, there are over 300 known variants in RyR1 at this time, but only about 30 have been shown to be causative for MH (an up-to-date list of causative mutations is kept at www.emhg.org). Genetic testing centers can be found in both North America and Europe at www.mhaus.org and www.emhg.org, respectively.

The other variants either have not yet had diagnostic criteria (clinical and/or laboratory) fulfilled to be considered causative, or are simply non-pathogenic variants. We simply do not yet know. The absence of a causative mutation, therefore, or the presence of a variant of unknown significance (VUS), unfortunately leaves the patient no more knowledgeable as to the genetic cause of their susceptibility than before the test.

Approximately 1% of patients have MH-causing mutations in the skeletal muscle isoform of the Dihydropyridine Receptor (DHPRs = CACN1S). Only specific populations seem to have the STAC3 gene mutation conferring MH susceptibility that is associated with Native American Myopathy.

As should be obvious from the above, the genetics of MH are yet to be fully worked. At least three other unknown genes, originally described by linkage analysis, seem to be causative as well. Hence, the difficulty in establishing preoperative genetic linkage to MH susceptibility.

4. Specific treatment

Drugs and dosages

Dantrolene 2.5 mg/kg initial dose and repeated until symptoms abate, then 1 mg /kg every 6 hours for 24 hours as long as symptoms do not return. If they do return, go back to the beginning of the protocol.

A word of caution: Delay in treatment with dantrolene can increase morbidity and mortality. If you suspect MH, it may be more prudent to treat first and ask questions later. In order to help ascertain whether a case was MH or not, it is better to get an arterial blood gas, electrolytes, CBC and CK prior to instituting dantrolene therapy so that (1) you will have a baseline with which to compare and guide clinical care, and (2) help you make the diagnosis that this was or was not MH, albeit in a retrospective manner.

Refractory cases

In particularly refractory cases you keep giving dantrolene at 2.5 mg/kg until symptoms abate. We do not know of any upper limit of dantrolene dosage that one can give, and particularly difficult cases have taken up to 20 mg/kg to bring down symptoms. This is not an upper limit, but the most dantrolene most of us on the MHAUS Hotline have heard of.

As a rough "guesstimate," if you must go well above 20 mg/kg of dantrolene (30 mg/kg?) in the attempts to truncate an MH episode, then one of two possibilities arise: either (1) this is MH, and the case is an outlier (i.e., dantrolene resistant); or (2) this is an MH mimic, and you should seriously start questioning your diagnosis.

A further note of caution: Dantrolene is a general antipyretic and will cause a temperature drop in almost any form of hyperthermia it is used in. Therefore, response to dantrolene is not a pharmacologic diagnostic indicator of an event having been MH!

5. Disease monitoring, follow-up and disposition

Expected response to treatment

If this is true MH, and you have made the diagnosis early enough, the response to dantrolene is in the range of minutes to tens of minutes. The temperature, PaCO2 and heart rate all will begin to improve rather dramatically, and in parallel. The acidosis will correct itself and the hyperkalemia will correct due to symptomatic treatment and to the reduction in acidosis.

Evidence of muscle breakdown (i.e. serum CK, and serum and urine myoglobin) will likely continue to rise for the next 24-36 hours, even with the successful treatment of autonomic and metabolic signs with dantrolene, and must be monitored and treated carefully to avoid acute renal failure.

If treated early, most patients recover uneventfully, but a significant proportion complain of muscle pain or discomfort. Indeed, a delay as short as 20 minutes from presenting signs to diagnosis and institution of dantrolene therapy may greatly increase morbidity. Furthermore, once an episode of MH is treated and truncated, it may take as long as 6 months to a year for a patient to feel back to "muscular normality." If a live muscle biopsy is planned to confirm the diagnosis of MH, the patient must wait at least 6 months before this is attempted, as skeletal muscle function and its pharmacological responsiveness is not "normal" for that long after an episode.

Incorrect diagnosis

You should suspect that you have made the wrong diagnosis if: (a) the patient only has a pure metabolic acidosis, since the acidosis is initially purely respiratory and evolves into a mixed respiratory-metabolic acidosis as the muscle enters anaerobic metabolism; or (b) the patient is not responding even to high-dose dantrolene, as described above.

Pathophysiology

MH results from a dysregulation of control of the Ca2+homeostasis in skeletal muscle in the presence of volatile anesthetics in a susceptible individual that results in a massive, sustained rise in myoplasmic Ca2+. Since this ion is responsible for the normal activation of muscle contraction, the sustained presence of high concentrations of Ca2+ induces skeletal muscle contracture and depletion of muscle ATP and glycogen as the energy source for muscle contraction.

The high rate of hydrolysis of ATP releases thermal energy, and, as a first approximation, induces a rise in skeletal muscle and then core temperature. The stressed muscle mitochondria, working at maximum capacity to produce more ATP, go from aerobic metabolism to anaerobic metabolism as glycogen stores are used up and as blood flow to muscle cannot meet the demand of muscle metabolism. In addition, this stressed muscle is known to produce IL-6, a known pyrogen.

Together, and likely along with yet to be discovered mechanisms, the patient becomes hyperthermic, the muscle stays in contracture, and the body goes from a purely respiratory acidotic state to a mixed respiratory-metabolic state.

Rhabdomyolysis begins soon after, and the secondary pathophysiology ensues: release of myoglobin into the circulation and subsequent renal failure as the myoglobin precipitates in the renal tubules; release of muscle potassium and resultant hyperkalemia; release of muscle acid and subsequent severe acidosis; stress-induced autonomic activation and resultant tachycardia and hypertension; and together, circulating adrenergic agonists, acidosis and hyperkalemia all sensitize the myocardium to the development of arrhythmias and resultant cardiovascular collapse.

Finally, there is the suggestion that neurological outcome in patients who survive even with successful treatment is sometimes out of proportion to the perceived clinical severity of the MH episode.

Molecular pathophysiology of MH

In order to begin to understand the pathophysiology and genetics of MH, one must first understand the molecular physiology of skeletal muscle excitation contraction coupling (ECC), which follows here.

Skeletal muscle depolarization as a result of neuromuscular transmission is sensed by an L-type voltage dependent calcium channel known as the dihydropyridine receptor (DHPR) and strategically positioned in a regular array along the surface membranes of the transverse tubules (TT) that are spaced regularly along the long axis of a muscle cell.

Immediately apposed to the array of DHPR molecules in the TT is an array of RyR1channels situated in the membrane of the intracellular storehouse for Ca2+, the sarcoplasmic reticulum (SR). Once the DHPR has sensed surface membrane depolarization, it undergoes a conformational change and an intracellular loop of this molecule physically interacts with a site on the RyR1, causing it to open and release Ca2+.

This process, voltage gated calcium release, stands in distinction to what happens in human cardiac muscle, where the cardiac isoform of the DHPR actually opens and allows Ca2+ into the cardiomyocyte, binding to the cardiac isoform, RyR2, causing this channel to open, thereby inducing further Ca2+ release in a process known as Ca2+-induced Ca2+ release, or CICR.

Calcium is absolutely required for muscle contraction, whether skeletal, cardiac or smooth, as it binds to a site on one of the troponins, causing it to move off an active binding site for myosin on actin, thereby allowing the molecular determinants of actin-myosin induced contraction to go through their ATP hydrolysis cycle and induce fiber shortening.

As the neuromuscular stimulus to contract fades, a specific Ca2+-ATPase in the SR membrane takes up Ca2+ from the myoplasm back into the SR against the Ca2+concentration gradient, in an energy requiring, ATP-driven, hydrolytic reaction. This process induces muscle relaxation. Thus, the cycle is ready to restart.

Within the SR, there are a number of Ca2+ binding proteins, the most abundant of which is calsequestrin (CSQ), which has the capacity to bind approximately 32 moles of Ca2+ per mole of protein. This allows for a rather concentrated store of Ca2+ to be maintained in the SR lumen. During periods of physiological stress (i.e. high muscle workloads), the amount of Ca2+ in the SR is potentially rapidly depleted.

Cells, including skeletal muscle cells, have developed a mechanism to replete the SR Ca2+ stores when they get too low; this process is known as store-operated Ca2+entry (SOCE). Additionally, there is another process that has been identified in myoblasts but not yet in myocytes called excitation-coupled Ca2+ entry (ECCE), in which high frequency trains of stimulation (as in high modes of skeletal muscle exercise) induces Ca2+ entry into the myoplasm via the DHPR.

Another potential physiological contributor to myoplasmic Ca2+ levels is a luminal SR process called store overload-induced Ca2+ release (SOICR), in which luminal Ca2+ concentrations get so high (from as yet undefined mechanisms) that they induce opening of RyR1 in the absence of external stimuli, thereby raising the concentrations of myoplasmic Ca2+ abnormally.

Interestingly, a mouse knock out of CSQ has been shown to be viable and demonstrates a sensitivity to heat and volatile anesthetics, producing a syndrome that too is a mimic of MH. Is the gene for CSQ a potential site of mutations conferring MH susceptibility in the human population?

There is evidence that a number of these processes may contribute to the molecular pathophysiology of MH. First, the dysfunctionally elevated myoplasmic Ca2+ in skeletal muscle is a hallmark of MH. Second, a majority of MH families have variants in RyR1, some of which have met the experimental criteria for causative mutations. Third, an experimental mouse knock in of a known causative MH mutation in RyR1 is sufficient to induce heat and halothane sensitivity that results in a syndrome that is an absolute mimic of the human syndrome. Fourth, a small number of families have MH-causative mutations in the DHPR subunit which interacts with RyR1 in ECC.

Dantrolene suppresses the rise in myoplasmic Ca2+associated with the triggering of MH and is known to have a binding site on RyR1, but only recently was it shown that the drug suppresses RyR1 activity in single channel studies in a calmodulin-dependent manner. Dantrolene also inhibits RyR1-dependent activation of the SOCE machinery, thereby suppressing Ca2+ entry from outside the cell. Dantrolene does the same for ECCE and SOICR in experimental models.

Therefore, it seems likely that the dysfunctional rise of myoplasmic Ca2+in MH results from multiple points of dysfunction that are likely tied together by as yet unknown mechanisms of RyR1 function/dysfunction. Clearly, the molecular mechanisms surrounding Ca2+homeostasis in skeletal muscle ECC are all dysfunctional in MH. Their molecular determinants are all potential targets for mutations conferring MH susceptibility.

We do not yet know the molecular determinants underlying the metabolic response, nor what the molecular targets of volatile anesthetic are in MH. We do not know what the other three genes that have been genetically linked to human MH susceptibility are, nor do we know what the molecular mechanisms underlying the incomplete penetrance and variable expressivity of MH are.

Epidemiology

Due to the phenomenon of incomplete penetrance, the incidence of MH is best described as incidence per standard number of anesthetics. The estimates of incidence has ranged from one in 3,000 to one in 50,000 anesthetics, with the most commonly accepted incidence in the range of one in 10,000-15,000 anesthetics in children and one in 30,000-50,000 anesthetics in adults. The prevalence of MH has been reported to be ~1/100,000 hospital admissions, but 3/100,000 in pediatric hospitals.

This variation or uncertainty of incidence probably results from population differences in both the gene mutations that lead to MH susceptibility, the background genetics that determine penetrance of the gene effect in the presence of trigger anesthetics, and the frequency of use of trigger anesthetics, particularly succinylcholine, in a particular region.

Monnier et al and Ibarra et al estimate the prevalence of causative mutations in RyR1 to be one in 2,000-3,000 individuals in the French and Japanese populations, respectively. Better data awaits definitive characterization of all the genes involved both in susceptibility and penetrance.

MH susceptibility is highly concordant with central core disease, multiminicore disease (both of which are due to causative mutations in RyR1), and King-Denborough syndrome, also associated with RyR1 mutations in the overhwhelming majority, but not all cases. Native American Myopathy is a recessive disease with mutation in STAC3. No other myopathies are yet known to have clear concordance with MH susceptibility.

The journal Anesthesia & Analgesia published a series of comprehensive reviews on various classes of myopathy (myotonias, muscular dystrophies, core myopathies, some enzymopathies, EHI and exertional rhabdomyolysis) and their potential association with MH susceptibility in October 2009 (vol 109), and the reader is referred to this volume for more detail.

Recent evidence shows that clinical history of MH is a not very reliable signal that a patient is MH susceptible (see Reference list).

Prognosis

All individuals with suspected MH should be worked up for MH susceptibility with genetic testing and/or muscle biopsy with contracture testing. A detailed family history of MH should be sought in conjunction with the supervision of a clinical geneticist. Patients definitely MH susceptible should wear a "Medic Alert" bracelet notifying health personnel to avoid volatile anesthetics and succinylcholine.

This is particularly important and potentially life-saving in medical emergencies, where the patient may be unconscious or unable to communicate and no patient chart is available. Genetic testing and counseling for a proband's family is extremely important to determine who might or might not be susceptible, if this can be determined.

All MH susceptible families should join those organizations and registries (i.e., MHAUS and NAMHR in North America and EMHG in Europe) that follow such families and dispense education and advice, in countries that have them.

Physicians in North America who care for patients with an active MH syndrome should report the conditions that surrounded the triggering and care of these patients to the North American Malignant Hyperthermia Registry using an Adverse Metabolic Response to Anesthesia (AMRA) form, available online through the NAMHR, available on the MHAUS website (MHAUS.org).

Generally speaking, once the acute event is controlled and successfully treated, there are no long-term negative outcomes, other than continued susceptibility to MH triggering agents. Rarely, patients continue to complain of vague muscle aches and pains or heat sensitivity, but these outcomes are not common.

Special considerations for nursing and allied health professionals

NA

What’s the evidence?

Rosenberg, H, Sambuughin, N, Dirksen, R, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K. "Malignant Hyperthermia Susceptibility". Gene Reviews [Internet]. University of Washington, Seattle. 1993-2003.

(Most comprehensive, up-to-date review of MH in the literature at the time of this writing.)

Hopkins, PM. "Malignant Hyperthermia: pharmacology of triggering". Br J Anesth. vol. 107. 2011. pp. 48-56.

(Reviews the pharmacodynamics of the ability of volatile anesthetics to trigger MH and the differences in triggering characteristics between modern volatile anesthetics and the classical anesthetic, halothane. Also discusses how skeletal muscle relaxants may modify the presentation.)

Larach, MG, Localio, AR, Allen, GC. "Aclinical grading scale to predict malignant hyperthermia susceptibility". Anesthesiology. vol. 80. 1994. pp. 771-9.

(Used an International panel of experts and the Delphi method to develop a clinical grading scale to retrospectively determine the likelihood of a clinical event having been MH. The most useful tool for diagnostic discrimnation available.)

Pinyavat, T, Rosenberg, H, Lang, BH, Wong, CA, Riazi, S, Brady, JE, Sun, LS, Li, G. "Accuracy of malignant hyperthermia diagnoses in hospital discharge records". Anesthesiology. vol. 122. 2015. pp. 55-63.

(Evaluation of the accuracy of a diagnosis of MH from hospital discharge records… not very encouraging!)

Visoiu, M, Young, MC, Wieland, K, Brandom, BW. "Anesthetic drugs and onset of malignant hyperthermia". Anesth Analg. vol. 118. 2014. pp. 388-96.

(Show among other things that succinylcholine alone can cause MH.)

Riazi, S, Larach, MG, Hu, C, Wijeysundera, D, Massey, C, Kraeva, N. "Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands". Anesth Analg. vol. 118. 2014. pp. 381-7.

(Show that delay in dantrolene therapy increase complications in MH, and that succinylcholine alone can induce MH.)

"Anesthesia & Analgesia". vol. 109. 2009.

(This volume contains a series of reviews on the relationship, or lack thereof, between various myopathies, EHI, exertional rhabdomyolysis and various enzymopathies, and susceptibility to MH.)

Veyckemans, F. "Can inhalation anesthetics be used in the presence of a child with myopathy?". Curr Opin Anaesthesiol. vol. 23. 2010. pp. 348-55.

(Short review of the topic.)

Dowling, JJ, Lillis, S, Amburgey, K, Zhou, H, Al-Sarraj, S, Buk, SJ, Wraige, E, Chow, G, Abbs, Lever S, Lachlan, K, Baralle, D, Taylor, A, Sewry, C, Muntoni, G, Jungbluth, H. "King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RyR1) gene". Neuromuscul Disord. vol. 21. 2011. pp. 420-7.

Horstick, EJ, Linsley, JW, Dowling, JJ, Hauser, MA, McDonald, KK, Ashley-Koch, A, Saint-Amant, L, Satish, A, Cui, WW, Zhou, W, Sprague, SM, Stamm, DS, Powell, CM, Speer, MC, Franzini-Armstrong, C, Hirata, H, Kuwada, JY. "Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy". Nat Commun. vol. 4. 2013. pp. 1952.

(The identification of STAC3 as the mutated gene in Native American Myopathy and its concordance with MH susceptibility.)

MacLennan, DH, Chen, SR. "Store overload-induced Ca2+ release as a triggering mechanism of CPVT and MH episodes caused by mutations in RyR and CSQ genes". J Physiol. vol. 587. 2009. pp. 3113-5.

(A review of a recently discovered, potential mechanism in the triggering of MH.)

Duke, AM, Hopkins, PM, Calaghan, SC, Halsall, JP, Steele, DS. "Store-operated Ca2+ entry in malignant hyperthermia-susceptible human skeletal muscle". J Biol Chem. vol. 285. 2010. pp. 25645-53.

Zhao, X, Weisleder, N, Han, X, Pan, Z, Parness, J. "Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor". J Biol Chem. vol. 281. 2006. pp. 33477-86.

(Demonstration that dantrolene mildly inhibits SR calcium release but inhibits RyR1-coupled SOCE strongly.)

Cherednichenko, G, Ward, CW, Feng, W, Cabrales, E, Michaelson, L. "Enhanced excitation-coupled calcium entry in myotubes expression malignant hyperthermia mutation R163C is attenuated by dantrolene". Mol Pharmacol. vol. 73. 2008. pp. 1203-12.

(The association of MH, ECCE and dantrolene efficacy.)

Oo, YW, Gomez-Hurtado, N, Walweel, K, van Helden, DF, Imtiaz, MS, Knollmann, BC, Laver, DR. "Essential role of calmodulin in RyR inhibition by dantrolene". Mol Pharmacol. vol. 88. 2015. pp. 57-63.

(First demonstration that dantrolene inhibits RyR1 and RyR2 in single channel studies, and does so in a calmodulin-dependent manner.)

Brandom, BW, Larach, MG, Chen, MS, Young, MC. "Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States". Anesth Analg. vol. 112. 2011. pp. 1115-23.

Larach, MG, Gronert, GA, Allen, GC, Brandom, BW, Lehman, EB. "Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006". Anesth Analg. vol. 110. 2010. pp. 498-507.

Epstein, Y, Roberts, WO. "The pathophysiology of heat stroke: an integrative view of the final common pathway". Scand J Med Sci Sports. 2011.

(A review of the pathophysiology of various aspects of EHI and an attempt to integrate what is known into a comprehensive understanding.)

McDermott, BP, Casa, DJ, Ganio, MS, Lopez, RM, Yeargin, SW. "Acute whole-body cooling for exercise-induced hyperthermia: a systematic review". J Athl Train. vol. 44. 2009. pp. 84-93.

(Review of various methods of total body cooling in the treatment of EHI, concluding that ice water baths are the most efficient way to bring core body temperature down.)

Capacchione, JF, Muldoon, SM. "The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia". Anesth Analg. vol. 109. 2009. pp. 1065-9.

Chelu, MG, Goonasekera, SA, Durham, WJ, Tang, W, Lueck, JD. "FASEB J". vol. 20. 2006. pp. 320-30.

(The first description of a knockin mouse model of MH that recapitulates the syndrome in a heterozygous animal.)

Monnier, N, Krivosic-Horber, R, Payen, JF, Kozak-Ribbens, G, Nivoche, Y. "Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis and incidence of malignant hyperthermia susceptibility". Anesthesiology. vol. 97. 2002. pp. 1067-74.

Ibarra, CA, Wu, S, Murayama, K, Minami, N, Ichihara, Y. "Malignant hyperthermia in Japan". Anesthesiology. vol. 104. 2006. pp. 1146-534.

Liechti, M. "Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling". Swiss Med Wkly. vol. 145. 2015. pp. w14043.

(Most up-to-date review of abused psychoactive drug effects and serotonin syndrome.)
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