Gregory L. Rose, MD; Thomas McLarney, MD; Raeford E. Brown, MD How to avoid this University of Kentucky College of Medicine, Lexington medical emergency [email protected] Avoiding an episode of malignant requires The authors reported no potential confl ict of interest relevant to this article. that you look for certain clues in a patient’s history.

ou are asked to perform a preoperative evaluation of a PRACTICE 6-year-old boy who is due to have a tonsillectomy. Th e RECOMMENDATIONS Y family history reveals that his father had an episode that › Suspect malignant hyper- sounds like malignant hyperthermia (MH). Also, a paternal thermia (MH) if a patient uncle experienced a high and almost died after undergo- has night sweats, cramping, ing . Th e boy’s parents tell you they took the boy to mottled skin, low-grade fever, a pediatrician, who did a “blood test” for MH. Th ey hand you and excessive sweating, or has a written report of an enzyme-linked immunosorbent assay, elevated kinase and on lab which tested negative for an allergy to succinylcholine. studies. B Has this child been adequately screened for MH? If you answered No, you are correct. Th e review that fol- › Make sure patients and lows explains why. their family members know that MH is life threatening, familial, and can even occur in patients whose previous The “disease of anesthesia” experiences with anesthesia MH is a pharmacogenetic disease process that occurs when have been uneventful. A predisposed individuals are exposed to certain triggering agents—specifi cally, . Succinylcholine and all Strength of recommendation (SOR) potent inhalational agents have been implicated A Good-quality patient-oriented (TABLE 1). Most episodes occur in the intraoperative period. evidence B Inconsistent or limited-quality MH is a familial disease and follows an autosomal domi- patient-oriented evidence nant pattern, but with incomplete penetrance. Surprisingly, C Consensus, usual practice, the disease was not described until 1961, when Denborough opinion, disease-oriented evidence, case series et al reported a string of anesthetic-related deaths in a fam- ily.1,2 A similar condition was described in pigs in 1966.3 Th is condition, porcine stress syndrome, was noted during re- search in which pigs had received succinylcholine. Th is syn- drome has become the animal model for the study of MH.4,5 Over time, this condition came to be known as malignant hyperthermia because a rapid rise in temperature was a com- mon feature in all reported cases. Additional possible include skin mottling, , elevated (CK), and rhabdomyolysis, among others (TABLE 2). ❚ Associated conditions. MH may occur with any condition requiring intervention with anesthesia. It was once believed that strabismus and MH were linked, but this assumption was based

30 THE JOURNAL OF FAMILY PRACTICE | JANUARY 2011 | VOL 60, NO 1 TABLE 1 Triggering and nontriggering anesthetic agents

Triggering agents Nontriggering agents

Succinylcholine (most common)

Desfl urane

Halothane

Isofl urane Local anesthetics

Sevofl urane

Nondepolarizing muscle relaxants

Opioids

Propofol

Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

Malignant on a statistical error related to an increased TABLE 2 hyperthermia number of surgical procedures in children with Signs and symptoms is a medical strabismus. Currently, a propensity toward MH emergency and seems associated only with rare myopathic con- of malignant hyperthermia requires that the ditions such as , hypokale- patient receive mic periodic paralysis, Evans myopathy, and Arrhythmias King-Denborough syndrome.6 Precise genetic Coagulopathy sodium. mapping will determine what, if any, relation- Elevated creatine kinase ship there is between these processes and MH. Elevated temperature Hypercarbia Awake triggering: Similar disorder without anesthesia Increased oxygen consumption Since 1980 there have been several reports of Masseter muscle spasm “awake triggering” in genetically predisposed Metabolic individuals, whereby stressful conditions alone Muscle rigidity unrelated to general anesthesia cause MH.7–10 Rhabdomyolysis Often, the presenting condition has been heat- Skin mottling stroke, but other symptoms are also common, such as rhabdomyolysis, increased CK, muscle pain, and cardiovascular collapse.11 Relatives Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th of those with a history of MH have also exhib- ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009. ited chronic muscle pain or chronic CK eleva- tion. All of these people, when tested, have had Should such fi ndings—especially elevat- a positive reaction to the caff eine- ed CK and rhabdomyolysis—come to your at- contracture test (CHCT), which is the gold tention by a patient’s report or during physical standard for confi rming MH.12 examination, consider further workup for MH. Th e Malignant Hyperthermia Association of the United States (MHAUS) lists signs and How MH develops symptoms that accompany awake triggering on MH occurs because of a defect in the ry- its Web site, www.mhaus.org. Th ey include heat anodine receptor, RYR1. Th is receptor is re- sensitivity, night sweats, cramping, mottled sponsible for intracellular release by skin, low-grade fever, and excessive sweating. its mediation of the . CONTINUED

JFPONLINE.COM VOL 60, NO 1 | JANUARY 2011 | THE JOURNAL OF FAMILY PRACTICE 31 RYR1 is found in all .13 Dur- ing an episode of MH, exposure to the trigger- Incidence of MH ing agent causes intracellular calcium release is increasing by the sarcoplasmic reticulum and sustained The number of reported cases of malignant skeletal muscle contractions and rigidity. In- hyperthermia (MH) has increased over creased oxygen consumption occurs, and this the last 20 years, but the exact incidence hypermetabolic state leads to hypercarbia, se- is unknown. It varies not only by country, vere , tachycardia, arrhyth- but, within the United States, from state to mias, hyperkalemia, and elevated temperature. state, and even within states, presumably due to variations in the genetic pool. Michi- Rhabdomyolysis and elevations in CK also oc- gan, Nebraska, West Virginia, and Wiscon- cur because of skeletal muscle breakdown. sin report especially high incidences.19 MH is more common in men than women (58% vs 42%, respectively, of affected How to treat patients ). The last major survey of MH inci- this medical emergency dence was published in 2009.20 In the survey Only rapid, specifi c treatment can save a years (2000-2005), MH incidence increased from 10.2 to 13.3 patients per million hospi- patient with MH from death. Before inves- tal discharges. Mortality in the same period tigators discovered that dantrolene sodium decreased from 16.1% to 6.5%. is an eff ective treatment for MH, >70% of Malignant patients who developed the disease died.12 hyperthermia Mortality has since dropped to ≤15%.14 With water, cold intravenous fl uid, or ice water la- can occur as a presumptive diagnosis of MH, dantrolene vage at the surgical site. Active cooling should long as 12 hours should be prepared and given immediately. stop when the patient’s temperature reaches after exposure Th e drug inhibits the release of calcium from 100ЊF (so as not to cause hypothermia). Cool- to a presumed the sarcoplasmic reticulum of skeletal muscle ing should not, however, prevent or slow the trigger. by limiting the activation of RYR1. administration of dantrolene. Successful resuscitation of patients with ❚ Treating acidosis, arrhythmias, elec- MH hinges on the following: trolyte disturbances, coagulopathy, excess ❚ Making a prompt diagnosis. While , and acute renal failure. Ar- most episodes of MH occur shortly after in- rhythmias should not be treated with calcium duction of anesthesia or during the intraop- channel blockers. erative course, nearly 2% of MH cases occur ❚ patients in the ICU for postoperatively15—some as long as 12 hours potential adverse eff ects of dantrolene that after exposure to the presumed trigger. can include and muscle weakness. ❚ Immediately discontinuing triggering Mechanical ventilation may be needed. (Th e anesthetics and starting dantrolene. Th e malignant hyperthermia hotline [800-644- patient should be kept anesthetized using 9737] at MHAUS is available 24 hours a day nontriggering agents (TABLE 1), and surgery to assist clinicians with questions regarding should be concluded as quickly as possible. diagnosis and treatment.) Preparation of dantrolene is a tedious pro- cess because of its poor water solubility. One Keeping patients safe to 2 minutes are needed for the preparation to by properly testing them solubilize. Initial treatment with dantrolene is Th e CHCT is 97% sensitive and 78% specifi c 2.5 mg/kg administered intravenously (via pe- for MH.16 It is an invasive procedure, requir- ripheral or central line). Th is dose (or up to 10 ing the patient to undergo anesthesia. Th e mg/kg) can be repeated every 5 to 10 minutes test costs more than $5,000, which most in- until major symptoms such as hypercarbia, surance companies will cover.17 arrhythmias, hyperpyrexia, and metabolic aci- Th e CHCT is performed only on fresh dosis abate. Th ereafter, dantrolene is contin- muscle, and only 5 centers in North America ued at 2.5 mg/kg every 4 hours for 24 hours. perform the test. Th e number of centers is kept ❚ Cooling the patient. A patient should be to a minimum to maintain high procedural cooled using ice packs, gastric lavage with ice quality. Th e specimen is taken from the

32 THE JOURNAL OF FAMILY PRACTICE | JANUARY 2011 | VOL 60, NO 1 MALIGNANT HYPERTHERMIA

vastus lateralis. Because of the size of the speci- should be presumed to be MH susceptible. men required to perform the test, a child weigh- ❚ Why is testing of relatives needed if ing <20 kg or <5 years of age is usually not tested a nontriggering anesthetic can be adminis- but simply presumed to be MH susceptible.18 tered? Nontriggering anesthetic agents are not routinely used in surgery, and problems can Counseling patients and their families arise in, say, emergency situations when MH Make sure aff ected individuals and family susceptibility in a patient is unknown to the sur- members know the life-threatening implica- gical team. Testing enables patients to learn their tions of this condition; that it is familial and status and to obtain a medical alert bracelet. that its onset does not always occur with a fi rst exposure to anesthesia, but sometimes with a What about the child subsequent exposure. Explain that MH is not in the opening scenario? an “allergy to anesthesia” or an “allergy to suc- It is evident that the child in the scenario cinylcholine.” Patients can undergo anesthesia at the beginning of this article was not ad- safely in the future if performed with a nontrig- equately screened for MH. Given that the gering agent and associated technique. Anes- child is >5 years of age, he should undergo the thesiologists today are well trained to manage CHCT. You would be wise to presume that his these patients with minimum risk. fi rst-degree relatives are also susceptible until Counsel fi rst-degree relatives of MH pa- proven otherwise by the CHCT. With children tients about undergoing the CHCT. Molecular not meeting the age or weight requirement The malignant genetic testing, which requires a blood draw but for CHCT, make sure the family understands hyperthermia is less sensitive than the CHCT, may be another the potential severity of MH and immediately hotline option. If an MH patient was diagnosed using inform the surgeon and anesthesiologist of (800-644-9737) this blood test, relatives may opt to be tested this the family history so appropriate precautions, is available 24/7 way, as well. If genetic test results for relatives including arrangements for nontriggering to assist are positive, these individuals are presumed to anesthetics, can be put into place. JFP clinicians with have MH and should be treated as such, sav- questions ing them the expense and risk of undergoing CORRESPONDENCE regarding Gregory L. Rose, MD, Department of Anesthesia, University muscle biopsy. If genetic test results are nega- of Kentucky College of Medicine, 800 Rose Street, diagnosis and tive, the CHCT should be considered or patients Lexington, KY 40536; [email protected] treatment.

References 1. Denborough MA, Lovell RRH. Anaesthetic deaths in a family. 1131–1136. Lancet. 1960;276:45. 13. Parness J, et al, eds. Ryanodine Receptors Structure, Function 2. Denborough MA, Forster JF, Lovell RRH, et al. Anaesthetic and Dysfunction in Clinical Disease (Developments in Cardio- deaths in a family. Br J Anaesth. 1962;34:395–396. vascular Medicine). New York, NY: Springer Press; 2005. 3. Hall L, Woolf N, Bradley J, et al. Unusual reaction to suxametho- 14. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. nium chloride. BMJ. 1966;2:1305. Orphanet J Rare Dis. 2007;2:21. 4. Stalder K, Conatser G. Porcine stress syndrome and its eff ects 15. Zucchi R, Ronca-Testoni S. Th e sarcoplasmic reticulum Ca2+ on maternal, feedlot and carcass quantitative and qualita- channel/: modulation by endogenous ef- tive traits. Agricultural Extension Service, Th e University of fectors, drugs and disease states. Pharmacol Rev. 1997;49:1-51. Tennessee. Available at: http://www.utextension.utk.edu/ 16. Allen GC, Larach MG, Kunselman AR. Th e sensitivity and speci- publications/pbfi les/PB1606.pdf. Accessed December 7, 2010. fi city of the caff eine-halothane contracture test: a report from 5. Harrison G: Control of the malignant hyperpyrexic syndrome the North American Malignant Hyperthermia Registry. Anes- in MHS swine using dantrolene sodium. Br. J. Anaesthesia. thesiology. 1998;88:579-588. 1975;47:62-65. 17. Malignant Hyperthermia Association of the United States. 6. Allen GC. Malignant hyperthermia and associated disorders. Available at: http://www.mhaus.org/index.cfm/fuseac- Curr Opin Rheumatol. 1993;5:719-724. tion/OnlineBrochures.Display/BrochurePK/71A5AFFC- 7. Kolb M, Horne M, Martz R. Dantrolene in human malignant 1BC7-4A36-970C6FDB27999FE5.cfm. Accessed: November hyperthermia. . 1982;56:254-262. 22, 2010. 8. Hopkins PM. Malignant hyperthermia: advances in clinical 18. Rosenberg H, et al. Malignant hyperthermia susceptibility. In: management and diagnosis. Br J Anaesth. 2000;85:118–128. Pagon RA, et al, eds. Gene Reviews [Internet]. Last Update: January 19, 2010. Available at: http://www.ncbi.nlm.nih.gov/ 9. Tobin JR, Jason DR, Nelson TE, et al. Malignant hyperthermia and books/NBK1146/#mhs. Accessed December 9, 2010. apparent heat stroke (Correspondence). JAMA. 2001;286:168. 19. Litman R, Flood C, Kaplan R, et al. Postoperative malignant hy- 10. Hopkins PM. Is there a link between malignant hyperthermia perthermia: an analysis of cases from the North American Malig- and exertional heat illness? Br J Sports Med. 2007;41:283-284. nant Hyperthermia Registry. Anesthesiology. 2008;109:825–829. 11. Hines RL, Marschall KE, eds. Stoelting’s Anesthesia and Co-Ex- 20. Rosero E, Adesanya A, Timaran C, et al. Trends and outcomes isting Disease. 5th ed. Philadelphia, PA: Saunders; 2008. of malignant hyperthermia in the United States, 2000 to 2005. 12. Denborough M: Malignant hyperthermia. Lancet. 1998;352: Anesthesiology. 2009;110:89-94.

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