Malignant Hyperthermia


Article Author:
Stacey Watt


Article Editor:
Russell McAllister


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
1/13/2019 11:45:11 PM

Introduction

Malignant Hyperthermia (MH) is a hereditary disorder of skeletal muscle that classically presents as a hypermetabolic response to halogenated anesthetic gasses and/or the depolarizing muscle relaxant succinylcholine. 

Etiology

Patients who are genetically susceptible can have an MH reaction in response to triggering agents such as halogenated anesthetic gasses and/or succinylcholine and more rarely to stressors such as vigorous exercise and heat exposure.  Nitrous Oxide and Xenon, although they are inhaled anesthetics, are not halogenated and have not been implicated in MH.  

Epidemiology

The exact incidence of MH is unknown.  Studies demonstrate that MH occurs in about 1:100,000 in adults and 1:30,000 in children.  The incidence of MH varies based upon geographic region. There are concentrations of MH susceptible families present in Wisconsin and the upper Midwest. The mortality is 3% to 5%, even when properly treated. 

Other disorders are also associated with MH susceptibility.  These include Central Core Disease (a rare, non-progressive myopathy characterized by hypotonia and weakness of proximal muscles) and King-Denborough Syndrome (a rare myotonia associated with multiple distinct physical features).[1]

Early researchers described rare episodes of stress induced "awake MH."  Later, Tobin described one of the most convincing cases of fatal, exercise-induced MH in a 13-year-old boy in whom the causative RYR1 mutation was present and was later found to be present in his family members.[2]

MH susceptibility has also been described in other species, particularly in swine, where much of the early research into the disease and its treatment originated.

Pathophysiology

MH is an autosomally dominantly inherited disorder that is characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. The gene for the ryanodine receptor RYR1 is the primary site for mutations linked with MH, but other genetic loci have been identified, such as CACNA1S and STAC3, as causative for MH. 

The uncontrolled release of calcium from skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP), and dramatically increases oxygen consumption and the production of carbon dioxide and heat. The depletion of ATP stores leads to the membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation.[3][4]

History and Physical

Signs and symptoms of MH include tachycardia, tachypnea, hypoxemia, hypercarbia, metabolic and respiratory acidosis, hyperkalemia, cardiac dysrhythmias, hypotension, skeletal muscle rigidity, and hyperthermia.  The earliest signs of MH are usually hypercarbia and tachycardia due to elevated carbon dioxide production. Fulminant MH reactions may have only a few of the usual signs, and it requires a high index of suspicion of MH to effect a timely and correct diagnosis and treatment. MH can occur at any time during the intraoperative and postoperative period.

Susceptible patients can exhibit masseter muscle spasm. If signs of hypermetabolism such as metabolic and respiratory acidosis or an elevation in body temperature accompany the muscle spasm, a diagnosis of MH must be considered.

Evaluation

The gold standard in the laboratory diagnosis of MH is the caffeine halothane contracture test (CHCT), although genetic testing is rapidly advancing and may one day replace the muscle biopsy. The CHCT involves exposing a sample of live muscle fibers to halothane and caffeine to determine the muscle response to halogenated anesthetics. Genetic testing for mutations of the RYR1 or other associated genetic variants associated with MH is becoming increasing more value as the testing improves. Testing can be expensive and is only available in certain centers.  Therefore, when presented with a patient for urgent or emergent surgery who has a history suggestive of a close relative who has had an MH episode, anesthesiologists will usually provide a "non-triggering anesthetic," which is typically a variety of combinations of intravenous anesthetic agents.The differential diagnosis for MH can include many other, unrelated disorders such as neuroleptic malignant syndrome, pheochromocytoma, sepsis, thyroid storm, serotonin syndrome, or iatrogenic overheating.[5][6][7]

Treatment / Management

The critical element in the treatment of MH is immediate dantrolene administration. Once an MH episode is suspected, all triggering agents must be discontinued and the patient hyperventilated with 100% oxygen with non-triggering anesthetic agents utilized for patient care and surgery should be ended as soon as possible. Dantrolene in a dose of 2.5 mg/kg must be administered intravenously as soon as possible, up to a maximum dose of 10mg/kg until the reaction subsides. In addition to administering dantrolene, attention also must be paid to correct hyperthermia, acidosis, hypoxemia, arrhythmias and preserving renal function. Arrhythmias can be treated with antiarrhythmics and renal function can be protected from possible acute tubular necrosis (due to precipitation of released myoglobin from the skeletal muscles) by maintaining a urine flow of at least 2 ml/kg/hr with furosemide.[8]

The management algorithm includes:

  • top the triggering agent.
  • Call for help.
  • Administer dantrolene 2.5 mg/kg until the reaction subsides up to a maximum of 10 mg/kg.
  • Increase ventilation to lower end-tidal CO2.
  • Cooling measures (cold IV fluids and ice packs to exposed surfaces).
  • Treat arrhythmias (e.g. Amiodarone;  avoid calcium channel blockers).
  • Laboratory studies to include arterial blood gas, electrolytes (especially potassium), serum and urine myoglobin, and coagulation profile.
  • Continue dantrolene at 1 mg/kg every 4 hours for 24-48 hours.
  • Ensure urine output of 2 ml/kg/hr (mannitol 3 grams is included in each vial of dantrolene) 

Better patient outcomes are associated with rapidity of diagnosis, rapid treatment with dantrolene, and prevention of the rapid rise in core temperature by using cooling measures.[9]

After the patient has been stabilized, he or she must be taken to the intensive care unit for at least 24 hours for monitoring and to watch for signs of recrudescence. Patients at highest risk for recrudescence are those with a large muscle mass or who have undergone at least 150 minutes of anesthetic exposure before triggering.  

Despite having been performed frequently in the past, pretreating MH susceptible patients with dantrolene does not play a role in their care and should not be done.  Instead, these patients should receive a non-triggering anesthetic.

Pearls and Other Issues

Dantrolene:  

Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum.  Its mechanism of action is through antagonizing the ryanodine receptors which lessens the excitation-contraction coupling of muscle cells.  

Dantrolene is currently the only specific medication used for treating an MH crisis. Dantrolene is available as two different formulations: Dantrium/Revonto and Dantrolene Sodium/Ryanodex. These two medications differ in the amount of sterile water required to reconstitute each vial and the concentration of dantrolene present within each vial. Dantrium/Revonto is available in 20 mg vials that must be reconstituted with 60 mL of sterile water per vial. Dantrolene Sodium/Ryanodex is available in 250 mg vials that must be reconstituted with 5 mL of sterile water per vial.  Regardless of which formulation of dantrolene administered, a dose of 2.5 mg/kg is recommended to treat an MH episode.  Dantrolene is a highly lipophilic drug with low solubility in water, making reconstitution of the drug in sterile water challenging.   Ryanodex is a newer formulation that combines nanosuspension technology with a lyophilized formulation resulting in a much faster reconstitution of the drug, which can greatly improve the time to treatment and may be especially useful in locations where only one provider is available to treat the patient.  

Keep in mind that additional doses of dantrolene might be necessary to adequately treat a MH triggering event, and a dose of 1 mg/kg every 4 to 6 hours is recommended for the first 24 to 48 hours after an episode of MH.

Dantrolene should not be combined with verapamil, as it may lead to hyperkalemia and hypotension.[1]

All facilities where MH triggering anesthetics are administered are recommended to stock a minimum of 36 vials of Dantrium/Revonto or 3 vials of Dantrolene Sodium/Ryanodex along with other medications and rescue equipment needed to treat an MH crisis.   

MH link to strenuous exercise, heat exposure or other causes of elevated body temperature:

MH susceptible patients are found to experience a metabolic crisis without exposure to triggering agents.  Exposure of these patients to strenuous exercise, heat exposure, or high internal body temperatures (e.g., infections) may precipitate this crisis.  Research is currently underway to evaluate this possible link.

Other Issues:

Life-threatening laryngospasm is a much more common event than MH that can be quickly treated with low dose succinylcholine.  Many office-based procedural facilities do not stock succinylcholine due to the risk of MH and the need to stock expensive dantrolene in case of an MH triggering event.  The Society for Ambulatory Anesthesia offered an opinion on the dilemma by stating that succinylcholine could be stocked at these locations for emergency use only with the caveat that procedures should never be done on known MH susceptible persons in those facilities.  

Patients and their families should be referred to the Malignant Hyperthermia Association of the United States (MHAUS) for information about this disorder and to receive follow-up from specialists in this area.  

Information can be located on the website mhaus.org, or they can be reached by e-mail for questions at info@mhaus.org.

Hotline Information:

MHAUS can be contacted at 1-800-644-9737 or outside the United States at 001-209-417-3722. 

North American MH Registry:

The North American MH Registry of the Malignant Hyperthermia Association of the United States (MHAUS) is a database of information about patients and their families that have experienced MH episodes. Healthcare providers are encouraged to report MH and MH-like episodes to the registry.  Information on how to contact the registry can be found on the MHAUS website at www.mhaus.org.

Enhancing Healthcare Team Outcomes

Malignant hyperthermia is a rare disorder which is life threatening. Because of the high morbidity the disorder is best managed by a multidisciplinary team that includes a neurologist, intensivist, anesthesiologist and an internist. Even though dantrolene is recommended for treatment, good data supporting its efficacy are still lacking. The patient should be managed in an ICU setting with close monitoring.


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Malignant Hyperthermia - Questions

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What is the drug of choice to treat malignant hyperthermia?



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A 5-year-old male twin presents with acute appendicitis. He is scheduled for an emergent appendectomy. His family history is significant for his twin brother suffering a malignant hyperthermia episode that led to a 2-week intensive care unit stay, but eventual recovery with treatment. Which of the follow ng anesthetic drugs should be avoided in this patient?



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What is the neuromuscular-blocking agent associated with malignant hyperthermia?



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A 34-year-old trauma patient receives general anesthesia and he develops malignant hyperthermia. Which of the following symptoms is not associated with malignant hyperthermia?



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A patient is undergoing surgery when the anesthesiologist notes that the patient is febrile and is beginning to retain carbon dioxide. The surgeon mentions that the patient is not adequately relaxed. What is the next step in the management of this patient?



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A patient is in surgery and develops extreme muscle rigidity soon after the procedure is started. The patient is tachycardic and has a fever of 104 F. What is the most likely diagnosis?



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A patient undergoes induction of general anesthesia with fentanyl, propofol, and succinylcholine. The patient develops muscle rigidity, hypercarbia, and fever of 39 degrees Celsius. Which of the following acid-base disturbances is most associated with a diagnosis of malignant hyperthermia?



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What causes high fever, tachycardia, and muscle rigidity during halothane general anesthesia?



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Which of the following is not seen in malignant hyperthermia?



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Which medication is used to treat malignant hyperthermia?



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Which is the initial sign of malignant hyperthermia?



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Which of the following statements about malignant hyperthermia is true?



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What should a patient who develops high-grade fever and muscular rigidity after receiving general anesthesia be given?



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Which of the following is not seen in patients with malignant hyperthermia?



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Which of the following medications is commonly implicated in malignant hyperthermia?



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A 17-year-old male is undergoing operative repair of a femur fracture and develops a fever of 39.5 C, heart rate of 125 beats/min, blood-tinged urine, and muscle rigidity. What is the appropriate initial management?



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A patient is having an elective inguinal hernia repair. After induction of anesthesia the patient develops a fever of 103.2 F, muscle rigidity, blood tinged urine, and tachycardia. What should be done?



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A 5-year-old child has myringotomy and tube placement for recurrent otitis media under general anesthesia. She develops high fever, muscle rigidity, metabolic acidosis, and respiratory acidosis in the recovery room. Select the most probable diagnosis.



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A 17-year-old female develops a seizure in recovery after wisdom teeth extraction using general anesthetic. Initially, she became febrile and hemodynamically unstable. She was tachycardic, but there was little respiratory effort. She was intubated and given lorazepam. Paramedics transferred her to the emergency room from the surgical center. Exam shows blood pressure 155/90 mm Hg, heart rate 135, and temperature 42.2 degrees Celsius. Cardiac exam shows tachycardia and lungs are clear. She is unresponsive to pain. Pupils are 3 mm and reactive to light. There is increased muscle tone, hyperreflexia, and myoclonus. ECG shows sinus tachycardia with peaked T-waves. Which diagnostic test is least likely to be useful?



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Which of the following findings is not common in malignant hyperthermia?



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Which of the following is not a standard treatment for malignant hyperthermia?



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A 17-year-old female has an extraction of her wisdom teeth in an outpatient surgical center, but has a seizure and is transported to an emergency room. Which of the following can be excluded from the diagnosis with the corresponding rationales?



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Malignant Hyperthermia - References

References

Tobin JR,Jason DR,Challa VR,Nelson TE,Sambuughin N, Malignant hyperthermia and apparent heat stroke. JAMA. 2001 Jul 11     [PubMed]
Rosenberg H,Pollock N,Schiemann A,Bulger T,Stowell K, Malignant hyperthermia: a review. Orphanet journal of rare diseases. 2015 Aug 4     [PubMed]
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. Anesthesia and analgesia. 2014 Dec     [PubMed]
Altamirano F,Riazi S,Ibarra Moreno CA,Kraeva N,Uryash A,Allen PD,Adams JA,Lopez JR, Is malignant hyperthermia associated with hyperglycaemia? British journal of anaesthesia. 2019 Jan;     [PubMed]
Dirksen RT,Allen PD,Lopez JR, Understanding malignant hyperthermia: each move forward opens our eyes to the distance left to travel. British journal of anaesthesia. 2019 Jan;     [PubMed]
Ratto D,Joyner RW, Dantrolene 2018 Jan;     [PubMed]
Hopkins PM, Succinylcholine and Dantrolene: Inseparable in the Emergency Cupboard? Anesthesiology. 2019 Jan;     [PubMed]
Lee SY,Szigeti GP,Szasz AM, Oncological hyperthermia: The correct dosing in clinical applications. International journal of oncology. 2019 Feb;     [PubMed]
Hopkins PM,Gupta PK,Bilmen JG, Malignant hyperthermia. Handbook of clinical neurology. 2018;     [PubMed]

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