Abstracts & Articles

New Research

New Research

A Retrospective Review of the Dantrolene Formulations Administered to Subjects Registered in NAMHR

Lobmeyer, Erica; Gravenstein, Nikolaus; Smith, Cameron; Gunnett, Amy; Woods, Anna; McDougall, Heather

Introduction: Dantrolene is the primary injection treatment for malignant hyperthermia (MH). Dantrolene powder requires considerable effort to reconstitute because in its traditional formulations (dantrolene sodium for injection), it takes approximately 129 seconds to dissolve 20 mg in the required 60 mL of sterile water1. In 2015, a more concentrated and soluble dantrolene formulation (lyophilized dantrolene sodium injectable suspension) entered the market. This newer formulation takes approximately 10 seconds to dissolve 250 mg in 5 ml of sterile water but is more expensive and has a shorter shelf life according to package insert.

Methods: After IRB approval (IRB# 201901131), we gathered data from the North American Malignant Hyperthermia Registry on patients who received dantrolene as part of their treatment for MH from 2013 to the present. We assessed whether the traditional formulation (dantrolene sodium for injection) or the new formulation (lyophilized dantrolene sodium injectable suspension) was administered and also collected the MH Clinical Grading Scale scores2 of the cases in the registry where either formulation was used.

Results: The Clinical Grading Scores of 97 cases where dantrolene was administered ranged from 15 to 100, with a mean of 43.75 (Figure 1). There were three cases where dantrolene was administered but a Clinical Grading Scale score was not computed. The distribution of cases where old and new formulations were used is shown in Figure 2. Dantrolene sodium for injection is shown in blue, the lyophilized dantrolene sodium injectable solution in orange, and where the formulation was not specified in gray.

Conclusion: From the registry data, it appears that in the 5 years since the lyophilized dantrolene came on the market, the new formulation has exceeded 50% use in cases reported to the North American Malignant Hyperthermia Registry where dantrolene was administered. This new formulation, though much more concentrated, requires less time and volume of sterile water to dissolve lending itself to quicker administration. These data reflect a fairly quick but still incomplete adoption of the new formulation for the initial treatment of a presumed MH event. The Clinical Grading Scale scores in the registry reported cases where dantrolene was administered ranged from an MH likelihood score of “somewhat less than likely” through “almost certain,” with a mean likelihood of MH score of “very likely.”

References

1. Anesth Analg 2019;129:e201–e202.
2. Anesthesiology 1994;80:771–779.

Abstracts

• Presented to the International Anesthesia Research Society (IARS) 2020: Lobmeyer, Erica; Gravenstein, Nikolaus; Smith, Cameron; Gunnett, Amy; Woods, Anna; McDougall, Heather: A Retrospective Review of the Dantrolene Formulations Administered to Subjects Registered in NAMHR.
• Presented to the International Anesthesia Research Society (IARS) 2015: Werneid K, Riazi S, Brandom BW: Long-term sequelae in patients who experienced a malignant hyperthermia event.
• Presented to the American Society of Anesthesiologists (ASA) 2013: Larach MG, Brandom BW, Allen GC, Gronert GA: Failure to rescue from fulminant malignant hyperthermia: deaths and their genetic variants 2007-2012.
• Presented to the American Society of Anesthesiologists (ASA) 2011: Barbara W. Brandom, M.D., James Wilde, B.A., Michael C. Young, M.S.: Pain Reported by Malignant Hyperthermia Susceptible Subjects.
• Presented to the American Society of Anesthesiologists (ASA) 2011: Brandom BW, Wilde J, Young MC: Chronic pain symptoms in malignant hyperthermia.
• Presented to the European Malignant Hyperthermia Group 2010: Brandom BW, Muldoon, SM, Sambuughin N: More than Anesthetic Induced Malignant Hyperthermia (MH).
• Presented to the European Malignant Hyperthermia Group 2009: Brandom BW, Muldoon SM, Wong C, Rosenberg H, Tautz T, Sambuughin N: An Update on the Ryanodine Receptor Gene Variants found in the USA.
• Presented to the American Society of Anesthesiologists (ASA) 2008: Larach MG, Allen GC, Brandom BW, Gronert GA, Lehman EB: Temperature changes are not late signs of malignant hyperthermia: A NAMH Registry of MHAUS Study
• Presented to the American Society of Anesthesiologists (ASA) 2008: Scientific Papers, in review. Larach MG, Allen GC, Brandom BW, Gronert GA, Lehman EB: Serious complications associated with malignant hyperthermia events: A NAMH Registry of MHAUS Study.
• Presented to the American Society of Anesthesiologists (ASA) 2007: Sambuughin N, Brandom B, Capacchione J, Rosenberg H, Muldoon S: Toward updating the North American Malignant Hyperthermia Mutation Panel.
• Presented to the American Society of Anesthesiologists (ASA) 2006: Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB: Deaths associated with malignant hyperthermia (1987-2006). A North American MH Registry of MHAUS Study.
• Presented to the American Society of Anesthesiologists (ASA) 2005: Torp KD, Brandom BW, Capacchione JF, Voelkel ML, Muldoon SM: Caffeine halothane contracture test and ryanodine receptor type 1 analysis in patients who experienced MH episodes.
• Presented to the American Society of Anesthesiologists (ASA) in 2005: Burkman JM, Posner KL, Domino KB: Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions.
• Presented to the American Society of Anesthesiologists (ASA) in 2004: Sambuughin N, Holley H, Brandom B, Nelson T, Muldoon S: Comprehensive screening of the RYR1 gene for malignant hyperthermia susceptibility.
• Presented to the European Congress of Nursing in 2004, previously presented to the American Association of Nurse Anesthethists 2003: Ciceron MC, Lauriello R, McCarthy EJ, McDonough JP: Differences in clinical manifestations in malignant hyperthermia episodes with succinylcholine or volatile anesthetics.
• Presented to the Society for Pediatric Anesthesia 2003: Brandom BW, Larach MG, Gurgis F: Comparison of pediatric and adult patients with regard to the safety and efficacy of dantrolene.
• Presented to the American Society of Anesthesiologists 2002: Kozack JK: A survey of chronic muscle pain and other symptoms in malignant hyperthermia susceptible individuals.
• Presented to the American Society of Anesthesiologists 2002: Brandom BW, Larach MG: Reassessment of the safety and efficacy of dantrolene.

Articles

The following articles include data from or otherwise depend upon the North American MH registry.

• Guglielminotti J, Rosenberg H, Li G.  Prevalence of malignant hyperthermia diagnosis in obstetric patients in the United States, 2003 to 2014.  BMC Anesthesiol. 2020;20(1):19.
• Müller-Wirtz, Lukas & Godsch, Christine & Sessler, Daniel & Volk, Thomas & Kreuer, S. & Hüppe, Tobias. (2020). Residual volatile anesthetics after workstation preparation and activated charcoal filtration. Acta Anaesthesiologica Scandinavica. 64. 10.1111/aas.13571.
• Guglielminotti, J., Rosenberg, H. & Li, G. Prevalence of malignant hyperthermia diagnosis in obstetric patients in the United States, 2003 to 2014. BMC Anesthesiol20, 19 (2020)
• Rutkowsky JM, Knotts TA, Allen PD, Pessah IN, Ramsey JJ. Sex-specific alterations in whole body energetics and voluntary activity in heterozygous R163C malignant hyperthermia-susceptible mice. FASEB J. 2020 Jun;34(6):8721-8733.
• Chang L, Daly C, Miller DM, Allen PD, Boyle JP, Hopkins PM, Shaw MA. Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals. Br J Anaesth. 2019 May;122(5):613-621.
• Altamirano F, Riazi S, Ibarra Moreno CA, Kraeva N, Uryash A, Allen PD, Adams JA, Lopez JR. Is malignant hyperthermia associated with hyperglycaemia? Br J Anaesth. 2019 Jan;122(1):e3-e5.
• Dirksen RT, Allen PD, Lopez JR. Understanding malignant hyperthermia: each move forward opens our eyes to the distance left to travel. Br J Anaesth. 2019 Jan;122(1):8-9.
• Larach MG, Klumpner TT, Brandom BW, Vaughn MT, Belani KG, Herlich A, Kim TW, Limoncelli J, Riazi S, Sivak EL, Capacchione J, Mashman D, Kheterpal S on behalf of the Multicenter Perioperative Outcomes Group. Succinylcholine use and dantrolene availability for malignant hyperthermia treatment:  database analyses and systematic review.  Anesthesiology 2019; 130:41-54
• Lopez JR, Kaura V, Diggle CP, Hopkins PM, Allen PD. Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the p.G2435R variant of RYR1. Br J Anaesth. 2018 Oct;121(4):953-961.
• Larach, MG. A primer for diagnosing and managing malignant hyperthermia susceptibility.  Anesthesiology 2018; 128:8-10
• Merritt A, Booms P, Shaw MA, Miller DM, Daly C, Bilmen JG, Stowell KM, Allen PD, Steele DS, Hopkins PM. Assessing the pathogenicity of RYR1 variants in malignant hyperthermia. Br J Anaesth. 2017 Apr 1;118(4):533-543.
• Butala, B. & Brandom, B. Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility. Can J Anesth/J Can Anesth. 2017; 64: 396
• Lu Z, Rosenberg H, Li G. Prevalence of malignant hyperthermia diagnosis in hospital discharge records in California, Florida, New York, and Wisconsin. J Clin Anesth. 2017;39:10-14.  
• Wang, Mi & Singh, Asha & Qureshi, Hashim & Leone, Alexander & Mascha, Ed & Sessler, Daniel. (2016). Optimal Depth for Nasopharyngeal Temperature Probe Positioning. Anesthesia and analgesia. 122. 10.1213/ANE.0000000000001213.
• Lu Z, Rosenberg H, Brady JE, Li G. Prevalence of Malignant Hyperthermia Diagnosis in New York State Ambulatory Surgery Center Discharge Records 2002 to 2011. Anesth Analg. 2016;122(2):449-53.
• Joseph M, Theroux MC, Mooney J, Falitz S, Brandom B, Byler D. Intra-operative presentation of malignant hyperthermia (confirmed by RYR1 gene mutation, c.7522C>T; p.R2508C) leads to diagnosis of King-Denborough syndrome in a child with undiagnosed myopathy.  Anesthesia Analgesia. 2016.
• Butala BN, Kang A, Guron J, Brandom BW. Long term oral dantrolene improved muscular symptoms in a malignant hyperthermia susceptible individual. Journal of Neuromuscular Diseases. 2016; 3: 115-9.
• Werneid K, Brandom B. Survey of long-term sequelae in survivors of a malignant hyperthermia reaction. Open Journal of Anesthesiology. 2016; 6: 1-7.
• Cacheux M, Blum A, Sébastien M, Wozny AS, Brocard J, Mamchaoui K, Mouly V, Roux-Buisson N, Rendu J, Monnier N, Krivosic R, Allen P, Lacour A, Lunardi J, Fauré J, Marty I. Functional Characterization of a Central Core Disease RyR1 Mutation (p.Y4864H) Associated with Quantitative Defect in RyR1 Protein. J Neuromuscul Dis. 2015 Nov 20;2(4):421-432.
• Brandom BW, Kang A, Sivak EL, Young MC. Update on dantrolene in the treatment of anesthetic induced malignant hyperthermia. SOJ Anesthesiol and Pain Manag. 2015; 2(2):1-6.
• Pinyavat T, Rosenberg H, Lang BH, Wong CA, Riazi S, Brady JE, Sun LS, Li G. Accuracy of malignant hyperthermia diagnoses in hospital discharge records. Anesthesiology. 2015;122(1):55-63.
• Aderibigbe T, Lang BH, Rosenberg H, Chen Q, Li G. Cost-effectiveness analysis of stocking dantrolene in ambulatory surgery centers for the treatment of malignant hyperthermia. Anesthesiology. 2014;120(6):1333-8.
• Wu X, Brady JE, Rosenberg H, Li G. Emergency Department Visits for Heat Stroke in the United States, 2009 and 2010. Inj Epidemiol. 2014;1(1):8.
• Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesth Analg 2014; 119(6): 1359-1366
• Nelson P, Litman RS. Malignant hyperthermia in children: an analysis of the North American Malignant Hyperthermia Registry. Anesth Analg 2014; 118: 369-374
• Visoiu M, Young MC, Wieland K, Brandom BW. Anesthetic drugs and onset of malignant hyperthermia. Anesth Analg 2014; 118: 388-396
• Brandom BW, Bina S, Wong CA, Wallace T, Visoiu M, Isackson PJ, Vladutiu GD, Sambuughin N, Muldoon SM. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg 2013; 116:1078-86
• Lavezzi WA, Capacchione JF, Muldoon SM, Sambuughin N, Bina S, Steele D, Brandom BW. Death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old. Anesth Analg 2013; 116:420-3
• Li G, Brady JE, Rosenberg H, Sun LS. Excess comorbidities associated with malignant hyperthermia diagnosis in pediatric hospital discharge records. Paediatr Anaesth. 2011;21(9):958-63.
• Brandom BW, Larach MG, Chen MA, Young MC. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Association of the United States. Anesth Analg 2011; 112:1115-23
• 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; 110:498-507
• Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth Analg. 2009;109(4):1162-6.
• Litman RS, Flood CD, Kaplan RF, Kim YL, Tobin JR. Postoperative malignant hyperthermia; an analysis of cases from the North American Malignant Hyperthermia Registry. Anesthesiology 2008; 109:825-9
• Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Cardiac arrests and deaths associated with malignant hyperthermia in North America from 1987 to 2006. Anesthesiology 2008; 108:603-11
• Newmark JL, Voelkel M, Brandom BW, Wu J. Delayed onset of malignant hyperthermia without creatine kinase elevation in a geriatric, ryanodine receptor type 1 gene compound heterozygous patient. Anesthesiology 2007; 107(2):350-3
• Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology 2007; 106:901-6
• Fink EL, Brandom BW, Torp KD. Heat stroke in the super-sized athlete. Pediatric Emergency Care 2006; 22: 510-3
• Sambuughin N, Holley H, Muldoon S, Brandom BW, de Bantel AM, Tobin JR, Nelson TE, Goldfarb LG. Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the North American Population. Anesthesiology 2005; 102:515-521
• Sei Y, Sambuughin NN, Davis EJ, Sachs D, Cuenca B, Brandom BW, Tautz T, Rosenberg H, Nelson TE, Muldoon SM. Malignant hyperthermia in North America; Genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824-830
• Barbara W. Brandom, M.D., Sheila M. Muldoon, M.D. Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Estimation of the Incidence of Malignant Hyperthermia Using a Capture-Recapture Method in the USA. Anesthesiology 2004; 101:A1267
• Muldoon SM, Deuster P, Brandom BW, Bunger R: Is there a link between malignant hyperthermia and exertional heat illness. Exercise and Sport Sciences Reviews 2004; 32:174-179
• Sei Y, Sambuughin NN, Davis EJ, Sachs D, Cuenca PB, Brandom BW, Tautz T, Rosenberg H, Nelson TE, Muldoon SM: Malignant Hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824-830
• Sei Y, Brandom BW, Bina S, Hosio E, Gallagher KL, Wyre HW, Pudimat PA, Holman SJ, Venzon DJ, Daly JW, Muldoon SM: Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes. Anesthesiology 2002; 97:1052-1058
• Allen GC, Larach MG, Kunselman AR, The North American MH Registry: The sensitivity and specificity of the caffeine halothane contracture test. Anesthesiology 1998; 88:579-588
• Albrecht A, Wedel DJ, Gronert GA: Masseter muscle rigidity and non-depolarizing neuromuscular blocking agents. Mayo Clin Proc 1997; 72:329-332
• Larach MG, Rosenberg H, Gronert GA, Allen GC: Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila) 1997; 36:9-16
• Antognini JF: Creatine kinase alterations after acute malignant hyperthermia episodes and common surgical procedures. Anesth Analg 1995; 81:1039-1042
• Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, et al: A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771-779
• Larach MG, Landis JR, Bunn JS, Diaz M, The North American MH Registry: Prediction of malignant hyperthermia susceptibility in low-risk subjects. Anesthesiology 1992; 76:16-27
• Larach MG: Standardization of the caffeine halothane muscle contracture test, North American Malignant Hyperthermia Group. Anesth Analg 1989; 69:511-515