Malignant Hyperthermia Prevention and Treatment

Malignant hyperthermia is a life-threatening, rare complication that develops suddenly after exposure to succinylcholine or halogenated volatile anesthetics (desflurane, isoflurane or sevoflurane).1-3 Genetically predisposed patients can develop uncontrolled calcium release within their muscles after receiving these triggering meds.1,4,16 This surge of calcium causes severe muscle spasms that lead to rapid core body temperature increases (1°C to 2°C every 5 minutes).1,2,4 If calcium release is not quickly stopped, malignant hyperthermia crisis causes rhabdomyolysis, hyperkalemia, arrhythmias, acute renal failure, brain damage, internal bleeding, and death.1-4 Prompt treatment with dantrolene (Dantrium, Revonto, Ryanodex, etc) is critical for halting calcium release and preventing poor outcomes.1-5,14,16 The chart below reviews prevention and treatment of malignant hyperthermia crisis, and provides suggestions for ensuring readiness and regulatory preparedness.

Abbreviations: IV = intravenous; PO = oral; SWFI = sterile water for injection; MHAUS = Malignant Hyperthermia Association of the United States


Topic/Issue

Suggestions/Pertinent Information

Risk factors for malignant hyperthermia


Affects 1 in 2,000 people, is more common in males, and often presents during childhood or young adulthood.1,4,16,20

Family history of malignant hyperthermia, known RYR-1 gene mutation, or prior reaction to inhaled anesthetics or succinylcholine.1,4,13,14,16

  • Documentation of this info during med history taking can help ensure preventative measures are taken.4,14,16

Administration of succinylcholine and/or volatile anesthetics including desflurane, isoflurane, and sevoflurane in susceptible patients.2,4,16

Usually occurs within minutes of triggering-drug administration, but may occur up to 10 hours after exposure.1,13,20


Prevention of malignant hyperthermia crisis


Avoid triggering medications, including succinylcholine and halogenated volatile anesthetics (see above).4-8,16,24

  • Safe alternatives include non-depolarizing neuromuscular blocking agents (rocuronium, vecuronium, etc), nitrous oxide, propofol, and local anesthetics.1,4,5,16,23,24

Prophylactic dantrolene for at-risk patients is no longer recommended.4,16,19,24 Very small likelihood of benefit is outweighed by risk of dantrolene-related muscle weakness and added cost.4,19

Observe closely for signs of crisis including tachycardia, muscle spasm or rigidity, or rise in temperature.1,5,24


Treatment of malignant hyperthermia crisis




Immediately discontinue volatile anesthetics and succinylcholine.1,6-8,14,16,24 Provide 100% oxygen.1,6,7,14,16,24

Cancel or abort surgical procedure if possible.5,14,16,24 Switch to non-triggering agents if surgery must proceed.1,16

Administer dantrolene 2.5 mg/kg rapid IV push to treat acute crisis.1,2,10,11,24

  • Continue repeating doses every 5 minutes until symptoms subside, or until 10 mg/kg has been given.1,4,6-8,10,16,24
  • Regimen can be repeated if signs of crisis return.4,7,8 Total doses of up to 30 mg/kg may be needed.4,10,11,14,24

Treat hyperkalemia.14,24

Control arrhythmias with amiodarone and/or beta-blockers (metoprolol, esmolol, etc).14,16

  • Avoid use of calcium channel blockers (verapamil, etc) in combination with dantrolene due to risk for hyperkalemia and cardiac arrest.4,6-8,16,19,24

Manage metabolic acidosis (pH <7.2) with hyperventilation and/or sodium bicarbonate 1 to 2 mEq/kg IV.8,14,16,24

Initiate cooling protocol if needed to maintain core temperature below 38°C to 38.5°C.4,14,16

  • Infusion of cold saline (up to 2 Liters) and/or surface cooling are recommended.4,14,16

Give diuretics to promote urinary output of 1 to 2 mL/kg/hr to prevent myoglobinuria-related kidney injury.8,14,16,24



Post-crisis management

Prevention of symptom recurrence and management of sequelae from the crisis can limit morbidity.1,5

Continuation of dantrolene therapy:

  • IV: 1 mg/kg per dose every 4 to 6 hours for 24 hours followed by PO regimen.1,5-7,17,24

  • PO 4 to 8 mg/kg/day, divided into four doses for 1 to 3 days post-crisis.1,6,7

Continue IV hydration, urinary alkalinization and/or diuretics to manage rhabdomyolisis.14,24

Monitor core temperatures arterial blood gas (ABG); electrolytes; CPK; and renal, hepatic, and coagulation function for at least 24 to 48 hours.4,14,24

Watch for dantrolene-related adverse effects including transient muscle weakness, phlebitis, and confusion.4,18,19

Encourage referral for genetic counseling and DNA testing and/or muscle biopsy.5,13,15,16,24


Readiness to manage malignant hyperthermia














Dantrolene needs to be immediately available, making it to the patient’s bedside within 10 minutes.3,4

Stock at least 700 mg of dantrolene, which is enough to provide four treatment doses to a 70 kg patient.3,4 Consider keeping 800 mg on hand (enough for three treatment doses for a 100-kg patient) to be prepared for heavier patients.9 It is recommended to stock the following quantities of dantrolene:

  • 36 to 40 vials of Dantrium or Revonto containing 20 mg dantrolene powder per vial, along with 60 mL preservative-free SWFI for reconstituting each vial (36 to 40 diluent vials needed).3,4,6,7,12
  • 3 to 4 vials of Ryanodex 250 mg, with 5 mL preservative-free SWFI for reconstitution of each vial.3,4,8,9,12
  • Only preservative-free SWFI should be used, and vials are preferred to IV bags.4,6-8,21
    • Avoid bacteriostatic water due to toxicity risk related to the preservative it contains.21
    • If IV bags are used, the 2 liter size is preferred due to lower risk for confusion with other 1 liter bags.25 This may decrease risk for accidental infusion of SWFI.25
      • Ensure label includes “for drug diluent use only” to reduce risk for mix-ups.

Consider storing dantrolene in all areas where general anesthesia or succinylcholine is administered.4,9

  • Ensure vials are protected from light.6-8


Keep back-up stock in the main pharmacy for episodes that present outside of the operating room.2

Use of dedicated carts or kits containing dantrolene and diluent vials can facilitate transport and expedite mixing.2,3

  • Ensure used carts or kits are promptly refilled and put back into stock in preparation for another episode.
  • Alert your purchasing agent whenever carts or kits are restocked to ensure prompt replenishment.

Collect expired stock for possible credit towards purchase of in-date product from supplier.2,9


Dantrolene product selection


Malignant hyperthermia complications increase drastically with delays in dantrolene administration.2,20

Mixing and dissolution of dantrolene varies by product type, with older formulations (Dantrium, Revonto) requiring more preparation time than Ryanodex.2,5

Ryanodex costs more ($6,900) to stock than older formulations ($2,500 to $3,190), but may be preferred due to:2,22

  • Substantially shorter time needed to prepare, leading to faster initiation of crisis treatment.2,5
  • Elimination of need for (and associated risks with) 2 liter SWFI bags on malignant hyperthermia carts.25
  • Less storage space needed, potentially eliminating need for malignant hyperthermia carts.2

Ryanodex may be less cost-effective for hospitals with low surgical volumes.2

Consider one-time change out if switching from one formulation to another to improve safety and reduce confusion.2


Regulatory preparedness

Malignant hyperthermia preparedness is essential, and may be scrutinized during regulatory surveys.3,12

Recommended preparedness activities include:

  • Training for all procedural staff on the signs of malignant hyperthermia, its treatment, dantrolene availability, storage location(s), and preparation.3,9,12
  • Performance of mock drills that include obtaining malignant hyperthermia cart or kit, with evaluation for continued need for improvement.12
  • Emergency meds readily available in accordance with accepted standard of care:12
    • MHAUS recommends keeping at least 700 mg dantrolene readily available within ten minutes.3,4,12,17
  • Regular review of your hospital’s malignant hyperthermia policy and any related procedures.3
    • Ensure that stocking levels and location(s) used in practice match those outlined in the policy.3
  • Provide refresher education and consider posting diagnosis and treatment posters in surgical areas.4,5,14,24


Project Leader in preparation of this clinical resource (340223): Leslie Gingo, PharmD, BCPS

References

  1. Musselman ME, Saely S. Diagnosis and treatment of drug-induced hyperthermia. Am J Health Syst Pharm 2013;70:34-42.
  2. Zavilla CM, Skledar S, Lang MB, Gross C. Implementation of a new dantrolene formulation across a multifacility health system. Am J Health Syst Pharm 2016;73:463-7.
  3. Traynor K. Readiness for malignant hyperthermia can be survey stumbling block. Am J Health Syst Pharm 2016;73:852-3.
  4. Malignant Hyperthermia Association of the United States. Frequently Asked Questions. http://www.mhaus.org/faqs/. (Accessed Jan 5, 2018).
  5. Chapin JW. Malignant hyperthermia treatment & management. December 13, 2017. Medscape. https://emedicine.medscape.com/article/2231150-overview. (Accessed January 5, 2018).
  6. Product information for Dantrolene. West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724. October 2017.
  7. Product information for Revonto. US WorldMeds. Louisville, KY 40241. October 2016.
  8. Product information for Ryanodex. Eagle Pharmaceuticals, Inc. Woodcliff Lake, NJ 07677. September 2017.
  9. Dart RC, Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking antidotes in hospitals that provide emergency care. Ann Emerg Med 2017. doi: 10.1016/j.annemergmed.2017.05.021.
  10. Clinical Pharmacology powered by ClinicalKey. Tampa, FL: Elsevier. 2017. http://www.clinicalkey.com (Accessed January 6, 2018).
  11. Malignant Hyperthermia Association of the United States. Managing a crisis. Emergency treatment for an acute MH event. http://www.mhaus.org/healthcare-professionals/managing-a-crisis/. (Accessed January 6, 2018).
  12. Mansur J. The Joint Commission medication management update for 2018. Joint Commission Resources. November 8, 2017. http://www.njha.com/media/476876/EDU-1736-PPT-Mansur-Joint-Commission-Update-2018.pdf. (Accessed January 10, 2017).
  13. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet J Rare Dis 2007;2:21.
  14. Glahn KP, Ellis FR, Halsall PJ, et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European malignant hyperthermia group. Brit J Anesth 2010;105:417-20.
  15. Hopkins PM, Ruffert H, Snoeck MM, et al. European malignant hyperthermia group guidelines for investigation of malignant hyperthermia susceptibility. Brit J Anesth 2015;115:531-9.
  16. Schneiderbanger D, Johannsen S, Roewer N, Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag 2014;10:355-62.
  17. Malignant Hyperthermia Association of the United States. MHAUS Recommendations. http://www.mhaus.org/healthcare-professionals/mhaus-recommendations/. (Accessed January 10, 2018).
  18. Brandom BW, Larach MG, Chen MS, Young MC. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American malignant hyperthermia registry of the Malignant Hyperthermia Association of the United States. Anesth Analg 2011;112:1115-23.
  19. Krause T, Gerbershagen MU, Fiege M, et al. Dantrolene—a review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004;59:364-73.
  20. Riazi S, Larach MG, Hu C, et al. Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands. Anesth Analg 2014;118:381-7.
  21. Malignant Hyperthermia Association of the United States. What should be on an MH cart? https://www.mhaus.org/faqs/what-should-be-on-an-mh-cart/. (Accessed January 6, 2018).
  22. Medication pricing by Elsevier, accessed January 2018.
  23. Wappler F. Anesthesia for patients with a history of malignant hyperthermia. Curr Opin Anaesthesiol 2010;23:417-22.
  24. Malignant Hyperthermia Association of the United States. Emergency therapy for malignant hyperthermia. http://img.medscape.com/pi/emed/ckb/general_surgery/188616-188617-1445509-1467381.pdf. Accessed Jan 6, 2018).
  25. ISMP 2018-2019 Targeted medication safety best practices for hospitals. http://www.ismp.org/Tools/BestPractices/TMSBP-for-Hospitalsv2.pdf. (Accessed January 17, 2018).

Cite this document as follows: Clinical Resource, Malignant Hyperthermia Prevention and Treatment. Pharmacist’s Letter/Prescriber’s Letter. February 2018.

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