Malignant hyperthermia (MH), discovered in 1960, became one of the anesthesiologist’s “worst nightmares” because it was so often fatal and only a very early diagnosis and discontinuation of trigger agents provided effective therapy. When we first started diagnostic testing of patients in 1976 at the University of Texas Medical Branch (UTMB), Galveston, there was considerable anxiety over having these individuals undergo anesthesia for a muscle biopsy. Today patients are “routinely” anesthetized for MH diagnostic muscle biopsies, and there is little to no anxiety involved. This level of comfort about MH has derived from excellent research efforts that have 1) identified the cause of MH, 2) defined the clinical diagnostic features, and 3) discovered an efficacious therapeutic agent. All potent inhaled anesthetics and succinylcholine are triggers and MH is still occurring, but, fortunately, deaths from this unexpected, catastrophic syndrome are (and should be) very uncommon today. Vigilance, an important element in the practice of anesthesia medicine, is the key to preventing mortality and morbidity from MH. To help maintain the levels of vigilance necessary, we review the key features for appropriate management of MH.

Clinical Diagnosis

There is no “classical” clinical presentation of the MH syndrome as it may present in either benign or malignant forms. Previous, uneventful general anesthesia in MH-susceptible individuals is not uncommon. Any clinician analyzing a peri-anesthetic event associated with either masseter muscle rigidity, signs of hypermetabolism, and/or skeletal muscle damage (i.e., rhabdomyolysis), not explained by other causes, must entertain MH as a diagnostic possibility. A clinical grading scale, constructed to assist in evaluation of peri-anesthetic events leading to a suspicion of MH for research purposes,1 may be helpful. Quantitative values based on the occurrence of signs such as inappropriate tachycardia, tachypnea, hypercapnea/ hypercarbia, hyperkalemia, metabolic acidosis, and so forth led to probability estimates for MH susceptibility. Consultation with an MH Hotline (800-644-9737) expert when these MH suspicious events occur is highly recommended. The MH Hotline received 734 crisis calls (2040 total calls) during the year 2000, which were handled by qualified volunteer anesthesiologists.

Treatment of MH

A fulminant episode of MH demands immediate action to prevent mortality and morbidity. Administration of triggering agents should be immediately stopped and intravenous dantrolene, 2.5 mg/kg, should be rapidly administered. A rapidly rising temperature should be controlled by aggressive cooling and acidosis treated by administration of bicarbonate and a minute ventilation adequate to maintain a normal end-tidal CO2. A hypermetabolic crisis demands higher FIO2 to compensate for the increased oxygen consumption. Arterial blood gas determinations will facilitate these management strategies for MH. Diuresis, to protect against renal failure secondary to rhabdomyolysis, will be facilitated by mannitol contained in the dantrolene formulation, and intravenous fluids should be administered. Arrhythmias can be managed by commonly used agents except for calcium channel blockers which are contraindicated in the presence of dantrolene. A 30% incidence of recrudescence in fulminant MH cases strongly encourages close patient monitoring for 24 hours after the initial event. Serum levels of CK are likely to be affected by dantrolene therapy but can be expected to peak within 12 to 24 hours and then slowly decline.

MH Patient/Family Management Responsibilities

When an anesthesia-related event produces a possible or certain diagnosis of MH, what is the appropriate response? Since anesthesia providers should be the most informed about MH, they become the primary responsible patient manager for this disease. The following actions are highly recommended for appropriate post-treatment management of an MH episode:

1. Inform the patient about MH and of his or her possible predisposition. Emphasize the inherited aspect and the need to inform close relatives of their potential risk.
2. Strongly encourage the use of medic alert identifiers for MH and reinforce the importance of informing all health care providers of the MH history. Providing the patient with a written summary of the episode, which can be shown to other health care providers, is helpful.
3. Direct the patient to the Malignant Hyperthermia Association of the US (MHAUS) for educational materials and support. (Phone 607-674-7901 or e-mail www.mhaus.org.)
4. Discuss diagnostic testing for MH by contracture testing of surgically biopsied skeletal muscle. Testing centers locations can be found on the MHAUS web site.

Since not everyone considers the muscle test necessary, some pros and cons are considered:

Pros: a) Diagnostic confirmation of MH susceptibility. After 30 years of MH diagnostic testing in pigs, dogs, and humans, I have learned that the clinical data are not always reliable for predicting MH. Negative muscle contracture results have been found in high index clinical episodes, but more common is the finding of very positive muscle contracture results in patients with benign clinical signs. A significant value in MH testing is a negative finding in an apparent proband. This relieves all relatives of an uncertain, concerning diagnosis; b) Identification of predisposed families will reduce the possibility of adverse MH events in the future; and c) Identification and confirmation of MH in families provides new material for genetic screening and facilitates discovery of all mutations predisposing to MH. Once this is accomplished, simple genetic screening will be possible.

Cons: Muscle contracture testing is an invasive, expensive procedure that may have limited benefit to the proband. The proband can simply be assumed positive and be provided with MH non-trigger anesthesia when necessary. The negative impact of this approach is the effect on close relatives who must also be assumed positive until proven otherwise. It is not uncommon for such relatives to be refused elective surgery until testing is completed.

Genetics and the Future Management of MH

In 1991 Dr. David MacLennan’s lab discovered that a mutation in the 614th of 5021 amino acids comprising the ryanodine receptor (RYR1) calcium release channel protein linked to MH in pigs. High expectations that this would lead to resolution of the genetics for MH in humans were soon thwarted. Not only was the same mutation found in humans, but over 40 different mutations in RYR1 have been discovered, and these account for MH in less than 50% of predisposed families.² Two unrelated MH families have mutations in the voltage-gated dihydropyridine-sensitive calcium channel that link to MH,³ and several other proteins involved in skeletal muscle calcium regulation could be candidate causal proteins. The exciting aspect for future genetic screening of MH is the rapid change in technologies that will shorten the time for resolution of MH genetic screening. The RYR1 gene is enormous, and past technologies permitted only searching small pieces of the gene at a time. Current technology provides a method for screening the entire gene in a rapid, simple manner and will also speed up the search for MH-linking mutations in other genes. Future technological changes in gene screening are expected to produce a means for rapid, inexpensive screening of all patients undergoing anesthesia to identify those with a genetic predisposition to MH and drastically reduce, if not eliminate, the occurrence of this life-threatening disorder. In the meantime, vigilance and appropriate response will remain the key to reducing morbidity and mortality from MH.

Dr. Nelson is a Professor of Anesthesiology at the Wake Forest University School of Medicine, Winston-Salem, North Carolina.

References

1. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771-9.
2. Sambuughin N, Sei Y, Gallagher, et al. North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology 2001;95:594-9.
3. Jurkat-Rott K, McCarth T, Lehman-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000;23:4-17