Evidence-Based Patient Safety Advisory: Malignant Hyperthermia

PATIENT SAFETY Outcomes Article Evidence-Based Patient Safety Advisory: Malignant Hyperthermia

Raffi Gurunluoglu, M.D., Summary: As more and more routine plastic surgery procedures move from the Ph.D. hospital to outpatient surgery facilities, plastic surgeons must be aware of the risk Jennifer A. Swanson, B.S., factors for life-threatening events that might occur in this setting. This awareness M.Ed. includes recognition of the signs and symptoms and the management of a rare Phillip C. Haeck, M.D. but life-threatening condition, malignant hyperthermia. This article reviews the and the ASPS Patient Safety current understanding of the concepts pertinent to malignant hyperthermia Committee diagnosis and treatment in the outpatient setting and current standards and Denver, Colo.; and Arlington Heights, Ill. recommendations for physicians and support personnel regarding malignant hyperthermia preparedness in office-based surgery and anesthesia. (Plast. Re- constr. Surg. 124 (Suppl.): 68S, 2009.)

s more and more routine plastic surgery information and improvements in medication, procedures move from the hospital to out- successful treatment has become the norm rather Apatient surgery facilities, plastic surgeons than the exception. The incidence of malignant must be aware of the signs and symptoms and the hyperthermia episodes during anesthesia is management of a rare life-threatening condition, thought to be between one in 5000 and one in malignant hyperthermia. Although the abrupt, 50,000 to 100,000 anesthetic encounters, but be- unpredicted death of a healthy individual under- cause of accurate diagnosis, timely recognition, going surgery in any setting is extremely unusual, and appropriate treatment, mortality rates have when it occurs in an outpatient facility, it will al- fallen from 70 percent when the first cases came ways be questioned whether this person should to light to less than 5 percent over 30 years later. have had their procedure performed instead as an This article reviews the current concepts per- inpatient. It is imperative then that all surgeons tinent to malignant hyperthermia in the outpa- using general anesthesia understand what malig- tient setting, with particular emphasis on presur- nant hyperthermia risks are for their patients, and gical evaluation, identification of susceptible what to do if confronted by it. individuals and selection of the appropriate set- Malignant hyperthermia is an inherited my- ting for these patients, appropriate anesthetic opathy that presents as a hypermetabolic reaction agents for susceptible patients, early diagnosis and to potent volatile anesthetic gases, such as halo- management of acute malignant hyperthermia, and thane, enflurane, isoflurane, sevoflurane, and des- postoperative vigilance and care. Also discussed are flurane, and the depolarizing muscle relaxant current standards/guidelines and recommenda- succinylcholine. Critical worldwide insight into tions for physicians and support personnel re- malignant hyperthermia began in 1960, when garding facility and equipment requirements and Denborough and Lovell described a series of an- malignant hyperthermia preparedness in office- esthetic deaths in a family.1 Since that time, aware- based surgery and anesthesia. ness of malignant hyperthermia has reached crit- This patient safety advisory was developed ical mass where, through widely disseminated through a comprehensive review of the scientific literature and a consensus of the Patient Safety From the Denver Health Medical Center and the American Committee. The supporting literature was criti- Society of Plastic Surgeons’ Patient Safety Committee. cally appraised for study quality according to cri- Received for publication March 3, 2009; accepted May 27, teria referenced in key publications on evidence- 2009. Approved by the ASPS Executive Committee, January 10, 2009. The members of the ASPS Patient Safety Committee are listed Disclosure: The authors have no commercial asso- at the end of this article. ciations that might pose or create a conflict of inter- Copyright ©2009 by the American Society of Plastic Surgeons est with the information presented in this article. DOI: 10.1097/PRS.0b013e3181b54626

68S www.PRSJournal.com Volume 124, Number 4S • Malignant Hyperthermia based medicine.2–6 Depending on study design of medical care are determined on the basis of all and quality, each reference was assigned a corre- the facts or circumstances involved in an individ- sponding level of evidence (I through V) with the ual case and are subject to change as scientific American Society of Plastic Surgeons (ASPS) Ev- knowledge and technology advance, and as prac- idence Rating Scales (Table 1),7 and the evidence tice patterns evolve. This practice advisory reflects was synthesized into practice recommendations. the state of knowledge current at the time of pub- The recommendations were then graded (A lication. Given the inevitable changes in the state through D) with the ASPS Grades of Recommen- of scientific information and technology, periodic dation Scale (Table 2)8; grades correspond to the review and revision will be necessary. levels of evidence provided by the supporting literature for that recommendation. Practice TRIGGERING OF MALIGNANT recommendations are discussed throughout this HYPERTHERMIA document, and graded recommendations are Anesthetic drugs that trigger malignant hyper- summarized in Appendix A. thermia include halothane, enflurane, isoflurane, desflurane, sevoflurane, and succinylcholine (Ta- 9 DISCLAIMER ble 3). Desflurane and sevoflurane are less potent triggers, producing a more gradual onset of ma- Practice advisories are strategies for patient lignant hyperthermia.10,11 The onset may be ex- management, developed to assist physicians in plosive if succinylcholine is used.12 clinical decision-making. This practice advisory, Volatile anesthetics and succinylcholine rep- based on a thorough evaluation of the present resent a stress for skeletal muscle because they scientific literature and relevant clinical experi- ϩ perturb membranes and disturb Ca2 homeosta- ence, describes a range of generally acceptable sis. In general, normal muscle can withstand and approaches to diagnosis, management, or preven- compensate for these stresses. In susceptible mus- tion of specific diseases or conditions. This prac- cle, however, these membrane changes induced tice advisory attempts to define principles of prac- by halothane (or depolarization induced by suc- tice that should generally meet the needs of most cinylcholine) may cause an earlier calcium release patients in most circumstances. However, this that strikingly stimulates a calcium cascade.13 practice advisory should not be construed as a ϩ When these abnormal amounts of Ca2 build up rule, nor should it be deemed inclusive of all in the myoplasm, the muscle remains in a con- proper methods of care or exclusive of other tracted state, producing abnormal amounts of lac- methods of care reasonably directed at obtaining tic acid, carbon dioxide, phosphate, and heat. the appropriate results. It is anticipated that it will This will result in metabolic acidosis, hypercapnia, be necessary to approach some patients’ needs in hyperphosphatemia, and fever in the patient with different ways. The ultimate judgment regarding a malignant hyperthermia crisis. As myoplasmic the care of a particular patient must be made by ϩ Ca2 remains elevated, it will prevent the myosin the physician in light of all the circumstances pre- and actin fibrils in the muscle from detaching and sented by the patient, the diagnostic and treat- sliding back to their relaxed position. When myo- ment options available, and available resources. ϩ plasmic Ca2 levels increase further, mitochondria This practice advisory is not intended to define are uncoupled and adenosine triphosphate pro- or serve as the standard of medical care. Standards duction decreases, whereas the consumption of both adenosine triphosphate and oxygen in- Table 1. Evidence Rating Scale for Studies Reviewed creases. As adenosine triphosphate becomes scarce, the function of ion transport systems of the Level of Evidence Qualifying Studies sarcolemmal membrane ceases. Ions such as po- I High-quality, multicentered or single-centered, tassium, phosphate, and magnesium, and myoglo- randomized controlled trial with adequate bin, begin to leak across the sarcolemma into the power; or systematic review of these studies extracellular fluid, causing a rise in serum levels II Lesser quality, randomized controlled trial; 14 prospective cohort study; or systematic review (Fig. 1). of these studies III Retrospective comparative study; case-control GENETICS OF MALIGNANT study; or systematic review of these studies HYPERTHERMIA IV Case series V Expert opinion; case report or clinical Malignant hyperthermia is an inherited skel- example; or evidence based on physiology, etal muscle disorder. Genetic evaluation is con- bench research, or “first principles” sistent with autosomal dominant inheritance

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Table 2. Scale for Grading Recommendations Grade Descriptor Qualifying Evidence Implications for Practice A Strong Level I evidence or consistent Clinicians should follow a strong recommendation recommendation findings from multiple studies of unless a clear and compelling rationale for an levels II, III, or IV alternative approach is present. B Recommendation Levels II, III, or IV evidence and Generally, clinicians should follow a recommendation findings are generally consistent but should remain alert to new information and sensitive to patient preferences. C Option Levels II, III, or IV evidence, but Clinicians should be flexible in their decision-making findings are inconsistent regarding appropriate practice, although they may set bounds on alternatives; patient preference should have a substantial influencing role. D Option Level V: Little or no systematic Clinicians should consider all options in their empirical evidence decision-making and be alert to new published evidence that clarifies the balance of benefit versus harm; patient preference should have a substantial influencing role.

Table 3. Safety of Agents in Malignant suggest that mutations cluster largely within three Hyperthermia–Susceptible Individuals* regions of RYR1; however, complete screening of Agents the entire coding regions of RYR1 has shown that mutations can occur in almost all regions of the Malignant hyperthermia–triggering agents 15–17 ● Halothane (most potent), isoflurane, desflurane, gene. RYR1 mutations occur in at least 50 per- enflurane, sevoflurane (volatile agents) cent of malignant hyperthermia-susceptible pa- ● Succinylcholine tients and almost all families with central core ● d-Tubocurarine ● Ether derivatives and chloroform disease. ● Phosphodiesterase inhibitors Another mode of malignant hyperthermia in- (enoximone/methylxanthines in supertherapeutic heritance is the gene that codes for the ␣ subunit doses) 1S ● Rapid intravenous potassium of the dihydropyridine receptor. Two causative ● Theophylline and aminophylline (supertherapeutic mutations in this gene are linked to less than 1 doses) percent of malignant hyperthermia–susceptible Safe drugs 17,18 ● Anticholinergics families worldwide. ● Anticholinesterases ● Barbiturates (e.g., thiopental) PATIENT SELECTION ● Benzodiazepines ● Droperidol Patients known to be susceptible to malignant ● Etomidate hyperthermia may actually undergo anesthesia ● Ketamine 19 ● Local anesthetics (both ester and amide type) several times before a clinical episode occurs. ● Narcotics Therefore, the population at risk may be consid- ● Nitrous oxide erably higher than believed. Thus, it is critical that ● Nondepolarizing muscle relaxants (e.g., vecuronium, rocuronium, pancuronium, atracurium, mivacurium, awareness and prevention of the condition play cisatracurium) significant roles in the management of malignant ● Nonsteroidal antiinflammatory drugs hyperthermia. ● Propofol Use with care Because of the autosomal dominant inheri- ● Catecholamines† tance pattern, the medical history should include ● Haloperidol questions regarding a family history of adverse ● Phenothiazines‡ (e.g., chlorpromazine, prochlorperazine) outcomes after general anesthesia. The preoperative history and physical examination form (see *Adapted from Adamson PA, Dahiya R, Litner J, Vosu H. Malignant hyperthermia: Successful management in a private surgery centre. Haeck et al., “Evidence-Based Patient Safety Ad- J Otolaryngol. 2006;35:186–189. visory: Patient Selection and Procedures in Am- †May cause secondary sympathetic response, though it is not a trigger. bulatory Surgery,” in this issue) can be expanded ‡May cause neuroleptic malignant syndrome and often is confused with malignant hyperthermia. to include family and personal history of malignant hyperthermia. The medical history should also inquire about with variable penetrance. It has been linked to other conditions that may predispose patients to the ryanodine receptor type 1 gene (RYR1), in true malignant hyperthermia, such as Evans my- which over 100 mutations associated with malig- opathy, King-Denborough syndrome, and central nant hyperthermia have been identified.14 Studies core disease.1,20,21 Patients with Duchenne muscu-

70S Volume 124, Number 4S • Malignant Hyperthermia lar dystrophy are at risk of life-threatening hyper- humans.12,14,24 Studies in mouse models suggest kalemia on administration of succinylcholine. similarities between exertional or environmental However, anesthetic-related complications in heat stroke and malignant hyperthermia.31 Clini- these patients do not exhibit classic signs of ma- cal studies have shown no clear evidence of asso- lignant hyperthermia. Patients with any form of ciation between duration or type of surgery and myotonia should not receive succinylcholine. Pa- risk of an episode for malignant hyperthermia– tients with hypokalemic periodic paralysis, central susceptible patients.32 Nevertheless, susceptible core disease,21 multi-minicore disease (RYR1-re- patients should be counseled about their decision lated forms),22 Duchenne or Becker muscular dys- to have elective surgery and their increased risk trophy, paramyotonia, or myotonia fluctuans of life-threatening complications associated with should not receive triggering agents.23 anesthesia. The U.S. Food and Drug Administration’s black box warning for succinylcholine was issued DETERMINATION OF MALIGNANT subsequent to its association with rare reports of HYPERTHERMIA SUSCEPTIBILITY acute rhabdomyolysis with hyperkalemia followed Caffeine-Halothane Contracture Test by ventricular dysrhythmias, cardiac arrest, and death in children with undiagnosed skeletal mus- When the diagnosis of malignant hyperther- cle myopathy. Its use in children should be re- mia susceptibility is in question, the standard means for determining susceptibility is the caf- served for emergency intubation, where securing 33–36 the airway is necessary. feine-halothane contracture test. Two com- Patients who report a malignant hyperthermia monly used forms of this test have been developed, crisis/susceptibility in their first-degree relatives one by the European Malignant Hyperthermia must be considered malignant hyperthermia suscep- Group (the in vitro contracture test) and the other tible until proven otherwise and must not receive by the North American Malignant Hyperthermia triggering agents. They therefore should be coun- Group (the caffeine-halothane contracture test). seled and referred to the Malignant Hyperthermia The test consists of excising a piece of skeletal Association of the United States for further investi- muscle from the patient’s thigh and determining gation. Any susceptible individual should be encour- its contractile properties when exposed to the ry- aged to wear a “medical alert” bracelet notifying anodine receptor agonist halothane and/or caf- emergency personnel of this diagnosis. feine. An abnormal level of contractile activity is Malignant hyperthermia–susceptible patients indicative of susceptibility. can undergo minor procedures, such as simple ex- Using the in vitro contracture test, an individ- cisional surgery, under topical or local anesthesia ual is considered to be susceptible when both the (i.e., level I office procedures) in the office or am- caffeine and halothane test results are positive. A bulatory surgical center because there is no evidence negative diagnosis is made when both tests are that local anesthetics, vasoconstrictors, or patient negative. A third possible result, known as malig- anxiety increase the chance of a malignant hyper- nant hyperthermia equivocal, is obtained when thermia reaction in this setting.24–26 Malignant hy- only one of the halothane or caffeine tests is pos- perthermia–susceptible patients undergoing com- itive. When the caffeine-halothane contracture plex procedures that require minimal or moderate test is used, an individual is diagnosed as suscep- intravenous or intramuscular sedation/analgesia, tible if either halothane or caffeine test result is positive. A negative diagnosis is obtained when general anesthesia, or major conduction blockade 33,37,38 (i.e., level II and III office procedures) should be both are negative. The in vitro contracture referred to an accredited ambulatory surgical center test may reduce the possibility of false-positive and or hospital for surgery (Fig. 2). false-negative results compared with the caffeine- Although hypermetabolic responses in swine halothane contracture test but, overall, similar re- have been documented after exposure to heat, sults are obtained. exercise, anoxia, and excitement,27 the role of stress in triggering malignant hyperthermia in hu- Genetic Testing: RYR1 Screening for Malignant mans is controversial. There is some evidence in Hyperthermia Susceptibility the literature that patients who have experienced There are a limited number of biopsy test cen- heat stress in the past are more likely to have ters available for caffeine-halothane contracture malignant hyperthermia–positive in vitro contrac- testing, eight in the United States and two in Can- ture tests.28–30 However, stress has not been shown ada. To ensure accurate results, the patient must to directly precipitate malignant hyperthermia in travel to the test center for surgical biopsy,39 thus

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Fig. 1. Pathophysiology of malignant hyperthermia. In normal muscle, an electric impulse from the nerve terminals produces a wave of depolarization of the sarcolemma and transverse tubules. This leads to a conformationalchangeinvoltage-gatedL-typeCa2ϩ channels,knownasdihydropyridine(DHP)receptors located in the sarcolemma of the transverse tubule. One of the dihydropyridine receptor subunits

72S Volume 124, Number 4S • Malignant Hyperthermia prompting some patients to initially elect muta- ents. The risks to the siblings of that patient de- tion screening, which simply involves blood test- pend on the genetic status of the parents. If a ing. However, because of its low sensitivity, a parent is identified as malignant hyperthermia negative mutation screen does not rule out ma- susceptible, each of the patient’s siblings have a 50 lignant hyperthermia susceptibility, and the caf- percent chance of also being susceptible. If both feine-halothane contracture test is then recom- parents receive a malignant hyperthermia normal mended for definitive diagnosis. The North result on in vitro contracture testing and RYR1 American mutation analysis protocol currently analysis, the patient’s siblings are at no greater risk screens for 17 of the most common RYR1 mu- than the general population. In addition, each tations and has a detection rate of 25 percent.40 offspring of an individual with proven susceptibil- The genetic test is very specific; patients with a ity has a 50 percent chance of being susceptible. positive test are virtually assured of being at risk of The patient’s grandchildren would be considered malignant hyperthermia. to be at 25 percent risk until their parents’ genetic DNA testing is confounded by the genetic het- status is known.33 erogeneity of the disorder33,41,42; thus, it should only be used in selected cases and within the Eu- FACILITY REQUIREMENTS ropean Malignant Hyperthermia Group or North It is recommended that plastic surgeons use American Malignant Hyperthermia Group guide- guidelines and recommendations for safe office- lines for DNA testing.43,44 At present, there are based anesthesia and surgery published by the two laboratories in the United States that per- American Society of Anesthesiologists, the Amer- form molecular genetic testing for malignant ican College of Surgeons, the ASPS, and the Amer- hyperthermia.45 ican Society for Aesthetic Plastic Surgery.46–54 Both the American Society for Aesthetic Plastic Surgery Interpreting Risk for Family Members and the ASPS require that their members operate An affected patient will have inherited malig- only in an accredited or licensed facility for all nant hyperthermia sensitivity from one of the par- procedures that essentially involve anesthesia greater than just local. All office surgical suites where general anes- ␣ Fig.1.(Continued)( 1S subunit)providesphysicallinksbetween thesia is used should be equipped to manage a dihydropyridinereceptorswithintransversetubulesandCa2ϩ re- malignant hyperthermia emergency. Surgeons lease channels within junctional sarcoplasmic reticulum. Those should be encouraged to review their state and calcium channels are known as ryanodine receptors. Then, the national guidelines, because several state medical free Ca2ϩ stored within the sarcoplasmic reticulum terminal cis- boards have established regulations concerning ternae is released to the cytoplasm of the muscle fibers. The in- availability of dantrolene in the office. For increase in Ca2ϩ removes the troponin inhibition from the contrac- stance, the Massachusetts Medical Board devel- tile proteins, resulting in muscle contraction. Sarcoplasmic/ oped office-based surgical guidelines and recom- endoplasmic reticulum Ca2ϩ–adenosine triphosphatase mended that the office have at least 20 ampules of (ATPase) rapidly reaccumulate Ca2ϩ back into the sarcoplasmic dantrolene for level II and III procedures. The reticulum, and relaxation occurs. Exposure of a susceptible indi- Mississippi Medical Board and Florida Medical vidual to a triggering agent results in an abnormal amount of Board passed regulations requiring at least 12 and Ca2ϩ in the myoplasm; the muscle remains in a contracted state; 36 ampules of dantrolene in a level II and III andabnormalamountsoflacticacid,carbondioxide,phosphate, office, respectively. In those guidelines, it is rec- and heat are produced. This is the source of the metabolic aci- ommended that the office-based surgery suite dosis, hypercapnia, hyperphosphatemia, and fever in the patient must have sufficient equipment (i.e., pulse oximetry, with a malignant hyperthermia crisis. Mitochondria are uncou- capnography, temperature monitoring equip- pled and adenosine triphosphate (ATP) production decreases, ment, continuous electrocardiography, emer- whereas the consumption of both adenosine triphosphate and gency resuscitative equipment), supplies [i.e., oxygen increases. The function of ion transport systems of the sterile water sufficient to dilute Dantrium (JHP sarcolemmal membrane ceases. Ions such as potassium, phos- Pharmaceuticals, Parsippany, N.J.)], D50, antiar- phate, and magnesium, in addition to myoglobin, begin to leak rhythmics, calcium chloride, sodium bicarbonate, acrossthesarcolemmaintotheextracellularfluidandtheirserum insulin, furosemide, and adequate ice), trained levels rise. (Reproduced with permission from Litman RS, Rosen- personnel, transfer and emergency protocols, berg H. Malignant hyperthermia: Update on susceptibility test- and facility accreditation to treat a malignant ing. JAMA. 2005;293:2918-2924. Copyright 2005, American Med- hyperthermia emergency (Fig. 3).48 Although ical Association. All rights reserved.) having the necessary medication and equipment

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Fig. 2. An algorithm for the surgeon to work up a patient with a family history of malignant hyperthermia (MH). A first-degree relative (the surgical candidate or the patient) of a proband who has been determined to be susceptible to malignant hyperthermia by a clinical episode plus either a positive caffeine-halothane contracture test (CHCT) result or a mutation analysis should be counseled and referred to the Malignant Hyperthermia Association of the United States (MHAUS) for susceptibility testing. Biopsy test centers and mutation analysis laboratories are provided by the Malignant Hyperthermia Association of the United States at http://www.mhaus.org. If testing cannot be performed, a first-degree relative (the patient) should be considered malignant hyperthermia susceptible and referred to an ambulatory surgical center (ASC) or hospital for surgery. (Adapted from Litman RS, Rosenberg H. Malignant hyperthermia: Update on susceptibility testing. JAMA. 2005;293:2918-2924.) to treat a malignant hyperthermia reaction is free” and contains no traces of volatile gas. This essential, more importantly, it should be the can be ensured by selectively using a vaporizer- goal of managing the rare reaction in the office free anesthesia machine or by changing circuits, to quickly stabilize the patient and transfer them disabling or removing the vaporizers, and flush- to an acute care facility where extensive person- ing the machine at a rate of 10 liters/minute for nel, laboratory resources (e.g., blood gases, elec- 20 minutes.58 trolytes), and critical care staff are suited to Malignant hyperthermia can also be trig- manage this life-threatening situation. gered by nontriggering agents in less than 1 percent of susceptible patients.59,60 Therefore, MANAGEMENT continued and reasonable use of general anes- Pretreatment of susceptible patients with dan- thesia, especially with triggering agents, in office trolene is no longer recommended to prevent trig- settings and ambulatory surgical centers man- gering of malignant hyperthermia with general dates active malignant hyperthermia protocols. anesthesia.55–57 Instead, nontriggering agents Practice drills should be considered if triggering must be used in all susceptible and suspect pa- agents, including succinylcholine, are used in the tients, and these procedures should be performed facility. Printed protocols on management of malig- in a facility fully equipped to treat malignant nant hyperthermia are available through the Malig- hyperthermia. Nitrous oxide is safe to use, pro- nant Hyperthermia Association of the United vided that the anesthesia machine is “vapor- States.58,61

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Fig. 3. A malignant hyperthermia cart and close-up view of malignant hyperthermia drugs. Dan- trolene sodium (Dantrium) is stocked on the hyperthermia cart. Unreconstituted product is stored at controlled room temperature (59° to 86°F or 15° to 30°C), and prolonged exposure to light should be avoided. The contents of the vial must be protected from direct light and used within 6 hours after reconstitution. Reconstituted solutions are stored at controlled room temperature (59° to 86°F or 15° to 30°C). The shelf life of dantrolene is 3 years and it costs $69 per bottle. The open drawer in this malignant hyperthermia cart can keep 36 bottles of dantrolene. Boxes contain six vials each.

Whenever possible, nontriggering agents without generalized muscle rigidity, can also oc- should be considered for outpatient procedures cur; Figure 4 provides an algorithm for its man- to help avoid or minimize malignant hyperther- agement. mia cases. For instance, one study62 used only the The treatment of malignant hyperthermia in nontriggering agents propofol and vecuronium the acute phases involves discontinuation of vol- (nondepolarizing muscle relaxant), and reported atile agents and succinylcholine, and simulta- no malignant hyperthermia in 23,000 office-based neous mobilization of all available personnel. A plastic surgery procedures performed under gen- call to a 911 operator should be made to prepare eral anesthesia. In addition, multiple studies have for patient transfer to an acute care hospital. At demonstrated the safety of intravenous conscious the same time, the medical staff should continue sedation. to administer dantrolene; attempt to cool the patient; and correct any dysrhythmias, hyperkalemia, and metabolic acidosis.61 Diagnosis and Treatment of Malignant Dantrolene sodium, a hydantoin derivative, is Hyperthermia the drug of choice for preventing and reversing The onset of malignant hyperthermia signs the symptoms of malignant hyperthermia.64,65 It may vary in order and time, often making clinical appears that dantrolene acts to stabilize domain diagnosis rather difficult. Furthermore, a variety interactions within the ryanodine receptor,66–70 of unusual conditions that include sepsis, thyroid which in turn reduces calcium efflux from the storm, pheochromocytoma, and iatrogenic over- sarcoplasmic reticulum (Fig. 1). heating may resemble malignant hyperthermia In an acute episode, rapid dantrolene resus- during anesthesia. An impending episode is her- citation is of the highest priority; therefore, it is alded by a rising end tidal carbon dioxide level in imperative that all perioperative staff have the anesthetized patient.63 However, the differen- knowledge about the pathophysiology and treat- tial diagnosis of unexplained end tidal carbon di- ment of malignant hyperthermia. Thus, it is rec- oxide should include hyperthermia secondary to ommended that all staff frequently review pro- sepsis, iatrogenic warming, rebreathing, machine tocols for recognizing and treating malignant valve dysfunction, or equipment malfunction.33 hyperthermia. Skeletal muscle (particularly masseter muscle) When preparing dantrolene for injection, spasm, tachycardia, acidosis, hyperthermia, and each 20-mg vial of dantrolene should be dissolved hyperkalemia are other signs. Trismus, with or with at least 60 ml of sterile, preservative-free wa-

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Fig. 4. An algorithm for the management of masseter muscle spasm associated with or without generalized muscle rigidity in an anesthetized patient. MH, malignant hyperthermia.

ter. Prewarming (not to exceed 39°C) the sterile formed according to American Society of water may expedite dissolving of dantrolene. The Anesthesiologists guidelines. vial should be shaken until the solution is clear. The contents of the vial must be protected from CONCLUSIONS direct light and used within 6 hours after recon- Both level II and level III office procedures, stitution. Reconstituted solutions are stored at whether with deep sedation, general anesthesia controlled room temperature (59° to 86°F or 15° (with or without triggering agents), or major con- to 30°C).61 duction blockade, require malignant hyperther- In acute malignant hyperthermia, therapy mia preparedness with immediate availability of should be started by administering 2.5 mg/kg of dantrolene, as recommended by some medical dantrolene as a rapid bolus through a large-bore boards and accreditation agencies. In addition to intravenous line, repeating this administration proper patient selection, safe anesthesia proto- at 5-minute intervals until signs of an episode cols, adequate equipment, appropriate monitor- are reversed. Once the patient has been stabi- ing, availability of trained personnel, and appro- lized, continuous intravenous infusion of dan- priate accreditation of the facility, a malignant trolene at 10 mg/kg/day (or even up to 30 mg/ hyperthermia protocol should be considered as an kg) should be given for at least 24 hours after the integral part of safe office-based surgery and an- initial successful therapy, and the patient should esthesia, regardless of a patient’s susceptibility sta- be admitted to the hospital and observed in the tus. All office surgical suites should be ready and intensive care unit for at least 24 hours, because able to handle a malignant hyperthermia emer- of the risk of recrudescence.61 Oral dantrolene gency. Unless procedures involve the use of top- capsules can be administered following a ma- ical or local anesthetics, susceptible individuals are lignant hyperthermia crisis to prevent recur- not candidates for office-based surgery, and any- rence. Postoperative monitoring should be per- one identified for susceptibility to triggering

76S Volume 124, Number 4S • Malignant Hyperthermia agents should be referred to an accredited ambu- Plastic Surgery Center, and Holy Spirit Hospital, latory surgical center or hospital for surgery. Camp Hill, Pennsylvania. Raffi Gurunluoglu, M.D., Ph.D. 777 Bannock Street ACKNOWLEDGMENTS Denver, Colo. 80204 The Patient Safety Committee thanks DeLaine [email protected] Schmitz, R.N., M.S.H.L., and Patti Swakow at the ASPS for assistance with article review.

ASPS PATIENT SAFETY COMMITTEE REFERENCES MEMBERS 1. Denborough MA, Lovell RRH. Anesthetic deaths in a family. The ASPS Patient Safety Committee members Lancet 1960;2:45. are as follows: Phillip C. Haeck, M.D., chairman; 2. Greenhalgh T. How to Read a Paper: The Basics of Evidence-Based Medicine. 3rd ed. Oxford: Blackwell Publishing; 2006. Stephen B. Baker, M.D., D.D.S., Georgetown Uni- 3. Lang TA, Secic M. How to Report Statistics in Medicine. 2nd ed. versity Hospital, Washington, D.C.; Charles W. Philadelphia: American College of Physicians; 2006. Bailey, Jr., M.D., J.D., Austin, Texas; C. Bob Basu, 4. Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence- M.D., M.P.H., Center for Advanced Breast Resto- Based Medicine: How to Practice and Teach EBM. 3rd ed. Phil- ration and Basu Plastic Surgery, Houston, Texas; adelphia: Elsevier Churchill Livingstone; 2005. 5. Evidence-Based Medicine Working Group. Users’ Guides to the Lynn A. 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17. Robinson RL, Brooks C, Brown S, et al. RYR1 mutations Registry. The North American Malignant Hyperthermia Reg- causing central core disease are associated with more severe istry of MHAUS. Anesthesiology 1998;88:579–588. malignant hyperthermia in vitro contracture test pheno- 39. Malignant Hyperthermia Association of the United States. types. Hum Mutat. 2002;20:88–97. MH muscle biopsy test centers page. Available at: http:// 18. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant- www.mhaus.org/index.cfm/fuseaction/Content.Display/ hyperthermia susceptibility is associated with a mutation of PagePK/BiopsyTestCenter.cfm. Accessed May 24, 2008. the alpha 1-subunit of the human dihydropyridine-sensitive 40. Sei Y, Sambuughin NN, Davis E, et al. Malignant hyperther- L-type voltage-dependent calcium-channel receptor in skel- mia in North America: genetic screening of the three hot etal muscle. Am J Hum Genet. 1997;60:1316–1325. spots in the type I ryanodine receptor gene. 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Malignant hyperthermia and the oto- 46. American Society of Anesthesiologists. Office-based anesthe- laryngologist. Ear Nose Throat J. 2003;82:433–436. sia guidelines. Available at: http://www.asahq.org/Washington/ 27. Topel DG, Bicknell EJ, Preston KS, Christian LL, Matsushima oba.htm. Accessed June 3, 2008. CY. Porcine stress syndrome. Mod Vet Pract 1968;49:40–60. 47. Rohrich RJ, White PF. Safety of outpatient surgery: Is man- 28. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al. A datory accreditation of outpatient surgery centers enough? noninvasive investigation of muscle energetics supports sim- Plast Reconstr Surg. 2001;107:189–192. ilarities between exertional heat stroke and malignant hy- 48. American Society of Anesthesiologists. Office-based anesthe- perthermia. Anesth Analg. 2001;93:683–689. sia: State statutes, regulations and guidelines. Available at: 29. Hackl W, Winkler M, Mauritz W, Sporn P, Steinbereithner K. http://www.asahq.org/Washington/rulesregs.htm. 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Part II. Can J facilities: II. Patient selection. Plast Reconstr Surg. 2002;110: Anaesth. 2004;51:782–794. 1785–1790; discussion 1791–1792. 33. Rosenberg H, Davis M, James D, Pollock N, Stowell K. Ma- 52. Horton JB, Reece EM, Broughton G II, Janis JE, Thornton JF, lignant hyperthermia. Orphanet J Rare Dis. 2007;2:21. Rohrich RJ. Patient safety in the office-based setting. Plast 34. Larach MG. Standardization of the caffeine halothane mus- Reconstr Surg. 2006;117:61e–80e. cle contracture test. North American Malignant Hyperther- 53. Byrd HS, Barton FE, Orenstein H, et al. Safety and efficacy mia Group. Anesth Analg. 1989;69:511–515. in an accredited outpatient plastic surgery facility: A review 35. Litman RS, Rosenberg H. Malignant hyperthermia: Update of 5316 consecutive cases. Plast Reconstr Surg. 2003;112:636– on susceptibility testing. JAMA. 2005;293:2918–2924. 641; discussion 642–646. 36. Rosenberg H, Antognini JF, Muldoon S. Testing for malig- 54. 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58. Malignant Hyperthermia Association of the United States. 70. Murayama T, Oba T, Kobayashi S, Ikemoto N, Ogawa I. The ABC’s of managing malignant hyperthermia. Available Postulated role of interdomain interactions within the type at: http://www.mhaus.org/index.cfm/fuseaction/Online 1 ryanodine receptor in the low gain of Ca2ϩ-induced Ca2ϩ Brochures.Display/BrochurePK/BCD9151D-3048-709E- release activity of mammalian skeletal muscle sarcoplasmic 5A445BC0808B4767.cfm. Accessed November 5, 2008. reticulum. Am J Physiol. 2005;288:C1222–C1230. 59. Carr AS, Lerman J, Cunliffe M, McLead ME, Britt BA. 71. Larach MG, Localio AR, Allen G, et al. A clinical grading scale Incidence of malignant hyperthermia reactions in 2,214 to predict malignant hyperthermia susceptibility. Anesthesi- patients undergoing muscle biopsy. Can J Anaesth. 1995; ology 1994;80:771–779. 42:281–286. 72. Sambuughin N, Sei Y, Gallagher K, et al. North American 60. Hackl W, Mauritz W, Winkler M, Sporn P, Steinbereithner K. malignant hyperthermia population: Screening of the ryan- Anaesthesia in malignant hyperthermia-susceptible patients odine receptor gene and identification of novel mutations. without dantrolene prophylaxis: A report of 30 cases. Acta Anesthesiology 2001;95:594–599. Anaesthesiol Scand. 1990;34:534–537. 73. Anderson AA, Brown RL, Polster B, Pollock N, Stowell KM. 61. Malignant Hyperthermia Association of the United States. Identification and biochemical characterization of a novel Emergency therapy for malignant hyperthermia. Available at: ryanodine receptor gene mutation associated with malig- http://medical.mhaus.org/PubData/PDFs/treatmentposter. nant hyperthermia. Anesthesiology 2008;108:208–215. pdf. Accessed May 24, 2008. 74. Britt BA, Endrenyi L, Frodis W, Scott E, Kalow W. Com- 62. Hoefflin SM, Bornstein JB, Gordon M. General anesthesia parison of effects of several inhalation anaesthetics on in an office-based plastic surgical facility: A report on more caffeine-induced contractures of normal and malignant than 23,000 consecutive office-based procedures under hyperthermic skeletal muscle. Can Anaesth Soc J. 1980;27: general anesthesia with no significant anesthetic compli- 12–15. cations. Plast Reconstr Surg. 2001;107:243–251; discussion 75. Reed SB, Strobel GE Jr. An in-vitro model of malignant 252–257. hyperthermia: Differential effects of inhalation anesthetics 63. Baudendistel L, Goudsouzian N, Cote’ C, Strafford M. End-tidal on caffeine-induced muscle contractures. Anesthesiology 1978; CO2 monitoring: Its use in the diagnosis and management of 48:254–259. malignant hyperthermia. Anaesthesia 1984;39:1000–1003. 76. Flewellen EH, Nelson TE. Masseter spasm induced by suc- 64. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. 1975. Br J An- cinylcholine in children: Contracture testing for malignant aesth. 1998;81:626–629; discussion 625. hyperthermia. Report of six cases. Can Anaesth Soc J. 1982; 65. Kolb ME, Horne ML, Martz R. Dantrolene in human ma- 29:42–49. lignant hyperthermia. Anesthesiology 1982;56:254–262. 77. Snoeck MM, Gielen MJ, Tangerman A, van Egmond J, 66. Paul-Pletzer K, Yamamoto T, Bhat M, et al. Identification of Dirksen R. Contractures in skeletal muscle of malignant a dantrolene-binding sequence on the skeletal muscle ryan- hyperthermia susceptible patients after in vitro exposure odine receptor. J Biol Chem. 2002;277:34918–34923. to sevoflurane. Acta Anaesthesiol Scand. 2000;44:334–337. 67. Ikemoto N, Yamamoto T. Postulated role of inter-domain 78. Gallant EM, Godt RE, Gronert GA. Mechanical properties of interaction within the ryanodine receptor in Ca(2ϩ) chan- normal and malignant hyperthermia susceptible porcine nel regulation. Trends Cardiovasc Med. 2000;10:310–316. muscle: Effects of halothane and other drugs. J Pharmacol Exp 68. Yamamoto T, Ikemoto N. Spectroscopic monitoring of local Ther. 1980;213:91–96. conformational changes during the intramolecular domain- 79. Louis CF, Zualkernan K, Roghair T, Mickelson JR. The ef- domain interaction of the ryanodine receptor. Biochemistry fects of volatile anesthetics on calcium regulation by malig- 2002;41:1492–1501. nant hyperthermia-susceptible sarcoplasmic reticulum. An- 69. Kobayashi S, Bannister ML, Gangopadhyay J, Hamada T, esthesiology 1992;77:114–125. Parness J, Ikemoto N. Dantrolene stabilizes domain interac- 80. Nelson TE, Flewellen EH. Rationale for dantrolene vs. pro- tions within the ryanodine receptor. J Biol Chem. 2005;280: cainamide for treatment of malignant hyperthermia. Anes- 6580–6587. thesiology 1979;50:118–122.

Appendix A. Summary of Recommendations Recommendations Supporting Evidence Grade PATIENT SELECTION ● During patient assessment, patients should be asked about personal and 58, 61, 71 D family history of: –MH – Adverse anesthesia reactions (unexplained fever or death during anesthesia) ● Patients with suspected MH should be referred for appropriate diagnostic 37, 38 B testing: – CHCT or in vitro contracture test is the standard. – Genetic testing for mutations in the RYR1 gene may be considered; 16, 72, 73 B however, it typically cannot replace contracture tests, as it has low sensitivity. Results do not always correlate with a positive contracture test, which suggests that there may be other loci involved with MH. (Continued)

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Appendix A. (Continued) Recommendations Supporting Evidence Grade ● Patients susceptible to MH may undergo outpatient surgery, provided that 58, 61 D nontriggering anesthetics are used. All office surgical suites should be equipped to manage an MH emergency. However, anyone identified with MH susceptibility should be referred to an accredited ambulatory surgical center or hospital for surgery. PREOPERATIVE MANAGEMENT ● In patients susceptible to MH, do not use the following MH-triggering drugs: 74–79 B Inhaled general anesthetics: – Desflurane – Enflurane – Halothane – Isoflurane – Sevoflurane Depolarizing muscle relaxants: – Succinylcholine ● The surgical suite should be equipped to manage malignant hyperthermia. 58, 61 D Drugs and supplies should include: – Dantrolene sodium IV (36 vials) – Sterile water for dantrolene reconstitution – Sodium bicarbonate – Furosemide – Dextrose – Calcium chloride – Regular insulin (refrigerated) – Antiarrhythmics – A protocol for treating MH crisis. For additional information on how to treat a malignant hyperthermia crisis, consult the MHAUS documents, Emergency Therapy for Malignant Hyperthermia or The ABC’s of MH Management, both found on the MHAUS web site: http://medical.mhaus.org/. ANESTHESIA ● Local or regional anesthesia and monitored anesthesia care are considered 58, 61 D to be safe for individuals susceptible to MH; this includes spinal, epidural, and nerve block anesthesia using local anesthetics (e.g., lidocaine, bupivacaine). ● General anesthesia can be performed with alternative anesthetic regimens, 58, 61 D including barbiturates (e.g., thiopental), propofol, nondepolarizing paralytic agents (e.g., vecuronium) and their reversal agents, nitrous oxide, and opioids (e.g., fentanyl) (anesthesia machine preparation: change circuits, disable or remove the vaporizers, flush the machine at a rate of 10 liters/ min for 20 min). ● If general anesthesia will be used, patients should undergo body temperature 58, 61 D and capnographic monitoring. INTRAOPERATIVE MANAGEMENT ● Monitor for clinical signs of MH: 58, 61, 71 D – Signs of respiratory acidosis: ETCO Ͼ55 mmHg, PaCO Ͼ60 mmHg (with 2 Ͼ 2 Ͼ appropriately controlled ventilation); ETCO2 60 mmHg, PaCO2 65 mmHg (with spontaneous ventilation); inappropriate hypercarbia and/or tachypnea – Trunk or total body rigidity – Masseter muscle spasm or trismus – Sinus tachycardia; ventricular tachycardia; ventricular fibrillation – Rapidly increasing temperature, or inappropriately increased temperature (Ͼ38.8°C); may be a late sign – Signs of muscle breakdown: elevated serum creatine kinase after anesthetics that included succinylcholine (Ͼ20,000 IU) or anesthetics without succinylcholine (Ͼ10,000 IU); cola-colored urine; excess myoglobin in urine (Ͼ60 ␮g/liter) and serum (Ͼ170 ␮g/liter); blood/ plasma/serum Kϩ Ͼ6 mEq/liter (in absence of renal failure) – Other: arterial base excess Ͻ–8 mEq/liter; arterial pH Ͻ7.25; rapid reversal of MH signs of respiratory and/or metabolic acidosis with IV administration of dantrolene (Continued)

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Appendix A. (Continued) Recommendations Supporting Evidence Grade ● Treatment of MH crisis: – Call for help; summon emergency medical service. – Patient should be transferred to an acute care facility as soon as possible. – Administer dantrolene. 65, 80 B – Hyperventilate with 100% oxygen. 58, 61 D – Cool the patient. – Check electrolytes, especially potassium. – For specific treatment recommendations, consult the MHAUS documents, Emergency Therapy for Malignant Hyperthermia or The ABC’s of MH Management, both found on the MHAUS web site: http://medical.mhaus.org/. MH, malignant hyperthermia; CHCT, caffeine-halothane contracture test; IVCT, in vitro contracture test; IV, intravenously; MHAUS, Malignant Hyperthermia Association of the United States; ETCO2, end tidal carbon dioxide; PaCO2, partial pressure of carbon dioxide.

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