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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Current State of Malignant Hyperthermia And the Use of Dantrium IV as Treatment

Henry Rosenberg, MD

President Malignant Hyperthermia Association of the United States Director, Department of Medical Education and Clinical Research Saint Barnabas Medical Center Livingston, New Jersey

Introduction

Malignant hyperthermia (MH) exemplifies how the combination of clinical observation and laboratory science can lead to the identification, clarification, and improvement of patient care of an uncommon but potentially fatal disorder. MH is an autosomally inherited disorder characterized by an increase in heart rate, respiratory rate, body temperature, and muscle rigidity when the patient is exposed to potent volatile anesthetic gases (eg, halothane, sevoflurane, desflurane) and succinylcholine, a muscle relaxant.1

Prevalence

The onset of MH is unpredictable and the course of action is variable. Although anywhere from 500 to 800 cases of the syndrome are reported to the Malignant Hyperthermia Association of the United States (MHAUS) each year,2,3 the prevalence and incidence of MH are difficult to determine because patients display no characteristic signs until anesthetized with one of the triggering agents, and even then do not always develop the disorder.1 Based on the most recent study, the incidence of MH is 1 in 100,000 patients.4 Despite the rarity of this syndrome, the mortality rate was once as high as 80%.4 Overall, the mortality rate has decreased to less than 10%5; however, a recent study showed that patients who develop MH in a non-hospital setting (eg, an office or ambulatory surgical center) have a higher mortality rate than those developing MH in a hospital setting (19.8% vs 13.6%, respectively).6

Pathophysiology and Genetics of MH

Although there are pathognomonic clinical signs,7 a patient susceptible to

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MH will experience an increase in metab- Treatment of MH olism as a result of a rapid and unconInitial treatment of MH requires immetrolled increase in calcium within the muscle cells.8,9 Failure to regulate the cal- diate recognition of associated symptoms cium channels will cause the muscles to and removal of the triggering agent.9 With contract7 and increase the breakdown of the introduction of Dantrium IV (dantadenosine triphosphate, resulting in sig- rolene sodium for injection), a skeletal nificant heat production.7,8 Other changes muscle relaxant, patients with MH have include muscle rigidity, acidosis, mus- an effective treatment that binds to RyR1 cle membrane breakdown leading to receptors to block the release of calcium. rhabdomyolysis, and release of cellu- Patients with MH from 65 centers in the lar potassium.6 Consequently, the patient United States and Canada were enrolled can experience hyperthermia, cardiac in a 20-month study to assess the effiarrhythmias, or death.9 cacy of dantrolene sodium in humans.16 Genetic predisposition for MH is indi- Of the 21 patients treated with dantcated in 1 of 3,000 individuals.10 Studies rolene sodium, 11 recovered without indicate that patients susceptible to MH recrudescence.16 A recommended dose have mutations within the calcium chan- of 1 mg/kg every 4 to 8 hours for 24 to nel receptor--ryanodine receptor 1 (RyR1) 48 hours is effective in regulating the calgene--causing the uncontrolled release cium channels in the sarcoplasmic reticuof calcium from the sarcoplasmic retic- lum.17 Although 2.5 mg/kg of dantrolene ulum.1,11,12 RyR1 mutations proven to be sodium is the recommended dose by causal for MH have been found in at least MHAUS,18 some patients may require a 25% of patients susceptible to the syn- higher dose,7 as noted in a case report drome.1,13 About 50% of patients suscep- in which a 6-year-old child weighing tible to MH will display other mutations 25 kg required a dose of 42 mg/kg.19 Dantwhose significance is not yet deter- rolene sodium preparation requires 60 mL mined.14 Patients can be tested for MH of sterile water to dissolve a 20-mg using the caffeine­halothane contrac- vial.9 If the average dose for treatment ture test, which determines the con- of MH is 2.5 mg/kg, this means that for tractile properties of the skeletal muscle an average 70-kg patient, 9 vials of danwhen exposed to caffeine and halothane trolene are needed (2.5 mg × 70/20 mg (ie, RyR1 agonists).1,15 Recently, DNA anal- per vial). However, many adults are much ysis of the RyR1 gene has been introduced heavier than 70 kg. Given that some as a clinical diagnostic test for MH suscep- patients may need 10 mg/kg for treattibility under specific circumstances.7 How- ment, it has been recommended that ever, because DNA testing is not highly 36 vials be on hand (10 mg × 70/20 mg per sensitive, further research is required vial). The number of vials needed based before it becomes standard practice in on patient weight and potential dosing diagnosing MH susceptibility. are provided in the Table below.20

When Dantrium IV (dantrolene sodium for injection) was developed in 1979, it included sodium hydroxide and mannitol in order to stabilize the drug, but was available only in a dried, powder form. Dantrolene sodium was packaged in a 20-mg vial requiring reconstitution with 60 mL of non-bacteriostatic water. It took about 1 to 2 minutes to mix and draw up each vial of the drug.5,21 In 2007, US World Meds introduced the generic formulation of dantrolene sodium. Administering dantrolene sodium proved to be challenging because the agent was poorly soluble and multiple vials needed to be reconstituted for effective treatment.7 Studies also have indicated that, despite acute treatment of the MH crisis, recrudescence occurred in about 20% of cases.22 This has been shown to be related to the muscular build of the patient, temperature increases during the episode, and extended amount of time from induction to the onset of the syndrome.22 Because MH can progress to a life-threatening situation within a few moments, this was less than optimal. Recommendations were developed to guide clinicians on how to administer dantrolene sodium for injection: The recommended dose is 1 mg/kg and should be continued until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.20 In September 2009, a more rapidly soluble form of Dantrium® IV was FDAapproved that reduces the time needed for reconstitution. Now Dantrium® IV reconstitutes in approximately 20 seconds--4 times faster than the earlier version of the agent.23 A separate unblinded study

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Table. Number of Vials of Dantrium® IV (20 mg/vial) Needed to Treat an MH Crisis

Patient Weight kg lb

99

88 103 118 133 148

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Number of Vials to Achieve Dantrium Dose of: 1 mg/kg

2.3 3.7 4.4 5.2 5.9 6.7 7.4 2.9

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2.5 mg/kg

5.6 7.3 9.1 11.0 12.9 14.8 16.6 18.5

5 mg/kg

11.3 14.5 18.3 22.0 25.8 29.5 33.3 37.0

7.5 mg/kg

16.9 27.4 33.0 38.6 44.3 49.9 55.5 21.8

10 mg/kg

22.5 29.0 36.5 51.5 59.0 66.5 74.0 44.0

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128 161 194 227 260 293 326

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Supported by JHP Pharmaceuticals

by 4 independent observers compared older and new Dantrium® IV with regard to reconstitution time, time of transfer, and withdrawal time (Figure 1).24 A mean reconstitution time of 12.1 seconds was reported with the new Dantrium® IV. The packaging for the new Dantrium® IV has also been modified to reduce the time necessary for reconstitution. A red flip-off cap has been added to permit rapid opening of the vial, and a vacuum has been added to each vial to facilitate the entry of the diluent (non-bacteriostatic water) into the vial (Figure 2). All of these changes are significant and permit rapid mixing of Dantrium® IV. Dantrium® IV continues to have a shelf life of 36 months.23 In October 2009, Health Canada approved the rapidly mixing Dantrium® IV for the Canadian market.

6.

Figure 1. Comparison of Dantrium IV Blue label vs Red label.

®

Rosero EB, Adesanya AO, Timaran CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology. 2009;110(10):89-94. Hopkins PH. Malignant hyperthermia. Curr Anaesth Crit Care. 2008;19(1):22-33. Nelson TE. Heat production during anestheticinduced malignant hyperthermia. Biosci Rep. 2001;21(2):169-179. Stratman RC, Flynn JD, Hatton KW. Malignant hyperthermia: a pharmacogenetic disorder. Orthopedics. 2009;32(11):835-838.

120 -

7. 8.

Individual Value, sec

Figure 2. Dantrium® IV

(dantrolene sodium for injection). For more information about Dantrium® IV please visit www.dantrium.com Management of Malignant Hyperthermia (MH) crises requires various supportive measures individualized for the patient's condition. Administration of Dantrium® IV is one component of therapy and should not be considered a substitute for these measures. Even when properly treated, an MH crisis can result in death. Adverse events with Dantrium® IV include loss of grip strength, weakness in the legs, drowsiness, dizziness, thrombophlebitis, and tissue necrosis/ injection site reactions secondary to extravasation. There have been rare reports of pulmonary edema, urticaria, and erythema. Please see accompanying full prescribing information for Dantrium® IV.

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10. Monnier N, Krivosic-Horber R, Payen JF, et al. Presence of two different genetic traits in malignant hyperthermia families. Anesthesiology. 2002;97(5):1067-1074. 11. MacLennan DH, Duff C, Zorzato F, et al. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature. 1990;343(6258):559. 12. Sambuughin N, Sei Y, Gallagher K, et al. North American malignant hyperthermia population. Anesthesiology. 2001;95(30):594-599. 13. Sei Y, Sambuughin NN, Davis EJ, et al. Malignant hyperthermia in North America. Genetic screening of three hot spots in the Type I ryanodine receptor gene. Anesthesiology. 2004;101(4):824-830. 14. Robinson R, Curran JL, Hallsall PJ, et al. Genetic heterogeneity and HOMO analysis in British malignant hyperthermia families. J Med Genet. 1998;35(3):196-201. 15. Ali SZ, Taguchi A, Rosenberg H. Malignant hyperthermia. Best Pract Res Clin Anaesthesiol. 2003;17(4):519-533.

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Blue = old; Red = new

LCL, lower control limit; UCL, upper control limit

Resources

Although much has been learned about With the introduction of Dantrium® IV the clinical presentation and management along with dissemination of educational of MH, the rarity of this syndrome poses material and a better understanding the concern that overall awareness may of the clinical presentation and manbe lacking among anesthesia providers, agement of MH, the mortality rate has patients, and their families. In the United decreased significantly over the past few States, MHAUS was established to pro- decades. Early administration of dantrovide clinicians and individuals with MH lene sodium for injection in adequate a support network and resource through doses is required to treat MH successfully. which they can obtain the most effective As minimally invasive diagnostic testing approaches to patient care.25 Through its becomes more sensitive and available, it Web site (www.mhaus.org), newsletters, is anticipated that patients at risk will be and numerous educational programs, identified prior to being exposed to the MHAUS has been a driving force in edu- triggering agents, leading to fewer epicating clinicians, encouraging research sodes of MH and eliminating disability and studies to improve diagnostic testing mortality from this syndrome. and treatment, and creating awareness.25 For further information, please contact Additionally, the North American Malig- MHAUS via its Web site, www.mhaus.org, nant Hyperthermia Registry (NAMHR) or call (607) 674-7901. MHAUS is a notwas established to provide a database of for-profit organization. information derived from actual clinical episodes of MH.26 The NAMHR data have been invaluable in the standardization of References MH testing, the description of the dif- 1. Litman RS, Rosenberg H. Malignant hyperferent clinical presentations of MH, and thermia: update on susceptibility testing. JAMA. 2005;293(23):2918-2924. the documentation of the incidence of its morbidity and mortality, as well as 2. Brandom BW, Muldoon S. Estimation of the incidence of malignant hyperthermia using a capturea better understanding of its molecular recapture method in the USA. Anesthesiology. 2004;101:A1267. genetics. Studies using the NAMHR database have documented the incidence of 3. Larach MG, Brandom BW, Allen G, Gronert GA, Lehman EB. Cardiac arrests and deaths associated and mortality from MH,3 as well as the with malignant hyperthermia in North America from 1987-2006. Anesthesiology. 2008;108(4):603-611. molecular genetics of the syndrome.12 In 4. Brady JE, Sun LS, Rosenberg H, Li G. Preva1995, the NAMHR merged with MHAUS to lence of malignant hyperthermia due to anestheform an organization that could provide sia in New York State, 2001-2005. Anesth Analg. 2009;109(4):1162-1166. the latest data and educational developFK, Murray WB. Dantrolene ments, while continuing to emphasize 5. Quraishi SA, Orkin warmed diluent make differreconstitution: can ence? J Clin Anesth. 2006;18(5):339-342. patient advocacy.

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Conclusion

16. Kolb ME, Honre ML, Martz R. Dantrolene in human malignant hyperthermia. Anesthesiology. 1982;56(4):254-262. 17. Rosenberg H, Sambuughin N, Dirksen R. Malignant hyperthermia susceptibility. GeneReviews. January 19, 2010. http://www.ncbi.nlm.nih.gov/bookshelf/ br.fcgi?book=gene&part=mhs. Accessed February 17, 2010. 18. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110(2):498-507. 19. Blank JW, Boggs SD. Successful treatment of an episode of malignant hyperthermia using a large dose of dantrolene. J Clin Anesth. 1993;5(1):69-72. 20. Dantrium® IV [prescribing information]. Rochester, MI: JHP Pharmaceuticals; 2008. 21. Harrison TK. The use of a cognitive aid for the treatment of malignant hyperthermia. Daniel Massik Award Winner--October 2004. http://medical. mhaus.org/index.cfm/fuseaction/Content.Display/ PagePK/AbstractTKHarrison/cfm. Accessed January 12, 2010. 22. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology. 2007;106(5):901-906. 23. Dantrium® IV 12 FAQs. JHP Pharmaceuticals. Data on File 2009. 24. Dantrium® IV Reconstitution Time Pilot Program. Data on File 2009. 25. Malignant Hyperthermia Association of the United States. Annual Report 2007-2008. http://www. mhaus.org/PubData/PDFs/2007-2008_Annual_ Report.pdf. Accessed January 13, 2010. 26. The North American Malignant Hyperthermia Registry. http//www.mhreg.org. Accessed January 13, 2010. BB106

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