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Running head: LITERATURE REVIEW OF MALIGNANT HYPERTHERMIA 1

Literature Review of Malignant Hyperthermia

Mark Keskes, Nathan Buchinger, Julie Ivey, Elizabeth Berkemeier, & Caroline Haugen

Ferris State University

LITERATURE REVIEW OF MALIGNANT HYPERTHERMIA 2

Abstract

This paper explores Malignant Hyperthermia (MH). MH is a rare, inherited muscle condition

triggered by anesthetics utilized during surgery and intubation. When left untreated, this

condition causes a rapid increase in body temperature, muscle rigidity, tachycardia, and other

symptoms that can be life-threatening. Specifically, this article details what current literature

reveals about MH and MH susceptibility when patients are exposed to potentially reactive

agents. Potentially reactive agents for MH include the anesthetic gases halothane, desflurane,

isoflurane, and sevoflurane, and the depolarizing muscle relaxant, succinylcholine. Four articles

related to MH are reviewed and critically appraised in the literature review portion of this report.

The information from the literature review is applied and incorporated into the nursing

profession. Lastly, recommendations for future research regarding MH are discussed.

Keywords: malignant hyperthermia, susceptibility, ryanodine receptor, inhaled

anesthetics, succinylcholine, halothane, desflurane, sevoflurane, isoflurane, enflurane,

dantrolene


Literature Review of Malignant Hyperthermia

Patients are intubated to protect their airways in many healthcare settings daily. EMS

and flight crews in the pre-hospital setting, the operating room, ER, recovery, and floors where

patients code or deteriorate in condition, are places where intubation occurs. Often, to be able to

do this safely, and to manage patients throughout procedures, medications and anesthetics are

used. Unfortunately, some of the medications that are used can trigger a potentially fatal

reaction called Malignant Hyperthermia (MH). Because there are so many nursing areas that

have exposure to this rare phenomenon, it leads us to our research question of, “What does the

literature reveal about the risk for Malignant Hyperthermia when intubated with a potentially

reactive agent?”

“Malignant hyperthermia is a pharmacogenetic disorder of skeletal muscle that presents

as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane,

desflurane, and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to

stresses such as vigorous exercise and heat” (Rosenberg, Davis, James, Pollock, & Stowell,

2007, p. 21). It is recognized by the symptoms of a rapidly increasing temperature greater than

38.8C, sinus tachycardia, ventricular tachycardia, or ventricular fibrillation, both respiratory

acidosis, (end-tidal CO2>55mmHg; PaCO2>60mmHg) and metabolic acidosis (pH<7.25), muscle

rigidity, and elevated creatine kinase, after exposure to one of the mentioned agents (Rosenberg,

Davis, James, Pollock, & Stowell, 2007).

A search was conducted with the PICO question of, “Are patients who are intubated

using succinylcholine, desflurane, isoflurane, halothane or sevoflurane at increased risk for

Malignant Hyperthermia compared with patients who are intubated using a non-reactive agent

during their intubation?” The PubMed database was searched using “malignant, hyperthermia,


trigger,” and the NIH Library was searched using “malignant hyperthermia, susceptibility, non,

volatile,” with both searches yielding multiple results. The four most applicable articles were

chosen from the extensive list of search results, and explored in detail. The following paragraphs

will discuss and critique the articles that were chosen.

The first article reviewed is from a 2011 edition of the scholarly journal, Anesthesia &

Analgesia. The article is a summary of the 2010 scientific conference sponsored by the

Malignant Hyperthermia Association of the United States (MHAUS). The article details a wide

range of topics covered during the conference including the pathophysiology of MH, genetic

testing for MH susceptibility, MH epidemiology, the future of practice in MH, educational

platforms, and MH research (Hirshey Dirksen et al., 2011).

Hirshey Dirksen et al. (2011) state that susceptibility to MH is transmitted through

autosomal dominant means. “The skeletal muscle ryanodine receptor (RyR1) is the Ca2+ release

channel within the sarcoplasmic reticulum (SR) membrane whose major known function is

supplying the myoplasmic Ca2+ for contraction” (Hirshey Dirksen et al., 2011, p. 3). The article

states that current research indicates that the gene for RyR1 is the primary site for mutations

which cause MH susceptibility (Hirshey Dirksen et al., 2011). The article states it is likely that

RyR1 mutations lower the threshold that volatile anesthetics (such as succinylcholine,

desflurane, isoflurane, halothane or sevoflurane) would activate Ca2+ leak, and cause an episode

of MH. The authors agree that intracellular Ca2+ homeostasis is a focus for research to better

understand MH pathophysiology. In fact, the article discusses the drug Dantrolene, the only

medication used to treat an MH crisis. Although the drug has been used for over forty years, its

specific mechanism of action is unknown. The authors identify Dantrolene research as an


important area of study in understanding MH pathophysiology and susceptibility (Hirshey

Dirksen et al., 2011).

Although the RyR1 link has been identified, Hirshey Dirksen et al. (2011) mention the

difficulty in identifying MH susceptibility through genetic testing. The authors report that 30

DNA variations have been proven causal for MH. However, only 30% of MH patients have one

of the identified 30 variants (Hirshey Dirksen et al., 2011). The article states that DNA testing,

along with the caffeine halothane contracture test (CHCT) help to identify MH susceptible

individuals. In addition, a family history should be obtained, and a clinical grading scale used to

score the clinical symptoms of MH (Hirshey Dirksen et al., 2011).

Hirshey Dirksen et al. (2011) expand on the epidemiology of MH in their article. The

authors state that Brady et al. (2009) have estimated MH prevalence to be 1:100,000 from 2001-

2005 (Hirshey Dirksen et al., 2011). Mortality rates for MH are mentioned as being low in the

article, with the rate of complications much higher. The authors discuss a study by Larach et al.

(2012) on a group of MH patients between 1987 and 2006. The study reports MH patients as

being predominantly male and young. Also, the Larach et al. (2012) study states that 75% of

patients having an MH episode had undergone general anesthesia at least one time prior to the

MH event (Hirshey Dirksen et al, 2011). The article also discusses the choice of anesthesia for

individuals with myopathies, enzyme deficiencies, and myotonias. Hirshey Dirksen et al. (2011)

state, “Succinylcholine should be avoided because it causes depolarization of the muscle and

some degree of increased resting tension in the process of inducing neuromuscular block” (p.

11). The article reports that succinylcholine leads to muscle injury in healthy individuals and

significant rhabdomyolysis in those with muscle disorders. According to the authors, this is a

less common occurrence when inhaled anesthetics are used (Hirshey Dirksen et al., 2011).


The Hirshey Dirksen (2011) article is a solid meta-analysis of the current research

regarding MH. The authors are educated and established medical doctors. The article is concise,

and written in understandable language. The abstract is clear, and the conclusion indicates the

purpose and direction of the research. One can conclude from the article that volatile inhaled

anesthetics such as desflurane, isoflurane, halothane, or sevoflurane, as well as succinylcholine,

should be avoided for MH susceptible individuals. The work by Hirshey Dirksen et al. (2011) is

not entirely applicable to the PICO statement presented in this paper. However, the overall

summary of current MH research provided in the article is extremely valuable, and adds to the

relevance as the paper progresses.

Corroborating what Hirshey Dirksen et al. (2011) found, evidence of the link between

MH susceptibility and RyR1 mutations is also shown in the second article. “Malignant

Hyperthermia” is a non-experimental, quantitative meta-analysis of research presented in a well-

respected rare disease journal. Dr. Rosenberg, the first author, is not only a co-author to a

second article in our review but is also the president of the Malignant Hyperthermia Association

of the United States (MHAUS). MHAUS is an advocacy and resource group for MH and assists

with the funding of ongoing research. In this 2007 article, only 90 mutations of the ryanodine

receptor (RyR1) gene at chromosome 19q13.1 had been found with only 25 of those considered

to be causal for MH (Rosenberg, Davis, James, Pollock, & Stowell, 2007). Although the

susceptibility was thought to be as rare as 1:50,000 to 100,000 people, in French descendants in

the Quebec region of Canada, it has been studied to be as prevalent as 1:3,000 at risk

(Rosenberg, Davis, James, Pollock, & Stowell, 2007). Males were noted to have a 2:1

prevalence, and all ethnicities were noted to have the mutations present (Rosenberg, Davis,

James, Pollock, & Stowell, 2007). At the time of publication of the article, mortality from MH


had dropped from 80% to less than 5% from the increases in both scientific understanding and

increased awareness and education in the medical community over the previous thirty years

(Rosenberg, Davis, James, Pollock, & Stowell, 2007).

Many different types of genetic testing were being evaluated, with no one test being

100% accurate in predicting susceptibility (Rosenberg, Davis, James, Pollock, & Stowell, 2007).

Diagnostic testing using caffeine and halothane remained the “gold standard” of muscle

contracture testing (Rosenberg, Davis, James, Pollock, & Stowell, 2007). Even with this

screening at the time of the writing, the predictive value of the genetic testing was thought to be

50-80% accurate (Rosenberg, Davis, James, Pollock, & Stowell, 2007). The response of

symptoms to treatment, and considering alternative diagnoses of sepsis, thyroid storm,

pheochromocytoma, iatrogenic overheating, cocaine overdose, ionic contrast injection to spinal

fluid, and neuroleptic malignant syndrome would be things to consider (Rosenberg, Davis,

James, Pollock, & Stowell, 2007). Prevention is optimized by a thorough pre-surgical history

and physical by the anesthesia provider, and adjustment of the anesthesia plan to use regional

and local interventions rather than volatile anesthetics if the history or screening reveals possible

susceptibility (Rosenberg, Davis, James, Pollock, & Stowell, 2007).

The third article reviewed is a literature review of articles focused on inhalation agents,

succinylcholine, and other non-reactive drugs that have been reported to affect MH susceptible

patients. Hopkins (2011) highlights several interesting findings from the studies he reviews.

First, he discusses how all inhalation agents have been shown to cause MH, though in different

times of onset, and reportedly at different doses (Hopkins, 2011). Succinylcholine has not been

shown to cause true MH when administered alone, states Hopkins (2011), but greatly increases


occurrences and severity of MH when given with any inhaled anesthetic. It also has been shown

to shorten the time of onset after administration with other anesthetics (Hopkins, 2011).

Next, the author reviews several articles claiming to show evidence of heightened

sensitivities to, as well as negative side effects from, other non-anesthetic drugs (Hopkins, 2011).

These include statins, tetracaine, and even ondansetron. He briefly shows how these studies do

not adequately support their claims and alternative explanations are given for the side effects

they report. He dismisses the claims that MH susceptible patients are to avoid these drugs

(Hopkins, 2011).

The report also briefly discusses newly-found evidence of how inhalation agents work on

MH susceptible patients on the cellular level. Patients with a genetic mutation of the RyR1

protein have specific cellular reactions to each inhalation agent used for anesthesia (Hopkins,

2011). It has been found that these drugs cause an inhibitory effect on magnesium ions and their

transport in and out of skeletal muscles cells (Hopkins, 2011). Calcium, a major ion involved in

muscle contraction, is also greatly affected since intracellular calcium is rapidly depleted in MH,

and a rapid influx of calcium occurs. This is cause for prolonged muscle rigidity and

contractions found in MH presentation (Hopkins, 2011).

The Hopkins (2011) article does a great job of addressing some aspects of the

pharmacology involved in MH triggering. It is a quantitative, non-experimental meta-analysis of

other recent studies on MH issues. The abstract and hypothesis are clear and concise.

Illustrations and tables are clear and well described. The author is fair in his appraisal of other

articles. The conclusion is comprehensive, yet direct, and describes the main points covered in

the review.


The fourth article reviewed is from a 2011 scholarly journal, Minerva Anestesiologica.

The article is a summary of a research experiment to examine the potency of sevoflurane

compared to the “gold standard” for diagnostic testing, halothane. “Halothane seems to be the

ideal substance for diagnostic MH testing” (Metterlein, Hartung, Schuster, Roewer, & Anetseder,

2011), since it quickly creates a muscle contracture. Two different diagnostic tests have been

developed to determine susceptibility to MH in patients by the contracture of muscle bundles.

The first test is from Europe. This test uses incremental concentrations of halothane in-vitro to

induce a contracture in the muscle, and is called the in-vitro contracture test (IVCT). The second

test is from North America and uses a rapid exposure to halothane and caffeine to produce a

contracture, and is called the caffeine halothane contracture test ([CHCT]; Metterlein, Hartung,

Schuster, Roewer, & Anetseder, 2011). “According to the North American test protocol, the

pathologic reaction to one of these two substances is sufficient to diagnose MHS [susceptibility]”

(Metterlein, Hartung, Schuster, Roewer, & Anetseder, 2011).

Metterlein, Hartung, Schuster, Roewer, and Anetseder (2011) examine skeletal muscle

bundles from thirty patients with a family history of MH. The muscle was excised, and dissected

into single bundles and put in three groups MH susceptible, MH non-susceptible (MHN), and

MH equivocal to halothane (MHEh), meaning the muscle bundle is only susceptible to halothane

(Metterlein, Hartung, Schuster, Roewer, & Anetseder, 2011). “Volatile anesthetics and

succinylcholine trigger an abnormal increase of intracellular calcium levels via a mutated

sarcoplasmic calcium channel” (Metterlein, Hartung, Schuster, Roewer, & Anetseder, 2011, p.

768). The two tests were utilized, both IVCT and CHCT. Sevoflurane was then used in each

test instead of halothane to determine a difference in the drugs and muscle contracture.

Sevoflurane given in incremental concentrations was concluded as having no difference in


muscle contractures between the groups (Metterlein, Hartung, Schuster, Roewer, & Anetseder,

2011). In the next test, a rapid exposure to sevoflurane was applied and strong contractures

occurred to MH susceptible group compared to MHN group (Metterlein, Hartung, Schuster,

Roewer, & Anetseder, 2011). No contractures to MHEh group occurred. “All volatile

anesthetics are potent MH triggers. However, the specific potency to clinically trigger MH

varies with the substance used” (Metterlein, Hartung, Schuster, Roewer, & Anetseder, 2011, p.

770). Sevoflurane does not produce a significant muscle contraction when given in increments

compared to halothane (Metterlein, Hartung, Schuster, Roewer, & Anetseder, 2011). Metterlein,

Hartung, Schuster, Roewer, and Anetseder (2011) state that if susceptibility to MH is known in a

patient beforehand, these trigger substances can be avoided, and safe anesthesia can be

performed.

The Metterlein, Hartung, Schuster, Roewer, and Anetseder (2011) article is a strong

research experiment regarding the current knowledge of MH, and standard tests used to diagnose

MH. The abstract gives a concise description of the research study with the methods, results,

and conclusion. The article clearly states the aim for the study, as well as the hypothesis. All

technical terms are clearly defined and summarized. The content is easy to read and understand,

and the conclusion describes the main points of the study. After reading the article, findings

conclude that patients who are susceptible to MH should avoid volatile anesthetics and

succinylcholine since they are an increased risk of developing MH when exposed. The work of

Metterlein, Hartung, Schuster, Roewer, and Anetseder (2011) is extremely important in

understanding triggers for MH, even though the PICO statement is not answered completely.


Summary

Researchers agree that the causation of MH is a genetic mutation that is not yet fully

understood (Rosenberg, Davis, James, Pollock, & Stowell, 2007; Hirshey Dirksen et al., 2011;

Hopkins, 2011; Metterlein, Hartung, Schuster, Roewer, & Anetseder, 2011). Muscle contraction

related to calcium and magnesium influx and regulation is altered when MH susceptible patients

are exposed to these drugs (Hopkins, 2011). The mechanism of action on MH susceptible

patient's muscle cells is complex and more is being learned about how these agents work at the

cellular level. The understanding of these mutations being studied has grown from >100 to >200

and causal mutations from 25 to 30 between 2007 and 2011 (Rosenberg, Davis, James, Pollock,

& Stowell, 2007; Hirshey Dirksen et al., 2011). This mutated part of the MH susceptible

patient's genes responds to all of the volatile inhalation agents used for anesthesia and

intravenous succinylcholine, triggering MH (Hopkins, 2011). However, each drug is dose

dependent and brings on MH symptoms at different times after administration (Hopkins, 2011).

There is little evidence in the literature about non-reactive anesthetics (i.e., propofol or nitrous

oxide) causing MH or MH-like symptoms when used for intubation (Hopkins, 2011). Patients

often do not know they are susceptible to MH until an anesthetic gas or depolarizing muscle

relaxant is used, or about the signs and symptoms of MH, the antidote Dantrolene sodium, and

triggers such as succinylcholine.

Implications for Nursing

The implications for nursing are challenging for those caring for individuals intubated

with volatile inhaled anesthetics or succinylcholine. The evidence discussed can be incorporated

into practice in every hospital department where intubations occur. Often the drug of choice for

intubations is succinylcholine, which can trigger an MH episode. Non-reactive medications,


such as propofol or nitrous oxide, should be considered as alternative anesthetics when an

intubation is required and/or if MH susceptibility is unknown. Dantrolene should be readily

available, easily accessible, and in a known location in the event of an MH crisis. Nurses caring

for peri- and post-intubated patients must be made aware of medications that trigger MH, and the

signs and symptoms for which to monitor. It is also essential that nurses be familiar with

interventions to quickly initiate a protocol of treatment for those who demonstrate signs of MH.

Although the articles discussed are not specifically geared to nursing, it is paramount that nurses

who may encounter an MH crisis are informed and prepared.

Future Research

In addition to the available information on MH, there are countless opportunities for

future MH research, or evidence-based application in nursing practice. There is a need for

education for peri-intubation nurses in recognition of MH, and resources for MH treatment.

Nursing interventions, practices, or standards of care that will increase detection of MH and

improve outcomes, should be explored. Nursing interventions, practices, or standards of care

that will decrease morbidities and mortality, secondary to MH, are also worthwhile areas for

study. Another area for scientific research of MH includes genetic research that delves into why

MH patients react to inhalation agents. Also, chemical research that studies the properties of

reactive agents that create an MH response would be invaluable. Finally, advances in MH

knowledge depend on pharmaceutical innovation, and research working toward the development

of an inhaled anesthetic that eliminates the risk for MH.

Conclusion

This paper has provided an overview of malignant hyperthermia and susceptibility when

volatile anesthetics and/or succinylcholine are administered to a patient. MH should be well


known to peri- and post-anesthesia nurses, and nurses caring for and assisting with intubated

patients. This topic is complex, and the research and evidence surrounding it is ever evolving.

The articles discussed what MH is, its signs and symptoms, what triggers MH, and the testing for

MH susceptibility. The evidence reveals the need for further research and understanding of MH.

Hopefully, the future of MH research will involve nurses, as they play a critical role in

recognizing and treating this complicated phenomenon.


References

Brady, J., Sun, L., Rosenberg, H., & Li, G. (2009). Prevalence of malignant hyperthermia due

to anesthesia in New York State, 2001–2005. Anesthesia & Analgesia, 109, 1162–1166.

Hirshey Dirksen, S. J., Larach, M. G., Rosenberg, H., Brandon, B. W., Parness, J., Lang, R. S.,

. . . Pezalski, T. (2011). Future directions in malignant hyperthermia research and patient

care. Anesthesia & Analgesia, 113(5), 1108-1119. doi:10.1213/ANE.0b013e31822af2e

Hopkins, P. M. (2011). Malignant hyperthermia: Pharmacology of triggering. British Journal

of Anaesthesia, 107(1), 48-56. doi:10.1093/bja/aer132

Larach, M., Gronert, G., Allen G., Brandom, B., Lehman, E. (2012). Clinical presentation,

treatment, and complications of malignant hyperthermia in North America from 1987 to

2006. Anesthesia & Analgesia, 110, 498–507.

Metterlein, T., Hartung, E., Schuster, F., Roewer, N., & Anetseder, M. (2011). Sevoflurane

as a potential replacement for halothane in diagnostic testing for malignant hyperthermia

susceptibility: Results of a preliminary study. Menerva Anestesiologica, 77(8), 768-773.

Rosenberg, H., Davis, M., James, D., Pollock, N., Stowell, K. (2007). Malignant hyperthermia.

Orphanet Journal of Rare Diseases, 2, 21. doi:10.1186/1750-1172-2-21

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