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Critical Care Nurse. 2008;28: 32-36
Copyright © 2008 by the American Association of Critical-Care Nurses.
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Clinical Article
CE Article

Genetics and Susceptibility to Malignant Hyperthermia

Kathryn Anderson-Pompa, RN, BSN, CCRN
 April Foster, RN, BSN, CCRN
 Lee Parker, RN, BA, CCRN, CEN
 Lance Wilks, RN, BSN, CCRN
 Dennis J. Cheek, RN, PhD

When this article was written, Kathryn Anderson-Pompa, April Foster, Lee Parker, and Lance Wilks were all graduate students in the nurse anesthesia program in the Harris College of Nursing and Health Sciences at Texas Christian University in Fort Worth, Texas. Dennis J. Cheek is the Abell-Hanger Professor of Gerontological Nursing in the School of Nurse Anesthesia and Harris College of Nursing and Health Sciences at Texas Christian University.

To purchase electronic or print reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

dotmore
To learn more about genetics, read "ECG Characteristics of a Genetic Disorder" by Michele M. Pelter et al in the American Journal of Critical Care, 2007;16:621-622. Available at www.ajcconline.org.

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Financial Disclosures
None reported.

This article has been designated for CE credit. A closed-book, multiple-choice examination follows this article, which tests your knowledge of the following objectives:

  1. Discuss how advances in the study of genomics will affect the practice of critical care nurses in the future
  2. Describe how genetic mapping can predict susceptibility to malignant hyperthermia
  3. Discuss the pharmacological triggers for malignant hyperthermia reactions

Corresponding author: Dennis J. Cheek, RN, PhD, FAHA, School of Nurse Anesthesia and Harris College of Nursing and Health Sciences, Texas Christian University, TCU Box 298620, Fort Worth, TX 76129 (e-mail: d.cheek{at}tcu.edu).


   Background
Top
 Background
Genes
 Pharmacogenetics
 Genetic Testing
 Conclusion
 PRIME POINTS
 References
 
Critical care nurses have seen the influences of genetics on their practice in many ways since the 1980s. These influences have been especially apparent since completion of the Human Genome Project in April 2003, leading to phenomenal advances in the practice of medicine in reference to genetics. Critical care nurses are seeing noticeable changes in patient care that will increase in the future. Because of these changes, understanding the science behind current advances is increasingly important so that the advances can be applied appropriately to critical care practice.

What must be more fully understood are the sciences of genetics and genomics. Genetics is the study of single genes or groups of genes.1 Genomics is the study of an organism’s genome, which is all the DNA contained in an organism or a cell, which includes both the chromosomes within the nucleus and the DNA in mitochondria.2,3 The study of the global properties of genomes of related organisms is usually referred to as genomics, which distinguishes it from genetics. The Human Genome Project provided a complete map of the human genome. This map identified genes that code for various proteins involved in the cellular workings of the human body.4 This information has made it possible for researchers to begin to show links and correlates between environmental and genetic influences and how these interactions relate to health conditions.5 Although, genetics will continue to play a role in the future of health care, genomics is where the bulk of the new advances will arise.6 Studying interactions between the genome and the environment in humans potentially can lead to new ways to diagnose, prevent, and treat disease by altering assessment and intervention strategies in health care. Currently, many investigators are examining the association between specific genes and disease processes, and much of this research will affect critical care nurses.


CASE STUDY

Mr F is a healthy 34-year-old man who is admitted to a local metropolitan hospital for a routine cholecystectomy. A preoperative assessment by the nurse anesthetist reveals no prior surgeries and a familial history of anesthetic complications, but Mr F is unsure of what the complications were called. During the surgery, no adverse effects are noted by the surgical team.

After successful removal of the gallbladder and an unremarkable anesthetic reversal, Mr F is transported to the postanesthesia care unit and monitored before transfer to a medical-surgical unit. Vital signs are as follows: heart rate, 75/min; blood pressure, 127/82 mm Hg; respiratory rate, 16/min; oxygen saturation, 100%; body temperature, 36.9°C. When Mr F arrives in the postanesthesia care unit, the receiving nurse notices an increase in his heart rate to 91/min and an increase in respirations to 21/min. After administering a 3-mg intravenous bolus of morphine sulfate for pain and increasing oxygen delivery to 4 L/min via Mr F’s cannula, the nurse continues to see a gradual increase in heart rate and respirations as well as an increase in blood pressure. Mr F’s vital signs are now as follows: heart rate, 114/min; blood pressure, 147/92 mm Hg; respirations, 25/min; oxygen saturation, 98%; and body temperature, 38.8°C. The nurse again treats Mr F with a 3-mg intravenous bolus of morphine sulfate and increases his oxygen to 5 L by mask.

During the nurse’s assessment, she notices that Mr F’s body temperature is increasing. As the surgeon and the certified registered nurse anesthetist are called to report Mr F’s condition, the patient begins to experience muscle rigidity of the trunk. At this point, vital signs are as follows: heart rate, 127/min; blood pressure, 167/101 mm Hg; respirations, 31/min; oxygen saturation, 89%; and body temperature, 39.5°C. Mr F’s electrocardiogram begins to show ventricular ectopy. A possible diagnosis of malignant hypertension is made by the nurse anesthetist, the malignant hyperthermia cart is brought in, and Mr F is immediately treated with 2.5 mg/kg of dantrolene intravenously and 2 mEq/kg of bicarbonate and is reintubated. Serial blood gas analyses are started, along with coagulation studies, a complete blood cell count, and measurements of electrolyte, creatine kinase, lactate, and myoglobin levels. Sequential samples are also collected from the urinary catheter to monitor myoglobin levels in the urine. Mr F is covered with a cooling blanket and ice packs.

Laboratory studies reveal the following: pH, 7.21; PCO2, 75 mm Hg; PO2, 85 mm Hg (oxygen saturation); and potassium level, 7.2 mEq/L. Mr F is given 10 units of regular insulin intravenously, 50 mL of 50% dextrose in water intravenously, and 10 mg/kg of calcium chloride. He is transferred to the intensive care unit for further evaluation. His vital signs upon transfer are as follows: heart rate, 115/min; blood pressure, 150/92 mm Hg; respiratory rate, 26/min; oxygen saturation, 93%; body temperature, 38°C.

 

Genomics-related research will allow for individualized or personalized medicine,7–9 with a more patient-specific care plan for each patient. Many of today’s emerging advances in cancer are directed at determining the best treatment for individual patients on the basis of the genome of the tumor the patient has. For example, a patient with breast cancer whose tumor is positive for the protein HER2 can be treated with the gene-specific drug herceptin. In patients with cardiovascular disease, genetic alterations are closely associated with medical conditions such as monogenic arrhythmia syndromes (eg, prolonged QT syndrome), as well as hypertension, familial hypertrophic cardiomyopathy, stroke, and elevated levels of low-density lipoprotein.6,10–14 Other conditions with research potential are asthma and chronic obstructive pulmonary disease. Researchers are examining the genes associated with the causes of these disorders and the responses to treatment.15–23 Other areas of research in genetics and genomics include, but are not limited to, type 2 diabetes, sepsis, transfusion medicine, kidney disease, and wound healing.24–32

In this article, we explore genetics and genomics in the context of the pathophysiology of malignant hyperthermia. In addition, we provide a glimpse of advances being made in genetic testing and application of pharmacogenetics to practice, specifically in patients with genetic susceptibility to malignant hyperthermia.


   Genes
Top
 Background
 Genes
Pharmacogenetics
 Genetic Testing
 Conclusion
 PRIME POINTS
 References
 
Susceptibility to malignant hyperthermia is an inherited genetic disorder that is manifested as an autosomal dominant pharmacogenetic trait.33 Identification of this disorder was based on a family in Australia and was first reported in the early 1960s.34 Genetic incidence is estimated to be 1 in 10000.35

In genetic studies, 6 loci within the human genome that are linked with susceptibility to malignant hyperthermia have been identified. Of these loci, 3 have been mapped and the genes identified; the other 3 loci have been mapped, but the genes have not been identified. Studies during the early 1990s revealed MHS1, a locus that is associated with mutations in the gene RYR1, which codes for ryanodine receptor 1 on band 19q13.1. MHS1 is a primary site where mutation occurs, resulting in susceptibility to malignant hyperthermia.36 Mutations at this locus account for 80% of all cases of susceptibility to malignant hyperthermia. Most RYR1 mutations occur in the areas of amino acid residues 35 to 614 (N-terminal region), 2117 to 2458 (central region), and 3916 to 4973 (C-terminal region). To date, approximately 42 mutations linked to this gene have been found. Most of these mutations are called missense mutations,33 meaning the mutation alters a single base within the section of DNA that codes for a certain amino acid; the mutation can result in an amino acid change and an altered protein.37 Another locus identified was MHS3, associated with mutations in the gene CACNA2D1, which codes for the {alpha}2{delta} subunit of a dihydropyridine-sensitive L-type calcium channel. This specific mutation has been reported in only a few persons and accounts for 1% of all cases of susceptibility to malignant hyperthermia.

The last identified locus is MHS5, which is associated with mutations in CACNA1S, the gene that codes for skeletal muscle calcium channels. Mutations in MHS5 also account for 1% of all cases of susceptibility to malignant hyperthermia. The other 3 loci (MHS2, MHS4, and MHS6) have been mapped, but the specific genes have not been clearly identified yet.


   Pharmacogenetics
Top
 Background
 Genes
 Pharmacogenetics
Genetic Testing
 Conclusion
 PRIME POINTS
 References
 
Malignant hyperthermia is a rare reaction and usually occurs when volatile inhalation agents and/or succinylcholine, a depolarizing muscle relaxant, are used. The volatile agents identified as triggers of malignant hyperthermia are halothane, isoflurane, enflurane, sevoflurane, and desflurane. The combination of succinylcholine and a potent volatile anesthetic agent triggers a more rapid reaction than does a volatile agent alone or succinylcholine alone.1 No evidence indicates that intravenous anesthetics such as opioids induce malignant hyperthermia.

Results of multiple studies have suggested links between susceptibility to malignant hyperthermia, the use of potent volatile anesthetics, and mutation of RYR1. In North America, 10 mutations account for 22% of the population susceptible to malignant hyperthermia.33 In Australia and New Zealand, a unique mutation was found in the malignant hyperthermia/central core disease region I of the RYR1 gene specific to 9 families.38

Mutations in RYR1 affect skeletal muscle, leading to the sustained release of calcium from the sarcoplasmic reticulum, causing a hypermetabolic state to occur within the muscle tissue. The mutated area of the ryanodine receptor is the site of action for the inhaled agents and/or succinylcholine. The mutation changes the receptor from one of regulation to one with an excitatory function that results in the abnormal release of intracellular calcium and causes the malignant hyperthermia cascade. The drastic and uncontrolled increase in skeletal muscle oxidative metabolism increases carbon dioxide production and causes a 3- to 5-fold increase in oxygen consumption. Other signs include muscle rigidity, rhabdomyolysis, and marked elevation in body temperature (see "Case Study"). This series of events can cause skeletal muscle damage as well as hypermetabolic states of crisis, such as cardiac arrhythmias, that if untreated result in death.

Research studies support the link between genetic mutation of the ryanodine receptor and pharmacological effects of halothane that cause malignant hyperthermia. Evidence from studies with the contracture test, in which halothane, caffeine, and ryanodine challenges are used, supports a similar individual pharmacogenetic effect among the 3 agents rather than a specific, different pharmacological action for each.33 Tammaro et al33 clearly found a connection between the use of halothane as a potent inhaled volatile anesthetic and its interaction with the mutated ryanodine receptor to directly induce malignant hyperthermia.


   Genetic Testing
Top
 Background
 Genes
 Pharmacogenetics
 Genetic Testing
Conclusion
 PRIME POINTS
 References
 
Genetic testing is used to detect whether someone has a genetic condition or is likely to acquire a disease. Generally, persons are tested if they have a familial history for a certain disease, they have signs or symptoms of a genetic disorder, or they are concerned about their children inheriting a genetic disorder (see "Case Study").

Genetic testing for malignant hyperthermia has only recently been developed and implemented.39–42 According to the June 2006 newsletter of the Malignant Hyperthermia Association of the United States43 and the September 2005 newsletter of the American Society of Anesthesiologists,44 PreventionGenetics, LLC, a company in Wisconsin, has begun offering molecular genetic testing for malignant hyperthermia, as has the University of Pittsburgh Medical Center for Medical Genetics.39 Genetic testing, which requires only a small sample of blood, is less invasive than the muscle contracture test, the previously used reference standard. The contracture test requires a biopsy specimen of muscle tissue, which is then exposed to halothane and caffeine through various techniques. Although the contracture test is sensitive, it is more invasive, expensive, and inconvenient to patients than is genetic testing.

The Malignant Hyperthermia Association of the United States Web site states that genetic testing detects only about 30% of persons at risk. The genetic test is very specific, however, so those with a positive test are almost certainly at risk for malignant hyperthermia. Sequence analysis, which is complete sequencing of the RYR1 gene, may detect mutation at a rate of up to 70%.39–42 The Malignant Hyperthermia Association of the United States42 also advises the following types of persons be considered for genetic testing:

As mentioned earlier, the advantages of genetic testing over the contracture test are reduced invasiveness, lower cost, and the lack of morbidity associated with muscle biopsy. In time, the sensitivity of the genetic test most likely will improve markedly.42


   Conclusion
Top
 Background
 Genes
 Pharmacogenetics
 Genetic Testing
 Conclusion
PRIME POINTS
 References
 
The completion of the Human Genome Project has changed the practice of medicine and will soon affect all facets of health care. Critical care nurses must understand the implications of genomics so that they can provide the safest and most patient-specific care available. The incidence of malignant hyperthermia is 1 in 10 000, so most likely most anesthesia providers and critical care nurses will be directly involved in at least one case of the disorder during their careers.1 Critical care nurses will be able to use genetic information to improve patients’ outcomes in several ways. Perhaps the most effective application of genetic information is in preventing malignant hyperthermia altogether. To do so, critical care nurses must be able to access a patient’s genomic information through genetic testing. Identifying patients and family members who are at high risk for malignant hyperthermia is critical to reducing adverse health conditions related to this disorder. Critical care nurses must also become knowledgeable about the pharmacogenomic implications related to the interaction of current anesthetic agents that will trigger malignant hyperthermia in susceptible patients. Finally, prompt assessment and recognition of postsurgical complications related to malignant hyperthermia can decrease the frequency of skeletal muscle damage, cardiac arrhythmias, and even death. At this time, researchers are focusing on the ryanodine receptor gene and its link to malignant hyperthermia.3 With the achievement of an inexpensive, noninvasive, genetically specific test available to all preoperative patients (see www.genetests.org), malignant hyperthermia may be eliminated sooner rather than later.


   PRIME POINTS
Top
 Background
 Genes
 Pharmacogenetics
 Genetic Testing
 Conclusion
 PRIME POINTS
References
 


   References
Top
 Background
 Genes
 Pharmacogenetics
 Genetic Testing
 Conclusion
 PRIME POINTS
 References
 

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