Introduction
Malignant hyperthermia crisis (MHC) is a potentially lethal inherited syndrome triggered by exposure to anesthetic agents. The anesthesia community is best prepared to deal with MHC and patients who have a diagnosis of malignant hyperthermia susceptibility (MHS). Most often, MH is triggered by anesthesia and stress. Identification and treatment of MHC is most common in the perioperative setting. The outcome of MHC has improved, and alternative methods of identifying other family members at risk have supplemented the expensive in vivo caffeine halothane contracture test (CHCT) and positive family history as a basis for establishing risk. There is an increasing population of MHS individuals who may require elective or emergent surgery. Anesthesia for MHS patients is high risk because anesthetic drugs or stress may induce an MHC with resultant death or major morbidity.
Malignant Hyperthermia Update
The incidence of unexpected MHC reported in surgical populations ranges from 1 : 5000 to 1 : 50,000 patients. MHC can follow anesthetic exposure to succinylcholine and all of the potent volatile anesthetic agents. It is characterized by hypermetabolism, a mounting fever, and evolving multiple organ failure. Clinical signs of MHC are progressive and nonspecific: tachydysrhythmias, tachypnea with hypercapnia, unstable blood pressure, and fever. The setting almost always involves anesthesia exposure. Laboratory findings of progressive mixed metabolic and respiratory acidosis, hyperkalemia, and rising creatine phosphokinase levels presage arrhythmias, rhabdomyolysis, disseminated intravascular coagulation, hepatic injury, renal dysfunction, encephalopathy, and death unless recognized promptly and treated. Treatment requires withdrawal of inhalational agents, hyperventilation, treatment of acidosis and hyperkalemia, control of fever, administration of dantrolene sodium, and preventive critical care. MHS is genetically determined.
Before the introduction of early recognition and treatment protocols, MHC was largely fatal. After widespread educational efforts in the 1970s that highlighted early suspicion of MHC and expectant management, the fatality rate decreased to 60% to 80%. With the introduction of dantrolene sodium and increased awareness of the syndrome in the late 1970s and 1980s, mortality rates fell to very low levels ; however, perioperative deaths continue to be attributed to MHC. Since the 1990s, genetics has been an important focus of MH research. A number of genetic variations have been identified in patients who have exhibited MHC in response to anesthetic triggers or demonstrated a phenotypic, positive reaction to the CHCT. Most genotypes are associated with abnormalities in the skeletal muscle ryanodine receptor. Although genetic testing offered the hope for a simple means of establishing which patients have MHS, the genetic background of individuals with phenotypic MH is increasingly complex. Indeed, genetic variability, together with the development of isolated mutations, may account for the observed variation in clinical presentations and severity of MHC.
Who Is Susceptible to Malignant Hyperthermia?
MHC has been observed in very young and elderly patients of both sexes. It is common in patients who have no indication in their histories and who have uneventful anesthetic procedures. In one report, only 35% to 50% of patients who had MHS developed MHC when exposed to triggering anesthetic agents. Anesthetic agents that trigger MHC are widely used because they are convenient and effective. Unfortunately, there is no simple means of establishing MH risk. MHC is relatively uncommon. Consequently, clinicians must assume that all patients may have MHS. MHC and other hypermetabolic perioperative crises provide a strong rationale for monitoring all anesthesia patients for signs of unexpected hypermetabolism, rigidity, and fever.
Although MH is associated with several neuromuscular syndromes, there are no physical findings that identify MHS patients. Individuals who have had family members die in the perioperative period of MHC or who, themselves, have had MH-like events often give a suggestive history or identify a family relationship with an MHS patient. When patients report an obvious, well-documented MHC, positive genetic screening, or a strong family history of the MHC, the clinician must be alert to a heightened risk of MHC in the perioperative period and must treat the patient as having MHS. When a patient provides a history of a suggestive perianesthetic episode without having had a CHCT, most clinicians would assume that the patient has MHS. Some recommend that any patient with an unknown neuromuscular disease be treated as having MHS because of a high correlation between CHCT MH and specific neuromuscular diseases such as central core and multi-mini central core disease. Both retrospective and prospective data show that the outcome will be optimal for patients who are thought to have MHS if they have anesthesia that is designed to prevent triggering the MHC.
Treatment Options for Patients Susceptible to Malignant Hyperthermia
Anesthesia plans for patients with MHS should avoid known triggering agents. These include all the potent, volatile, inhalational anesthetics and the nondepolarizing muscle relaxant succinylcholine. General anesthesia with a “balanced” technique that uses nitrous oxide and intravenous (IV) agents and total intravenous anesthesia (TIVA) with or without nondepolarizing muscle relaxants is considered safe. Regional anesthesia with any technique and any local anesthetic agent is safe. Nitrous oxide analgesia, regional analgesia, and all levels of sedation with any narcotic/sedative/hypnotic combination are acceptable. Nontriggering anesthetics are less likely to evoke MHC, but close monitoring is required because the anesthetic and procedural experience may trigger MHC even when specific triggering agents are not used.
Pretreatment of patients with MHS with oral or IV dantrolene may prevent or abort the MHC but is no longer recommended.
The ideal anesthetic approach should meet the needs of the patient, surgeon, and anesthesiologist. Unusual techniques that involve rarely used drugs, skills, or equipment are ill advised. Whatever the specific anesthetic chosen, MHC treatment protocols, equipment, and drugs must be available for management of the patient who develops MHC or MH-like reactions during anesthesia and surgery. Procedural facilities or offices that provide anesthesia but do not employ known triggering agents should carefully screen individuals with MHS. Rarely, patients with MHS may develop MH when stressed, even though triggering agents are not used. Evidence for the idea that MHC is a “stress syndrome” is tenuous, and the issue is controversial. If a patient presents with a history of unstable myopathic syndromes and has MHS, anesthesia care should not be undertaken without preparation because of phenotypic variability and an unknown risk of MH-like symptoms. If the anesthesia provider at an institution does not have access to MH support protocols, trained staff, rapidly available laboratory tests, and resuscitation equipment, the patient with MHS should be referred to another institution ( Table 37-1 ).
| Safe Anesthesia for the MHS Patient | Drug Choices |
|---|---|
| Local anesthesia with or without sedation | All local anestheticsAll sedative/narcotic drugs |
| General “balanced” anesthesia | Nitrous oxide, nondepolarizing muscle relaxants, opiates, all induction agents, sedatives, total intravenous anesthesia |
| Regional anesthesia and analgesia with or without sedation | All local anesthetic agentsAll IV/IM sedatives, opiates, hypnotic agents |
Evidence
Both experiential and prospective data support these approaches to the patient with MHS. Data regarding management of MHS are most often evidentiary or experiential. Important ethical questions limit prospective exposure of individuals to experimental anesthetic protocols if they are thought to be at risk of life-threatening MHC.
Experiential data demonstrate improved outcomes after MHC over the past four decades. The decrease in death and other morbidity after MHC is likely multifactorial. Improved outcomes are attributed to earlier recognition, withdrawal of triggering agents, early use of dantrolene, and supportive care designed to minimize secondary insults associated with MHC, together with attempts to identify patients with MHS for receipt of trigger-free anesthetics. One retrospective review of outcomes from New Zealand reported no deaths associated with MHC over two decades from 1981 to 2001.
In contrast with recent findings reported by Pollock and colleagues, sporadic case reports, court cases, and deaths reported in the press or known to volunteer physician MH Hotline Consultants (MHHLCs) in the United States ( https://about.mhaus.org/index.cfm/FUSEACTION/Hotline.Home.cfm , Malignant Hyperthermia Association of the United States [MHAUS], Sherbourne, NY) and abroad, confirm the impression of continued perioperative mortality from catastrophic MHC. Legal issues likely prevent or delay scientific reporting of MH deaths. Secondary complications of MHC also may be underreported as demonstrated by sporadic case publications and MHHLC reports.
In the era before dantrolene, clinicians were unwilling to provide elective anesthesia for patients with MHS, judging the risk of MHC to be too great. No one would undertake a comparison of management approaches involving triggering agents in humans known to have MHS for ethical reasons. Experience with animal models of MHC showed that anesthesia performed without triggering agents was safe. A specific in vivo test for MHS that required a muscle biopsy, the CHCT, was developed. A muscle biopsy could be performed in adults with local anesthesia or nerve block. In small children in whom a muscle biopsy for CHCT is not feasible without anesthesia, prospective controlled studies of the best elective anesthetic for the patient with MHS were undertaken as the only recourse. An experience with children in which nontriggering agents were used for CHCT muscle biopsy was reported to be safe. These experiences, together with sporadic case reports of successful avoidance of MHC in patients with MHS who required urgent anesthesia, provided evidence for a cautious approach to elective surgery for the patient with MHS. Consequently, anesthesia and surgical staff are more willing to undertake both emergency and elective surgery for patients with MHS.
Additional experiential evidence includes the content of approximately 650 phone calls a year made to volunteer advisory physicians serving as MHHLCs, sponsored by the MHAUS, a lay advocacy organization established in 1981. This experience is summarized and published quarterly in The Communicator, published by MHAUS. MHAUS also provides information on its website and produces a “case of the month” that discusses management of MHC or MH-like events. MHC and MH-like experiences collected as voluntary “Adverse Metabolic Reaction to Anesthesia” reports form the basis of a privacy-protected database, the MH Registry, established in 1987 ( www.mhreg.org ). These growing databases provide retrospective information but no denominator of MHC and MH-like events experienced by the general population, nor is there information establishing the frequency of MHS in the general population. Retrospective data provide invaluable insight into MHC management and MH-like episodes that take place in the anesthesia setting. They have also highlighted key aspects of MHC management. For example, although the average effective dose of dantrolene is approximately 2.5 mg/kg, MH registry reports of patients requiring as much as 10 mg/kg for control of MHC and occasional case reports illustrate the value of increasing dantrolene doses beyond the typical ceiling dose of 10 mg/kg. Similarly, case reports of delayed-onset MHC and recurrent MHC have led to evidence-based recommendations by MHHLCs for continued therapy for the MHC and at least an hour’s observation postoperatively.
Only a small number of prospective studies of management of MHS/MHC patients have been published. These, together with subsequent experience, add a higher level of evidence-based support for current management strategies. The multicenter U.S. Food and Drug Administration (FDA)-approved dantrolene trial, published in 1982, demonstrated that dantrolene sodium was effective in treating MHC, provided it was recognized and treated before sudden death or outcome-limiting organ system injury. In fact, the FDA approved the drug for this purpose in 1979, before formal peer-reviewed publication of outcome data. Subsequent experience with dantrolene after its acceptance as a treatment for MHC allowed prospective studies of patients undergoing muscle biopsies with sedation, as well as studies of “trigger-free” general and regional anesthetics, of which the majority were general anesthetics.
This prospective evidence, together with published case reports and accumulated reporting of encounters to the MH Registry and voluntary physician MHHLCs, has changed the anesthetic approach to patients with MHS by demonstrating that trigger-free anesthetics are safe. Not only is the frequency of MHC low when patients are given anesthetics that avoid triggering agents but also, when MHC occurs and is managed in a prepared setting, its outcome in this population is better than that after unexpected MHC in other environments.
Areas of Uncertainty
Dantrolene Pretreatment
Initial recommendations included preoperative pretreatment with dantrolene. Subsequently, clinical experience with patients with MHS, side effects of dantrolene, a small number of complications after oral dantrolene therapy, and the ability to measure serum dantrolene levels after Flewellen and colleagues demonstrated that effective serum dantrolene levels can be achieved with short-term IV loading supported a rationale for eliminating routine pretreatment of patients with MHS with oral dantrolene loading before anesthesia. IV dantrolene treatment was extended to children after demonstration of dantrolene pharmacokinetics in that population. Also, intermittent IV dantrolene injections, maintenance IV infusions, or both for continuing MH suppression after the crisis have been based on necessity during case experience. Evolving practice has been tested by experience, although not in controlled, prospectively blinded trials. Dantrolene pretreatment is no longer recommended for patients with MHS having elective surgery with trigger-free anesthetics.
There are unusual patients whose underlying muscle disease is so symptomatic that they take oral dantrolene when stressed in daily life outside the anesthesia setting. This, together with a pathologic similarity between MHC and heat stroke fatality, has raised the question of whether heat stroke is a variant, or more common, in MHS. Stress-induced MHC may be associated with unknown myopathy or may occur only in a unique genetic subset of patients with MHS. Data repositories are inadequate to guide the practitioner, but it would seem prudent to give dantrolene preoperatively and for some time postoperatively to very symptomatic patients who have myopathic, MH-like symptoms with stress and exercise.
Is Masseter Muscle Rigidity a Malignant Hyperthermia Crisis until Proved Otherwise?
Masseter muscle spasm or rigidity (MMR) in response to depolarizing muscle relaxants or MH triggering agents has been identified as an early clinical sign of MHC or as a myotonic reaction commonly followed by elevated muscle enzymes, hyperkalemia, dysrhythmias, and metabolic acidosis. The relationship between MMR and both acute myopathic response and MHC argues for a conservative approach to MMR. It is recommended that triggering agents and anesthesia be discontinued after observation of MMR while possible causes for MMR are evaluated. CHCT in adults who had various myopathies subsequently demonstrated a high incidence of MH-positive and MH-equivocal contracture responses. The extent to which the myopathic response to anesthetic agents resembles MHC is further confused by the fact that MH CHCT is probably less specific in these patients. This supported a clinical impression that various myopathies, in addition to MH, may manifest with MMR or muscle injury after anesthetic induction with MH-triggering agents.
The recognition of sudden cardiac arrest and rhabdomyolysis after succinylcholine administration to male infants and children amplified recognition of the risk, regardless of whether the etiology was the same. After administration of triggering agents, cardiac arrest and dysrhythmias that are seen during myotonic reactions are caused by acute hyperkalemia, myopathic muscle responses, or both. Subsequently, case reports and retrospective reviews of MMR after succinylcholine administration in children without either severe myotonic reactions or MHC generated controversy. Is MMR observed during anesthesia in children or adults a normal variant of the succinylcholine response or is it a high-probability sign of significant muscle injury associated with potentially lethal MHC or myotonic crisis?
It has long been known that adults and children who receive succinylcholine develop creatine phosphokinase elevation and myoglobinuria. One prospective study of 500 children has shown a low incidence of MMR and, more commonly, incomplete jaw relaxation after halothane anesthesia and succinylcholine. In a prospective study of more than 5000 children who had succinylcholine or a nondepolarizing relaxant after an induction and intubation technique with or without inhalational halothane, it was evident that the inhalational agent was associated with MMR. Of note, although MHC did not occur, three of 600 patients (0.5%) developed MMR after paralysis for intubation after a technique that used halothane before intubation. Two of these had MMR with highly increased CK enzyme levels after receiving halothane and thiopental with nondepolarizing relaxants. Therefore MMR is not simply a normal variant of the succinylcholine response in children and is also seen during administration of inhalational agents and nondepolarizing muscle relaxants.
The incidence of MH and sudden death after MMR is not as high as initially thought, but the implications of MMR are clear: a significant percentage of those who demonstrate MMR have rhabdomyolysis associated with an unknown myopathy that should be evaluated. Young boys with unrecognized muscular dystrophy, in particular, are at risk of hyperkalemia that could cause death or significantly complicate anesthesia and surgical care. Regardless of whether unrecognized myopathy or dystrophinopathy is the cause, MMR is often associated with significant muscle injury and the risk of secondary insults associated with rhabdomyolysis, for example, hyperkalemic dysrhythmia, myalgias, peripheral compartment syndrome and limb compromise, renal failure, and sudden death.
Although the subsequent anesthetic course may appear benign, MMR may be associated with rhabdomyolysis and the aforementioned associated insults. The incidence may vary with the population, but MMR is abnormal. MMR signals a need for careful monitoring of cardiorespiratory and metabolic parameters, urine testing for myoglobin, blood testing for electrolytes, CK measurement, and, possibly, arterial blood gas measurement. MMR associated with MHC or a severe myopathic response may require withdrawal of triggering anesthetic agents together with aggressive critical care management. It may be necessary to abort surgery. Clinical MMR should be investigated whenever it is observed.
The Pregnant Patient Susceptible to Malignant Hyperthermia
Aside from the recommendation that pregnant patients who have MHS should have a trigger-free anesthetic, whether it be regional or general, no specific data exist on the risk to the fetus. In addition, there is no evidence regarding safe maternal anesthesia when the infant in utero has MHS but the mother does not. The topic of infant exposure to maternally administered dantrolene has been raised, but withholding dantrolene treatment for MHC during cesarean section or other maternal surgery has not been recommended. No dantrolene side effect other than uterine atony after cesarean section has been reported. Collected case reports and inferential reasoning provide our only source of guidance. Newborn MHC has been suspected but not definitively confirmed, although MH has been sporadically reported in infants from 7 days to 6 months old.
The parturient with MHS should be given appropriate regional analgesia when needed. She should have operative procedures under trigger-free anesthetic techniques. Dantrolene prophylaxis is not indicated, but dantrolene should not be withheld in acute MHC for fear of fetal compromise or maternal complications.
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