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Item: Video and Test Booklet and Pocket Card
Item code: InSvKit
Length: 26 minute
Description: Describes participant roles during a Malignant Hyperthermia emergency.
Suggestion: Review of MH in a classroom setting.

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Henry Rosenberg MD

Recommendations

1. Any MHS (MH-susceptible) patient who experiences sudden collapse in association with muscle rigidity should be immediately treated for MH. This includes immediate cooling measures, the drug Dantrolene, and the avoidance of the muscle relaxant Succinylcholine. More information is available on the MHAUS website. All healthcare providers including school nurses and coaches should be aware of these precautions for all MHS patients.

2. MHS patients or their relatives who have not experienced adverse effects of heat and exercise should not restrict their activity. They should carry identification as to their susceptibility to MH. Some experts recommend that coaches and school nurses should be advised of the possibility that the MHS individual may require immediate treatment (as described in #1) in the event of sudden collapse in association with muscle rigidity and hyperthermia.

3. MHS patients who have experienced adverse effects of heat or exercise should restrict their activity based on their own experience.

4. Patients who develop rhabdomyolysis requiring hospitalization after exercise or with heat stroke should be referred to a neuromuscular specialist for evaluation. Testing for MH susceptibility should be considered in the evaluation process.

Supporting Evidence

Literature review: All articles that discussed the association of heat/exercise and MH since 1990 were reviewed as contained in my files derived from literature review over many years.

Background: Although it is clear that some patients who experience heat and exercise related rhabdomyolysis and/or outright heat stroke are MH susceptible (MHS), it is not possible at present to prospectively identify those MH susceptibles who will develop signs of MH with exercise and/or heat exposure. A direct causal relationship has not been proven between adverse effects in MHS patients and exposure to heat and exercise, but there is supporting evidence to support an association.

Supporting evidence: Significant evidence exists that swine carrying (skeletal muscle ryanodine receptor gene) RYR1 mutations that are causal for MH develop signs of MH upon exposure to heat and with exercise or stress (Aberle et al, 1974). Similarly, genetically engineered mice that display one or more RYR1 mutations will develop signs of MH with heat exposure (Durham et al, 2008).

The evidence for the deleterious effects of heat and/or exercise in humans is based on multiple individual cases reports. In many cases, particularly prior to 2000, supporting evidence derives from muscle contracture testing (IVCT or CHCT) or where the patient derived from a family with MH (Ryan and Tedeschi, 1997).

For example, a French study of 45 subjects with exertional heat stroke evaluated MH susceptibility and other adverse effects in these subjects, using IVCTs performed at least 3 months after the exertional heat stroke episode (Figarella-Branger et al., 1993). This study revealed 11 MHS, 8MHE subjects and 26 MHN. In both groups, whatever the IVCT results, pathological findings were heterogeneous and revealed various changes: rhabdomyolysis, mitochondrial myopathy, denervation, type II atrophy, AMPase deficiency, non-specific findings or normal features.

In 2001, Tobin and colleagues reported a 12 -year old patient with a clinical history of MH who developed signs of MH after soccer practice and died shortly thereafter. He and his family were found to have an MH-related RYR1 mutation (Tobin et al., 2001).

Wappler and colleagues (2001) described 12 healthy young men who developed exercise-induced rhabdomyolysis. Ten were MH positive on contracture test and three manifested RYR1 mutations.

Muldoon’s group reported (in an abstract) studies of 15 men who developed exercise- induced rhabdomyolysis, 6 had positive CHCT and three displayed RYR1 causal mutations (Capacchione et al., 2009).

Davis et al (2002) reported on two patients with exercise- induced rhabdomyolysis who also displayed a positive contracture test and RYR1 mutations suspected to be causal. Both patients came from families with MH susceptibility in other members.

Groom et al (2011) reported on two cases of ‘awake’ MH. In one case a nine year old male patient experienced anesthesia induced MH related to ptosis surgery and then experienced multiple episodes of high fever and rigidity possibly related to environmental factors. The child died following one of the episodes at age nine. The other case was a six year old girl who died suddenly after experiencing high body temperature and rigidity. A previous episode had been corrected with cooling only. The mutation in the RYR1 gene, although novel, effected intracellular calcium flux similar to causal mutations.

Capacchione et al (2011) reported on a six year old boy who developed high body temperature and muscle rigidity after playing in a splash pool. He and his father had marked hyperlordosis. The father’s muscle biopsy was positive for MH and displayed changes of CCD. A novel RYR1 variant was detected in the propositus and the father and a sibling with hyperlordosis. The variant was different from the ones reported by Groom et al (2011) for the nine year old boy and the six year old girl and by Tobin et al (2001) for the 12 year old boy.

Capacchione and colleagues (2010) also reported on a 30 year old patient with exercise induced rhabdomyolysis, positive CHCT and mutations in the RYR1 gene, the DHPR (dihydropyridine receptor) gene and the calsequestrin1 (CSQ1) gene. The RYR1 variant was in a different locus from the previous cases mentioned above.

One study of five MH susceptible and five non-susceptibles in an exercise laboratory at room temperature, showed that with vigorous exercise MH subjects developed higher core temperature than non MH subjects (Campbell et al., 1983). In the early stages of exercise a higher lactate level was noted in the MH subjects. However, there were no other signs of MH.

There has not been a large scale prospective study of MH susceptibility either by contracture testing or genetic testing of patients with either heat stroke or heat related problems with or without exercise induced rhabdomyolysis.

Finally, the importance of body temperature in the triggering of MH was demonstrated most clearly in studies of MHS swine who did not develop MH when hypothermic despite anesthesia with MH trigger agents, but did when body temperature was raised to normal levels (Iaizzo, 1996).

Author Commentary

The evidence supporting a relationship between heat, exercise and MH susceptibility is mostly level 4 as per AHRQ criteria, i.e., observational studies and expert opinion. Nevertheless in my opinion, there is a convincing case for associating problems related to heat and exercise with MH susceptibility because high quality data supporting this contention has been derived from genetically engineered animal models of MH as well as from calcium flux changes in response to SR (sarcoplasmic reticulum) calcium releasing agents in cells transfected with mutations from patients who experienced awake MH.

Hence it is prudent to follow the recommendations described above with emphasis on the importance of cooling during such an episode.

References

Aberle ED, Merkel RA, Forrest JC, Alliston CW. Physiological responses of stress susceptible and stress resistant pigs to heat stress. Journal of Animal Science 1974; 38:954-959.

Campbell IT, Ellis FR, Evans RT, Mortimer MG. Studies of body temperatures, blood lactate, cortisol, and free fatty acid levels during exercise in human subjects susceptible to malignant hyperpyrexia.

Acta Anaesthesiol Scand. 1983 27(5):349-55.

Capacchione JF, Muldoon SM, Blokin A, Karajan J, Sambuughin N. The association between exertional rhabdomyolysis and malignant hyperthermia. American Society of Anesthesiologists Abstracts 2009; A854.

Capacchione JF, M.D. Michael Nickerson, M.D. Wendy Lavezzi, M.D. Barbara Brandom, M.D., Sheila Muldoon, M.D. An Awake MH-like Reaction and Death in a Six-Year-Old Boy. Medically Challenging Cases, American Society of Anesthesiologists Meeting, 2011.

Capacchione JF, Sambuughin N, Bina S, Mulligan LP, Lawson TD, Muldoon SM. Exertional rhabdomyolysis and malignant hyperthermia in a patient with ryanodine receptor type 1 gene, L-type calcium channel ?-1 subunit gene, and calsequestrin-1 gene polymorphisms. Anesthesiology 2010; 112: 239-244.

Capacchione J, Muldoon S. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg 2009; 109:1065–9.

Davis M, Brown R, Dickson A, Horton H, James D, Laing N, Marston R, Norgate M, Perlman D, Pollock N, Stowell K. Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Br J Anaesth 2002; 88:508-15.

Durham WJ. Aracena-Parks P. Long C. Rossi AE. Goonasekera SA. Boncompagni S. Galvan DL. Gilman CP. Baker MR. Shirokova N. Protasi F. Dirksen R. Hamilton SL. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knock in mice. Cell 2008; 133(1): 53-65.

Figarella-Branger D, Kozak-Ribbens G, Rodet L, Aubert M, Borsarelli J, Cozzone PJ, Pellissier JF. Pathological findings in 165 patients explored for malignant hyperthermia susceptibility. Neuromuscul Disord 1993 Sep-Nov; 3(5-6):553-6.

Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee H-S, Qiu X, Sambuughin N, Dirksen RT. Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology 2011 Nov; 115(5):938-945.

Iaizzo PA, Kehler CH, Carr RJ, Sessler DI, Belani KG. Prior hypothermia attenuates malignant hyperthermia in susceptible swine. Anesth Analg 1996; 82(4):803-9.

Ryan JF, Tedeschi LG. Sudden unexplained death in a patient with a family history of MH .J Clin Anesth 1997; 9:66-68.

Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA 2001; 286(2):168-9.

Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte Am Esch J. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001; 94:95–100.

Other references:

Gronert GA, Tobin JR, Muldoon S: Malignant hyperthermia – Human stress triggering. Biochimica et Biophysica Acta 2011; 1813:2191-2192.

MacLennan DH, Zvaritch E: Response to “Malignant Hyperthermia – human stress triggering” in reference to original article “Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum” http://dx.doi.org/10.1016/j.bbamcr.2010.11.009. Biochimica et Biophysica Acta 2011; 1813:2193-2194 (Recent comments on a review article concerning MH pointing out several instances of awake MH.)

Watson DB, Gray GW, Doucet JJ. Exercise rhabdomyolysis in military aircrew: two cases and a review of aeromedical disposition. Aviat Space Environ Med 2000; 71:1137-41. (One patient was shown to be MHS on contracture testing. )

On January 5, 2012, an MH episode was portrayed on the popular TV program Grey’s Anatomy.

In the episode, the young patient undergoing emergency surgery develops elevated levels of carbon dioxide, increased heart rate and elevated temperature. The anesthesiologist recognizes the signs and informs the team of the problem. One of the OR personnel is dispatched to obtain ice and the anesthesiologist whips out a vial of dantrolene, injects it and waits for the signs of MH to respond. Interestingly the patient’s sibling is undergoing surgery in an adjacent OR and the team is astute enough to warn the other surgical team that the patient might develop MH also and modify the anesthetic regimen. While the writers of Grey’s Anatomy got the basic elements of MH diagnosis and treatment correct, they oversimplified the critical nature of the situation and omitted many important elements. (Here is the link to the episode: http://abc.go.com/watch/greys-anatomy/SH559058.)

For starters, when treating an MH episode with dantrolene, multiple vials (any where from 9 to 20) of the drug need to be obtained and reconstituted with sterile bacteriostatic water for injection. Secondly, a variety of blood studies need to be performed to gauge the extent of the physiologic changes and to measure the response to treatment. Thirdly, the patient needs to be treated post event in a critical care unit and further doses of dantrolene need to be administered until the patient is out of danger. Usually 36 hours. However, most importantly, what was not really emphasized is that treatment of MH requires a coordinated team approach. Some members of the team need to obtain the cart containing dantrolene (the medication is not kept in the medication cart next to the anesthesia provider), and then at least one or two people need to work on reconstituting the drug and handing it to the anesthesia provider. At the same time other team members need to obtain blood specimens for analysis of acid base balance, electrolytes such as sodium and potassium, and coagulation studies. It was curious how the team just sat there waiting for the dantrolene to work; while in the actual situation, either the patient responds immediately to dantrolene, or if not additional drug needs to be administered. It would have been icing on the cake if the team had called the MH hotline. On the positive side the episode emphasized the critical role of the anesthesia provider in directing the treatment of the MH episode and the fact that MH could appear unexpectedly during surgery in an apparently healthy patient. It would have been nice to have the discussion of what happens once the syndrome is under control. The impression was from the program that once the episode is done, nothing further needs to be done.

Although, there was a gross oversimplification of MH, I applaud the team for recognizing that MH is a life threatening disorder that requires prompt diagnosis and treatment. If this episode alerts the public and health care providers to some of the essential elements of diagnosis and treatment of MH that is of benefit. I certainly could not expect a program on prime time to go into ryanodine receptor variants, DNA versus muscle biopsy testing, association with other disorders and reference to resources such as MHAUS to assist in diagnosis and management. After the program aired, I was contacted by someone who has a web site that posts questions and comments as to the authenticity of the medical condition depicted in such programs. There is a web site for everything!

Shortly after the Grey’s Anatomy episode the public was made aware of a fascinating study examining the effect of a medication known to enhance athletic performance on the response to MH triggered by heat exposure in genetically susceptible mice. (reference 1) As I have mentioned previously, investigators at a variety of very well known universities, such as University of Rochester, Baylor Medical School and Harvard Medical School have developed an animal model to study MH by incorporating a known DNA change in the ryanodine receptor into mice.

These mice will develop MH on exposure to anesthetic trigger agents, as well as high environmental heat. Male mice are more at risk than female mice for reasons not well understood. In the study that was published recently, the investigators demonstrated that the drug, AICAR, acts in these animals to block release of calcium into the cell. This is also the basic defect in Malignant Hyperthermia, but curiously the drug does not block anesthesia induced MH. (AICAR works in a complex manner to reduce muscle fatigue and increase muscle endurance.) The connection between heat stroke and malignant hyperthermia has been demonstrated in some patients as I have described in several of my previous blogs. In general though the treatment of heat stroke has been limited to symptomatic treatment, namely cooling the patient with ice or infusion of cold solution. Nevertheless the mortality from heat stroke is quite significant. AICAR represents a possible means to block or prevent heat stroke in those susceptible to this syndrome. The study shows clearly that at least one ryanodine receptor genetic change that predisposes to anesthesia induced MH also predisposes, at least in the animal model of MH, to heat induced MH.

The study also shows that drugs other than dantrolene may be efficacious in anesthesia induced MH as well. For example, perhaps if the investigators used a higher dose of the drug in their model of anesthesia induced MH it would have been effective in reversing the signs of MH. Perhaps in cases of MH related to other genetic changes, it might have also been of value. Obviously, much more work is needed to determine the utility of this drug in humans.

Other intriguing studies

The ryanodine receptor a calcium channel found in skeletal muscle (RYR-1) is known to be defective in most cases of MH. For a while investigators have shown that the channel is also located in other tissues, such as certain white blood cells and even in nerves. A recent study from U Mass and U of Toronto (ref 2) again using genetically engineered MH susceptible mice demonstrated that a mutation in the RYR-1 gene affects the function of certain nerve cells (neurons) in the brain. The effect on calcium release in the neurons was measured and was found to be identical to the change in calcium movements in skeletal muscle cells in MH. Hence the ryanodine receptor in these brain neurons is important for the normal function of the neurons and therefore may affect brain cell function. The overall effect on the body depends on the role of the neuron and is hard to measure in animals. This is the first demonstration that I know of, that mutations associated with MH may have an effect on nerve cells.

Speaking of neurons yet another investigative group at the U of Texas Southwestern (ref 3) has demonstrated abnormal calcium movements in neurons in the brain of genetically engineered mice that express the signs of Huntington’s disease. This fatal inherited neurodegenerative disorder comes on in early middle age in humans and is associated with uncontrolled and disabling muscle movement. The investigators demonstrated that dantrolene administration when administered to the diseased mice protects the neurons from ongoing damage and improves performance of complex tasks involving muscle coordination. Yet to be demonstrated though are specific ryanodine mutations, but all signs point to a defect in the ryanodine receptor as a key factor in some forms of Huntington’s disease.

So, it seems that scientists are beginning to understand how important the ryanodine receptor is to the proper function of many organs in the body, not just skeletal and cardiac muscle. The implication is that drugs such as dantrolene and AICAR may over time prove to reverse or compensate for abnormal cell function in a variety of organ systems just as it does in skeletal muscle. Naturally there is a long road to follow between the demonstration of effect in animals and or isolated cells to studies in humans, but there are now some key insights that may underpin and explain how dantrolene may turn out to be a very effective therapeutic agent in a variety of disorders and drug reactions not involving muscle tissue directly.

Much more to follow.

References:

1.Lanner JT, Georgiou DK, Dagnino-Acosta A,………Dirksen RT and Hamilton SL. AICAR prevents heat-induced sudden death in RYR-1 mutant mice independent of AMPK activation. Nature Medicine published on line 8January 2012;doi:10.1038/nm.2598

2. De Crescenzo V, Fogarty KE, Lefkowitz,JI, ….WalshJV. Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):610-5. Epub 2011 Dec 27.www.pnas.org/cgi/doi/10.1073/pnas.1115111108.

3. Chen X, Wu J, Lvovskaya S, Herndon E, Supnet C, Bezprozvanny I.

Dantrolene is neuroprotective in Huntington’s disease transgenic mouse model.

Mol Neurodegener. 2011 Nov 25;6:81.

http://www.hdsa.org/research/news/dantrolene.html

The Malignant Hyperthermia Association of the United States (MHAUS), a non-profit organization, seeks part-time development officer to analyze and improve current fund raising activities, develop new sources of donations and support from individuals, corporations and foundations. He/she will advise the President, Executive Director and Board on opportunities for new fundraising efforts and report on program development and implementation. Read more about this employment opportunity.

Pill Study

Scientists have stumbled upon a drug that may prevent heat stroke for people prone to the deadly condition. Ironically, it’s the same drug flaunted three years ago as the “couch potato pill” for its ability to build muscle and increase endurance in mice that never break a sweat.

The study appeared Sunday in the journal Nature Medicine.

The Drug AICAR

As with the 2008 couch potato study, the researchers have only tested the drug, abbreviated as AICAR, in mice. However, the drug was 100-percent effective in preventing death in these mice genetically engineered to be susceptible to heat stroke. Thus, the finding has implications for anyone exposed to heat or with abnormal heat sensitivity, the researchers said.

Heat stroke is caused by prolonged exposure to temperatures over 100 degrees Fahrenheit (37.8 degrees Celsius), and it is common among the elderly and athletes. Many U.S. soldiers in Iraq and Afghanistan suffered from heat stroke brought on by high temperatures and heavy gear.

Some people have a genetic disorder called malignant hyperthermia that places them at high risk for heat stroke, even without the heat. The disorder is associated with a mutation in the RYR1 gene, which causes uncontrolled muscle contractions and increases in body temperature, typically induced by certain drugs such as general anesthesia.

Researchers led by Susan Hamilton at Baylor College of Medicine in Houston studied the effects of the drug AICAR on mice with this RYR1 mutation. When these mice exercise in a hot room, they suffer the hallmarks of malignant hyperthermia and die.

Hamilton’s group was inspired by the 2008 AICAR study, published in the journal Cell, which demonstrated how AICAR slowed muscle fatigue and increased muscle endurance. They wondered whether AICAR could control the muscle contractions typical of the RYR1 mutation, but in this case triggered by heat not anesthesia.

Sure enough, AICAR prevented an otherwise sure death in all the mice exposed to heat, even those mice given AICAR just 10 minutes before exercising.

While RYR1 mutations only account for a small percentage of heat stroke cases in the general human population, AICAR might offer broad protection, said Robert Dirksen, a study author at the University of Rochester Medical Center in Rochester, N.Y.

“We think the fundamental process that occurs during heat stroke in individuals with RYR1 mutations is likely to be similar to what happens … by exposure to even greater temperatures or a longer time” in people without the mutation, Dirksen said. “Our study takes an important first step towards developing a new drug therapy that may be part of the standard treatment regimen for heat stroke.”

Although promising, much more research is needed on AICAR and heat stroke, the scientists said, noting that the “couch potato” pill for humans has not come to fruition.

Read more click here.

Just a note that both Susan Hamilton and Robert Dirksen presented at the MHAUS Scientific Conference in 2010.

Recommendations (4 alternatives):

1. Flush and prepare workstation according to manufacturer’s recommendations or published studies; this may take 10 to >90 minutes. Most studies also physically disconnect vaporizers from the workstation; use a new, disposable breathing circuit; and replace the carbon dioxide absorbent. During the case, fresh gas flow must be kept at 10 liters per minute to avoid “rebound phenomenon” (increased release of residual volatile anesthetic agent when fresh gas flow is reduced after a set period of flushing).

2. Use commercially available charcoal filters that have been shown to remove trace levels of volatile anesthetic agents within 10 minutes of application, without additional preparation. These filters may have to be regularly replaced during the anesthetic; check manufacturer’s recommendations.

3. If available, use a dedicated “vapor free” machine for MH-susceptible patients. The machine must be regularly maintained and safety-checked.

4. If appropriate to the institution, use an ICU ventilator that has never been exposed to volatile anesthetic agents.

Supporting Evidence:

Search Strategy: We searched Medline (1948 to May 2011) for the keywords “malignant hyperthermia”, “anesthesia”, and “equipment”. We reviewed those abstracts for pertinent articles, and then hand searched those articles’ references for additional studies. We also searched the ASA Abstracts website for additional studies from 2006 to 2010. Finally, we reviewed data provided at the Dynasthetics website not found by earlier search (www.dynasthetics.com).

Background: MH is an inherited pharmacogenetic disorder that is triggered by commonly used volatile anesthetic agents (1). These agents should be avoided when providing general anesthesia to MH-susceptible patients. There is no known upper safe limit of exposure to these agents, and anesthesia workstations are “contaminated” by them, so efforts must be made to reduce patient exposure to a minimum. MH susceptible swine did not develop MH when exposed to halothane 5 ppm concentration (2). This trace level has been used as an arbitrary “safe limit” to study preparation of workstations and the occupational exposure of MH susceptible healthcare workers.

Key Points: The earliest solution to this problem was the use of a “vapor free” anesthesia circuit, either a dedicated anesthesia machine that had never been exposed to volatile anesthetic agents, or a disposable non-rebreathing circuit. However, maintaining a dedicated machine for the rare MH patient is impractical in most centers, because of cost and obsolescence (lack of familiarity, availability of spare parts).

Various preparation methods and flushing cycles have been used to wash volatile agents out of absorbent parts of the anesthesia machine that cannot be replaced. These machines have evolved into more sophisticated “workstations” that take longer to flush because more absorbent materials are used in their construction. Different manufacturers’ workstations require specific preparation, especially flush times, so a generic set of instructions on preparation cannot be provided (3). A common problem with flushing a contaminated anesthesia workstation is the “rebound phenomenon” (3), where residual anesthetic agents diffuse out of absorbent materials when the fresh gas flow used for flushing is reduced to “usual” clinical settings (e.g., from 10 to 2 liters per minute).

The idea of charcoal filters to remove volatile anesthetic agents is not new, but only recently has a commercially available product been tested to determine how quickly it could achieve a result equivalent to established preparation and flushing methods. The Vapor Clean™ charcoal filter system reduces trace volatile anesthetic concentrations to < 5 ppm in < 2 minutes, and keeps them < 5 ppm for up to 60 minutes, when the system should be replaced (4).

Author Commentary:

This is Level 5 evidence (bench research, expert opinion) following the Oxford Centre for Evidence Based Medicine’s (www.cebm.net) levels of evidence.

The threshold of 5 ppm is based on a 1996 study of MH susceptible swine (2), the most common in vivo model for human MH. However, this abstract was never published in full and the study has not been replicated. The upper safe limit of trace anesthetic agents in MH susceptible humans is actually unknown. Some cited bench studies measured in vitro trace gas levels using the Miran™ gas analyzer, which was designed for measurement of ambient air, not closed circuit bench experiments (4,5). Significant differences among brands and models of workstations mean that each model must be specifically prepared; adequate preparation is hypothetical for any workstation not reported in the literature or by its manufacturer.

Discontinuing the triggering anesthetic agent and increasing fresh gas flow with 100% oxygen is part of the treatment algorithm for MH (6). This recommendation is based on expert opinion, but anecdotally there are MH cases that resolved with only these measures. No study answers the question if the above mentioned machine alterations, or the addition of charcoal filters, would improve patient outcome during an acute MH episode. This question could be answered using the swine model of MH, but the result is unlikely to change current clinical practice.

References:

1. Hopkins PM: Malignant hyperthermia: Pharmacology of triggering. Br J Anaesth 2011; 107:1-9

2. Maccani RM, Wedel DJ, Kor TM, Joyner MJ, Johnson ME, Hall BA: The effect of trace halothane exposure on triggering malignant hyperthermia in susceptible swine. Anesth Analg 1996; 82:S287

3. Kim TW, Nemergut ME: Preparation of modern anesthesia workstations for malignant hyperthermia susceptible patients: A review of past and present practice. Anesthesiology 2011; 114:205-12

4. Birgenheier N, Stoker R, Westenskow D, Orr J: Activated charcoal effectively removes inhaled anesthetics from modern anesthesia machines. Anesth Analg 2011; 112:1363-70

5. Targ AG, Yasuda N, Eger EI: Solubility of I-653, sevoflurane, isoflurane, and halothane in plastics and rubber composing a conventional anesthetic circuit. Anesth Analg 1989; 69:218-25

6. 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 2010; 110:498-507

Recommendation:

MHAUS recommends that all patients undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during human malignant hyperthermia (MH) events.

Supporting Evidence:

Search Strategy: We searched the Medline (1948 to October 2011) for the keywords “malignant hyperthermia signs”, “malignant hyperthermia complications”, “malignant hyperthermia death”, “temperature abnormalities”, and “liquid crystal temperature”. We reviewed those abstracts for pertinent articles, and then hand searched those articles’ references for additional studies.

Background: MH is an inherited pharmacogenetic disorder that is usually triggered by commonly used volatile anesthetic agents and/or succinylcholine. The prevalence of MH has been estimated at approximately 1 per 100,000 New York state surgical inpatients and 0.3 per 100,000 New York and New Jersey ambulatory surgery patients (1,2). Although MH mortality rates are low, they are not zero (3) and MH has a 35% morbidity rate (4).

Temperature monitoring is important for the detection of MH because temperature abnormalities may be an early sign of an MH event. Temperature abnormalities were one of the first signs in 8% and the only initial sign in 4% of 255 MH patients. Temperature abnormalities were the first to third MH sign in 64% of patients with a median temperature maximum of 39.1ºC. (4)

Failure to detect and treat temperature abnormalities increases the likelihood of MH complications. Multivariable analysis demonstrated that the likelihood of MH complications increased 1.6 times for every 30 minute increase in time between the first sign and the first dantrolene dose and 2.9 times for every 2ºC increase in maximum temperature. (4)

Failure to detect and treat temperature abnormalities may increase the likelihood of cardiac arrest and death. For the 13 patients experiencing disseminated intravascular coagulation (DIC) as an MH complication, the median maximum temperature of 40.3ºC was higher than the median maximum temperature of 39.0ºC of those without DIC. (4) DIC was associated with a 50-fold increased likelihood of cardiac arrest and an 89-fold likelihood of death.(5)

Liquid crystal temperature probes do not always trend with core temperature in MH and, therefore, should not be employed for the detection of MH. Skin liquid crystal temperature indicators were inaccurate in 10 MH cases. (4) Forehead skin temperatures have previously been shown to not correlate with core temperature during porcine MH. (6)

Core temperature perturbations during the first 30 minutes are difficult to interpret, therefore the recommendation is made for anesthetics longer than 30 minutes. (7)

Author Commentary:

This is primarily Levels 3 and 4 evidence following the Oxford Center for Evidence Based Medicine’s (www.cebm.net) levels of evidence. The infrequent and unpredictable occurrence of MH combined with the potential morbidity and mortality of an experimentally triggered MH event makes it unlikely that these issues will be able to be studied in a fashion that would produce higher levels of evidence.

References:

1. Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth Analg 2009;109:1162-6.

2. Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in ambulatory surgery patients. American Society of Anesthesiologists Annual Meeting, 2009:A1521. Available at: http://www.asaabstracts.com/strands/asaabstracts/searchArticle.htm. Accessed March 29, 2011.

3. Li G, Warner M, Lang BH, Huang L, Sun LS. Epidemiology of anesthesia-related mortality in the United States, 1999-2005. Anesthesiology 2009;110:759-65.

4. 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 2010;110:498-507.

5. Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Cardiac arrests and deaths associated with malignant hyperthermia in North America from 1987 to 2006: a report from The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesthesiology 2008; 108:603-11.

6. Iaizzo PA, Kehler CH, Zink RS, Belani KG, Sessler DI. Thermal response in acute porcine malignant hyperthermia. Anesth Analg 1996;82:782-9.

7. Sessler DI. Thermal monitoring and perioperative thermoregulation. Anesthesiology 2008; 109;318-38

Click here to learn more about MHAUS Recommendations.