Malignant Hyperthermia in the Operating Room 

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Malignant hyperthermia (MH) is a rare, inherited disorder of skeletal muscle that presents as a hypermetabolic response triggered by halogenated anesthetics, succinylcholine, or both. The incidence of MH reactions ranges from 1 in 10,000 to 1 in 250,000 anesthetic exposures. ^[1]  It is possible that an anesthesiologist may practice for an entire career without encountering a single case. ^[2]  Nevertheless, given the seriousness of the condition, it is important that anesthesiologists be able to recognize MH promptly and treat it effectively.

Common symptoms of MH include hypercarbia, muscle rigidity, masseter muscle spasm, sinus tachycardia, arrhythmias, hyperthermia, and cyanosis. MH can be rapidly fatal; however, with current treatment, including the use of intravenous (IV) dantrolene, mortality from MH has been reduced from 80% to 1.4% percent in North America. ^[1]  

Management of an MH crisis includes the following steps ^{[1, 3]} :

MH is an inherited disorder of skeletal muscle that classically presents itself as a hypermetabolic response to halogenated anesthetic agents, succinylcholine, or both. It is a rare event, with an incidence ranging from 1 in 10,000 to 1 in 250,000 anesthetic exposures. In individuals who have the genetic predisposition to this disorder, administration of one of the aforementioned agents may trigger an MH crisis manifested by the following:

Without treatment, a fulminant MH crisis is almost invariably fatal. Although anesthetic agents are the most common trigger of MH in susceptible individuals, some patients may develop MH symptoms in response to heat or stress. ^[1]

The direct cause of MH when it is triggered is uncontrolled release of intracellular calcium from the skeletal muscle sarcoplasmic reticulum. This uncontrolled release is due to a defective calcium channel in the sarcoplasmic reticulum, known as ryanodine receptor 1 (RyR1). Many mutations associated with MH have been identified in RYR1, the gene coding for RyR1 in humans, and more are discovered as additional patients are identified and genetic mapping becomes more sophisticated. A few genetic loci besides RYR1 have also been associated with MH (eg, CACNA1S and STAC3).

Unlike some animal species (eg, pigs), humans appear to inherit all of the genes associated with MH susceptibility in an autosomal dominant manner. Therefore, if a parent or sibling of a given individual had had an episode of MH, that individual would have a 50% chance of inheriting a susceptibility to MH. ^[1]  

If an MH-susceptible patient receives a volatile anesthetic agent or succinylcholine, an MH reaction may be triggered. Often, MH-susceptible patients have never had MH and may even have had several exposures to MH-triggering anesthetics without developing the syndrome. Nevertheless, these patients are still at risk for MH, despite having tolerated previous exposures to triggering agents. Patients known to be susceptible to MH or to have close relatives who are susceptible should receive IV anesthesia without triggering agents via an anesthesia machine prepared for an MH-susceptible patient. ^[1]

MH may occur at any time during the induction and maintenance of anesthesia, as well as in the early recovery period. However, it does not occur more than 1 hour after discontinuance of the volatile anesthetic agents. The earliest signs of MH are as follows:

A marked increase in body temperature is also an early sign. Core temperature may rise by 1-2ºC every 5 minutes, sometimes reaching levels in excess of 44ºC. The uncontrolled hypermetabolism can lead to marked increases in carbon dioxide production and oxygen consumption, as well as both respiratory and metabolic acidosis. If untreated, the hypermetabolic state can lead to widespread organ dysfunction, myocyte death, rhabdomyolysis, myoglobinuria, hyperkalemia, and renal failure. Finally, fatal disseminated intravascular coagulation (DIC) develops; this is the usual cause of death in this setting. ^{[1, 2]}  

Other conditions in patients undergoing anesthesia can cause a fever and an unexplained increase in EtCO₂ that may mimic MH. Among these conditions are the following ^[1] :

Sepsis is particularly problematic in that patients who are in a septic state may develop marked hyperthermia on emergence from anesthesia. In such situations, given how rapidly devastating untreated MH can be, it may be necessary to treat these septic patients as if they had MH—that is, by administering IV dantrolene—until the diagnosis is established. Dantrolene has been shown to be well tolerated in animal models of septic shock and should be administered if there is any suspicion of MH. ^{[1, 4]}   

If the anesthesiologist suspects that MH is developing, a rapid response is required. This disorder can cause the patient’s condition to deteriorate rapidly, and action must be taken to reverse the syndrome before irreparable damage can occur. To this end, several things must be done simultaneously, as follows.

The anesthesiologist should immediately call for help, stop the inhaled anesthetic agents, and increase the ventilatory rate to correct the hypercarbia that always develops. By far the most important step, however, is to administer dantrolene, which inhibits calcium release from the sarcoplasmic reticulum by antagonizing the ryanodine receptors and is capable of stopping an MH episode. Dantrolene is given in an initial dose of 2.5 mg/kg IV, followed by 2.5 mg/kg every 5-10 minutes until the symptoms of hyperpyrexia, muscular rigidity, and acidosis are resolving. ^[3] If symptoms are not resolving by the time 10 mg/kg is given, the diagnosis should be reconsidered.

In the past, dantrolene was difficult to prepare because it was poorly soluble, with each 20-mg vial having to be mixed with 60 mL of sterile water; thus, eight to 10 vials were required for initial treatment. However, a preparation (Ryanodex; Eagle Pharmaceuticals, Woodcliff Lake, NJ) has been developed that contains 250 mg of dantrolene per vial and requires mixing with only 5 mL of sterile water; thus, initial treatment in most patients now requires only a single vial. ^[1]  It should be noted that oral dantrolene (see Case Example 2 below) is not absorbed rapidly enough to reverse a fulminant MH crisis. ^{[1, 2]}

In addition to treatment with dantrolene, patients should be cooled with IV normal saline chilled to 4ºC, ice packs, and gastric lavage with cold IV fluids until body temperature has cooled to 38.5ºC. Further cooling can trigger recrudescence of MH.

Diuresis should be established with fluids, mannitol, and furosemide to help prevent myoglobinuric renal failure and treat hyperkalemia. Hyperkalemia is common and may necessitate dialysis if it does not respond to hyperventilation and administration of glucose and insulin. ^{[1, 2]} Acidosis is common as well and can be treated with hyperventilation and buffering; however, administration of large amounts of sodium bicarbonate can increase the carbon dioxide load. ^[2]

If cardiac arrhythmias develop, they should be treated with beta blockers, lidocaine, amiodarone, or some combination thereof. Calcium-channel blockers, however, should not be used; these agents, when given in combination with dantrolene, can both raise intracellular calcium levels and induce fatal hyperkalemia. ^[2]

When an MH reaction is suspected, the surgical procedure should be terminated or, if that is not an option, completed as quickly as possible. Nontriggering agents (eg, propofol, narcotics, and nondepolarizing muscle relaxants) should be used until the patient can be transferred to the recovery room or ICU.

If further anesthesia is required, an anesthesia machine specifically prepared for MH patients, with removal of vaporizers and flushing of the circuit with high-flow oxygen, should be employed. Unfortunately, the time required for adequate flushing of a modern anesthesia machine may be as long as 50-60 minutes. ^{[1, 5]} Charcoal filters are available that can be inserted in the inspiratory and expiratory limbs of the machine and thus eliminate exposure to the triggering agent. ^{[1, 6, 7]} Alternatively, the patient can be placed on an ICU ventilator that has not been exposed to anesthetic gases for completion of the procedure.

Often, MH symptoms resolve after dantrolene administration, only to reappear later. Accordingly, it is important that the patient be admitted to the ICU for overnight observation. Some authors have advocated giving dantrolene 1 mg/kg every 8 hours for 24-48 hours after an MH episode. Alternatively, the patient may be observed in the ICU for 24-48 hours and receive dantrolene 2.5 mg/kg IV if signs and symptoms recur. ^[1]

The MH hotline (1-800-MH-HYPER; 1-800-644-9737) should be contacted as early as possible when a suspected MH crisis is occurring. Physicians are available 24 hours a day to answer questions and help guide treatment or transfer of patients for definitive therapy. This is particularly beneficial if the event occurs in an ambulatory care unit that lacks an ICU capable of treating MH patients.

Finally, patients and their family members should be referred to an MH center for MH testing. If the siblings or children are not MH-susceptible, there is no need to avoid triggering agents. On the other hand, if they are susceptible, anesthesia must be performed using MH precautions, with appropriate preparation of the anesthesia machine and use of nontriggering agents.

The gold standard for testing susceptibility to MH is the in-vitro contracture test, in which a live section of vastus lateralis muscle, obtained surgically with either regional anesthesia or general anesthesia without triggering agents, is exposed to graded concentrations of halothane and caffeine. Muscle from patients who are MH-susceptible will show an exaggerated response to these agents.

Genetic testing has been studied with the aim of developing a way to diagnose MH without having to perform a muscle biopsy. As previously noted, however, there is a great deal of genetic heterogeneity in MH, and so far, this has prevented the elimination of muscle testing. ^[1]

In the event of a suspected MH reaction, the following actions and treatments have been found to be beneficial or lifesaving ^{[1, 3]} :

 A 5-year-old 16-kg boy is brought to a freestanding dental office for dental restorations. He is otherwise healthy. There is no family history of anesthesia-related problems, and during preoperative evaluation, family members state that the patient has not had any such problems. At the age of 2 years, the patient underwent uneventful general anesthesia for pressure equalization tube placement.

General anesthesia is induced in the dental office by mask induction using nitrous oxide in oxygen and sevoflurane. A peripheral IV catheter is successfully placed and the patient nasally intubated by using sevoflurane alone without skeletal muscle relaxants. Anesthesia is maintained with sevoflurane plus nitrous oxide in oxygen. The patient is allowed to breathe spontaneously throughout the procedure and receives 3 cm H₂O of continuous positive airway pressure (CPAP).

Initially, vital signs are stable: heart rate (HR), 88 beats/min; blood pressure (BP), 95/65 mm Hg; oxygen saturation (SaO₂), 100%; axillary temperature, 36.3ºC; respiratory rate (RR), 21 breaths/min; EtCO₂, 42 mm Hg. After approximately 2.5 hours, however, the anesthesiologist notes that RR has increased from 21 to 35 breaths/min. In addition, EtCO₂ has steadily increased to 60, then 80, and finally 106 mm Hg over a period of 4 minutes. Axillary temperature has risen to 36.9ºC. HR has increased to 140 beats/min, while SaO₂ remains at 100%. The diagnosis of MH is made, and the surgical team is immediately notified.

The anesthesiologist stopped the sevoflurane and nitrous oxide and provided hyperventilation manually with 100% oxygen. A 911 ambulance call was made for an MH crisis, and 40 mg of dantrolene was quickly prepared and administered. Another, larger IV catheter was placed to allow administration of a fluid flush (normal saline 10 mL/kg). The procedure was terminated, and the blankets covering the child were removed to promote surface cooling with ambient air.

The emergency department (ED) was notified about the situation and a transfer arranged. The anesthesiologist administered rocuronium and propofol and accompanied the patient to the local ED. ABG sampling in the ED yielded the following findings: pH, 7.10; arterial carbon dioxide tension (PaCO₂), 93 mm Hg; arterial oxygen tension (PaO₂), 210 mm Hg; base excess of –4 mmol/L despite manual hyperventilation. Electrolytes, glucose, creatinine kinase levels were within normal limits. There was no skeletal muscle rigidity, the lungs were compliant, and the urine was clear.

Another dose of dantrolene (1 mg/kg) was administered, and the patient was transported to a pediatric hospital 20 miles away. Upon arrival, he was taken directly to the pediatric ICU, where further care included administration of dantrolene per Malignant Hyperthermia Association of the United States (MHAUS) guidelines. Over the next 12 hours, ABG values improved. The patient was awakened the next day, was extubated successfully, and recovered without complications. A genetics consult and a referral to an MH laboratory were obtained.

This case demonstrates the value of rapid treatment with dantrolene as soon as the diagnosis of MH is suspected. Prompt transfer to a hospital with an ICU was accomplished, and an excellent outcome was obtained.

A 22-year-old 75-kg African male soccer player presents for voluntary donor nephrectomy. There is no history of drug abuse, and the review of systems is negative for neuromuscular disorders, MH, or other anesthesia-related complications in both the patient and his close family. The patient is prepared for laparoscopic living related donor nephrectomy.

Anesthesia is induced with propofol, fentanyl, and vecuronium. Endotracheal intubation is performed without difficulty. A radial arterial catheter and a central venous line are also placed. Anesthesia is maintained with isoflurane, intermittent boluses of fentanyl, and vecuronium.

The laparoscopic procedure is begun with the patient in the right lateral decubitus position. Carbon dioxide pneumoperitoneum is instituted; intra-abdominal pressure is 14 mm Hg. Approximately 2.5 hours post induction and before the clamping of renal vessels, EtCO₂ gradually increases from 35 to 50 mm Hg. Minute ventilation is increased from 6 to 8 L/min, but despite this, EtCO₂ continues to increase over the next 20 minutes, rising to 70 mm Hg.

The surgeons release the pneumoperitoneum and halt the surgical procedure temporarily. ABG values are obtained and reveal profound respiratory acidosis; pH, 7.17; PaO₂, 165 mm Hg; PaCO₂, 80 mm Hg; base excess, –1.6 mmol/L. Nasopharyngeal temperature is increasing at the rate of 0.5°C every 5 minutes, and tachycardia (120 beats/min) develops. Total body rigidity is noted. Nasopharyngeal temperature peaks at 42.4ºC over the ensuing 25 minutes. A diagnosis of acute MH is made. ^[8]

Resuscitative measures included immediate discontinuance of isoflurane, initiation of IV propofol infusion, hyperventilation of the lungs with 100% oxygen, and use of a new anesthesia machine without vaporizers. Cooling measures were initiated immediately and included surface cooling with ice packs and gastric and bladder lavage with ice-cold saline. Cold IV saline was infused. No IV dantrolene was available for administration.

The patient developed severe hypotension (48/26 mm Hg), bradycardia, nodal rhythm, and ventricular ectopic beats. Dopamine (5 mg/kg/min IV) and norepinephrine (0.2 mg/kg/min IV) were infused to stabilize the hemodynamic derangement. Acute hyperkalemia (6.4 mmol/L) occurred and was vigorously treated with a 50-mL bolus of sodium bicarbonate (50 mEq) and an antipotassium cocktail. An 8-mg bolus of furosemide was administered along with hydration (the urine was cola-colored).

After 2 hours of resuscitation, the elevated EtCO₂ and body temperature began to fall, the muscle rigidity was alleviated, and the patient’s hemodynamic status showed improvement. The surgical procedure was terminated, and the laparoscopic port incisions were closed. The patient was transferred to the ICU with ventilatory and inotropic support.

In the ICU, oral dantrolene therapy was initiated at a dosage of 4 mg/kg q8hr via a nasogastric tube. After 48 hours, oral dantrolene was stopped, when an elevation in liver enzymes occurred. An additional spike in temperature (38ºC) occurred during the first 12 hours of the patient’s ICU stay and was treated with cold tepid sponging and cold IV fluids.

The patient remained sedated with propofol (100-150 mg/hr) for 40 hours during the ICU stay, after which time he was weaned and extubated. Hydration, diuretic use, and alkalinization were continued during the ICU stay to ensure a urine output of 2 mL/kg/hr. Urine was cola-colored for 9 days. Serum creatine phosphokinase (CPK) peaked at 286,800 IU/L on postoperative day 5, and transient increases in serum creatinine (1.7 mg/dL), D-dimer (3.3 mg/dL), and international normalized ratio (1.61) occurred during the first 48 hours in the ICU.

The patient was discharged from the hospital 10 days after the occurrence of MH. Gene testing done as a courtesy in the genetics laboratory at the University of Pittsburgh (by Drs Barbara Brandom and Jeffrey A Kant) revealed a European MH Group (EMHG)-registered disease-associated mutation (p.Gly341Arg). ^[8]

In this case from an underdeveloped country, IV dantrolene was not available. The patient was treated for MH as well as was possible with oral dantrolene and cooling, but it is likely that the MH crisis could have reversed more rapidly if IV dantrolene had been available.

A 23-year-old woman with a history of chronic cholecystitis is scheduled to undergo a laparoscopic cholecystectomy at an ambulatory surgery center. She has no reported history of anesthetic complications, though she has previously undergone no procedures other than wisdom teeth extraction under sedation. She also has no known family history of anesthetic complications.

Anesthesia is induced with propofol and rocuronium. Tracheal intubation is performed. Anesthesia is maintained with sevoflurane and fentanyl. While the patient is being prepared for surgery, EtCO₂ rises to 55 mm Hg over a period of 5 minutes. Esophageal temperature rises from 36ºC to 39ºC over the same time interval. The diagnosis of possible MH is entertained.

The surgical procedure was stopped, and sevoflurane was discontinued. The patient received 2.5 mg/kg of dantrolene and was hyperventilated with 100% oxygen via an Ambu bag. Ice packs were applied for cooling, and the MH hotline was contacted. Arrangements were made to transfer the patient by ambulance to a nearby hospital with an ICU capable of caring for the patient.

ABG values were not available at the ambulatory surgery center, but EtCO₂ had declined to 50 mm Hg soon after the administration of dantrolene, and the temperature had fallen to 38.8ºC. The patient was observed overnight in the ICU, and diuresis was established with fluids. On the following day, she was extubated. No further treatment with dantrolene was required. Subsequent in-vitro contracture testing of the patient’s parents determined that the mother was MH-susceptible.  

This case is from an ambulatory surgery center, where most operations under general anesthesia in the United States are now performed. Again,  rapid diagnosis of MH and prompt treatment with dantrolene are essential for a good outcome. In this case, neither the patient nor her father were aware that she was MH-susceptible.

Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015 Aug 4. 10:93. [Medline]. [Full Text].

Broman M, Islander G, Müller CR. Malignant hyperthermia, a Scandinavian update. Acta Anaesthesiol Scand. 2015 Sep. 59 (8):951-61. [Medline].

Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018 Jun. 65 (6):709-721. [Medline].

Beebe DS, Belani KG, Tuohy SE, Sweeney MF, Gillingham K, Komanduri V, et al. Is dantrolene safe to administer in sepsis? The effect of dantrolene after endotoxin administration in dogs and rats. Anesth Analg. 1991 Sep. 73 (3):289-94. [Medline].

Jones C, Bennett K, Kim TW, Bulger TF, Pollock N. Preparation of Datex-Ohmeda Aestiva and Aisys anaesthetic machines for use in malignant hyperthermia susceptible patients. Anaesth Intensive Care. 2012 May. 40 (3):490-7. [Medline].

Birgenheier N, Stoker R, Westenskow D, Orr J. Activated charcoal effectively removes inhaled anesthetics from modern anesthesia machines. Anesth Analg. 2011 Jun. 112 (6):1363-70. [Medline].

Bilmen JG, Gillies RI. Clarifying the role of activated charcoal filters in preparing an anaesthetic workstation for malignant hyperthermia-susceptible patients. Anaesth Intensive Care. 2014 Jan. 42 (1):51-8. [Medline].

Chinnamuthu M, Banakal S, Ahamed I, Mohanty SK, Jayanthkumar H, Harish B, et al. Acute fulminant malignant hyperthermia syndrome in the OR and no IV dantrolene: urgent need for a global initiative for worldwide patient safety (abstract A1171). Presented at the American Society of Anesthesiologists Annual Meeting. October 13-17, 2012. Washington, DC. [Full Text].

David S Beebe, MD Professor, Department of Anesthesiology, Chief, Division of General Anesthesiology, University of Minnesota Medical School; Staff Anesthesiologist, University of Minnesota Hospital, Maple Grove Ambulatory Center, and University of Minnesota Masonic Children’s Hospital

David S Beebe, MD is a member of the following medical societies: American Society of Anesthesiologists, Minnesota Medical Association, Minnesota Society of Anesthesiologists, Society for Ambulatory Anesthesia, Society for Pediatric Anesthesia, Twin Cities Medical Society

Disclosure: Nothing to disclose.

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Sheela Pai Cole, MD Clinical Associate Professor of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine

Sheela Pai Cole, MD is a member of the following medical societies: American Medical Association, American Society of Anesthesiologists, American Society of Echocardiography, California Society of Anesthesiologists, International Anesthesia Research Society, Pennsylvania Society of Anesthesiologists, Society of Cardiovascular Anesthesiologists, Society of Critical Care Anesthesiologists, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Malignant Hyperthermia in the Operating Room 

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