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Malignant hyperthermia (MH) is a rare genetic disorder of skeletal muscle manifested by a hypermetabolic crisis after a susceptible individual receives a volatile inhalational anesthetic or a depolarizing muscle relaxant. MH-susceptible individuals are at risk for life-threatening perioperative complications. The following case report describes the precautions taken to avoid an acute MH episode in a patient with a history of MH. The pathophysiology, prevention, and management of MH will also be reviewed.
A 29 year old, 78 kilogram, 65-inch (165-centimeter) female presented to the operating room for knee arthroscopy for complaints of knee pain and occasional dislocation of the patella. The anesthesia provider initially evaluated the patient in the preoperative holding area and a thorough preoperative anesthesia assessment was completed. The assessment revealed a health history of suspected malignant hyperthermia during an oophorectomy procedure one year prior. The patient did not have an adverse outcome but states she was hospitalized following the procedure for further monitoring. The patient also revealed a history of fibromyalgia, depression, gastroesophageal reflux disease (GERD) and ulcerative colitis with no other reported co-morbidities. In addition to MH, the patient indicated a history of postoperative nausea and vomiting. The patient was taking lexapro and omeprazole daily and reported good control of her reflux. The patient had not taken medication the morning of the surgery and was not experiencing any symptoms related to her GERD or ulcerative colitis. Other than the previously discussed conditions, the patient appeared to be in relatively good health and reported a high level of daily activity. All preoperative laboratory reports, which included a complete blood count and basic metabolic panel, were within normal limits. Preoperative vital signs were as follows: pulse of 79 beats per minute, blood pressure of 127/66 mmHg, respiratory rate of 14 breaths per minute, oxygen saturation of 98 percent on room air and temperature of 98.2 degrees Fahrenheit. Physical exam by the anesthesia provider the morning of surgery was within normal limits for neurological status as well as heart and lung sounds. The patient's airway was evaluated as a class two airway using the Mallampati classification system, and all other airway assessments were within normal limits and predicted that the patient would be an easy intubation. The anesthesia provider assigned the patient a physical status classification of two. A scopolamine patch was place behind the patient's left ear as a prophylactic measure to abate the symptoms of postoperative nausea and vomiting.
Prior to the procedure, necessary precautions were taken to avoid a malignant hyperthermia reaction. The anesthesia gas machine was flushed for 20 minutes on 15 liter per minute fresh gas flows. All circuits, carbon dioxide absorber, carbon dioxide line, bag was changed out. Inhalational agents were removed from the anesthesia machine and placed out of reach. Succinylcholine was removed from the anesthesia cart and also placed in an area out of reach to prevent accidental administration upon induction. The malignant hyperthermia cart was placed in the operating room and subsequently checked to ensure all components were within the cart. Instructions were clearly labeled on the outside of the cart to dictate treatment of a MH reaction. The attending anesthesiologist and certified registered nurse anesthetist was informed of the patient's history.
After placing an 18-guage intravenous catheter in a vein in the left arm, the patient was given midazolam, 2mg intravenously, and transported to the operating room. Additionally, the patient was pretreated with 10mg of metoclopramide and 50mg ranitidine intravenously for her history of GERD. After entering the operating room, the patient positioned herself on the operating table in a supine position. Standard ASA monitors were applied and the following vital signs were obtained: blood pressure of 132/72 mmHg, pulse rate of 80 beats per minute, respiratory rate of 16 breaths per minute, and SpO2 of 100% with pre-oxygenation of 10L/min via face mask. Entropy monitoring was initiated to monitor depth of anesthesia and to maintain entropy between 40-60.
The patient was induced with 80 mg of lidocaine, 100 mcg of fentanyl, 150mg of propofol, and 50mg of zemuron intravenously. A 7.5 oral endotracheal tube was placed and secured at 21 centimeters with positive end tidal carbon dioxide and auscultation of bilateral breath sounds. The patient was positioned supine with arms placed on arm boards, padded, ensuring they were less than 90 degrees. An esophageal stethoscope/temperature probe was placed for monitoring of core temperature. Anesthesia maintenance was initiated with a propofol drip at 100mcg/kg/min and titrated to entropy, heart rate, blood pressure, and movement. Additionally, fentanyl was titrated to surgical stimuli and increases in patient's heart rate, blood pressure, and respiratory rate. Total surgical time was ____ minutes and the patient's vital signs were stable for the duration of the procedure with no increases in end tidal carbon dioxide, heart rate, or temperature. The patient was taken to the post-anesthesia care unit where she was comfortable with no complaints of pain, nausea, joint stiffness or muscle pain. She was monitored for a minimum of _____ hours and then discharged home.
MH susceptibility is inherited in an autosomal dominant fashion with reduced penetrance. It is suspected in patients who have demonstrated a prior clinical event suspicious for MH, family history of MH, or myopathies associated with MH, such as Central core and Evans myopathy. Furthermore, Larach et al demonstrated predominance in young males.
The incidence of acute MH susceptibility is variable, depending on the geographical region. In Denmark, for example, it has been estimated to be as low as 1 in 250,000, whereas in a region of Quebec, incidence is estimated to be as high as 1 in 200. An accurate prevalence of patients with MH susceptibility is unknown because patients may never be exposed to triggering agents, and those that develop mild reactions can go unrecognized due to the variable penetrance. In the vast majority of MH-susceptible patients, they will only demonstrate clinical findings of MH upon exposure to triggering agents. Mortality historically has been reported as high as 70% to 80%, but has since dropped dramatically to less than 5%, and has even been reported as low as 1.4% in the United States. This is due in large part to the introduction of dantrolene in 1979, as well as improved monitoring allowing for early detection of hypercarbia.
Administration of halogenated agents and/or succinylcholine in MH susceptible patients may lead to an uncontrolled release of free calcium from the sarcoplasmic reticulum. The gene responsible is the RYR1 located on chromosome 19. Presently, more than 300 RYR1 mutations have been documented. However, only 29 have been formally accepted as causative mutations. In MH susceptible patients, the RYR1 is in a more open resting state than normal, which leads to a 50% reduction in the calcium ion loading capacity and loading rate. A sudden rise in myoplasmic calcium ion is the critical initial event. This results in a continued interaction between the actin and myosin filaments, with sustained muscle contractures. Biochemical pathways are activated to resequester the released calcium, but they are not successful. This leads to breakdown of adenosine triphosphate (ATP), lactic acidosis, hypercarbia and hyperthermia.
Clinical signs of MH are not uniform and their onset is variable. The most frequent and earliest sign of MH crisis is an unexplained, unexpected tachycardia with an unexplained, unexpected rise in EtCO2, which is the most sensitive indicator of potential MH. Tachycardia is most likely from an increase in catecholamine release. Sometimes tachycardia, hypertension and tachypnea may be misinterpreted as inadequate anesthetic depth and mistreated by administering a higher concentration of inhaled anesthetic. Muscle rigidity is a specific sign of MH and another common sign is masseter muscle spasm. Repiratory and metabolic acidosis usually occur in fulminant MH. It is important to note that an elevation in temperature is often a late sign and is best detected by core measurements such as tympanic, esophageal, pulmonary artery, etc. Additional late signs are complex arrhythmias, cyanosis, hypotension, electrolyte abnormalities and rhabdomyolysis.
Figure 1. Pathophysiology of Acute Malignant Hyperthermia
Exposure of an individual who has a genetic susceptibility (ryanodine receptor [RYR1] or dihydropyridine receptor [DHP] mutation) to an anesthetic triggering agent (i.e, volatile inhalational anesthetic agent, succinylcholine, or both) may result in malignant hyperthermia. This reaction is caused by an altered calcium balance between the lumen of the sarcoplasmic reticulum and the sarcoplasm. Normally, muscle cell depolarization is sensed by the DHP receptor, which is thought to signal RYR1 opening by a direct physical connection. In malignant hyperthermia, accumulation of abnormally high levels of calcium in the sarcoplasm causes uncontrolled anaerobic and aerobic metabolism and sustained muscle cell contraction. This results in the clinical manifestations of respiratory acidosis, metabolic acidosis, muscle rigidity, and hyperthermia. If the process continues unabated, adenosine triphosphate (ATP) depletion eventually causes widespread muscle fiber hypoxia (cell death, rhabdomyolysis), which manifests clinically as hyperkalemia and myoglobinuria and an increase in creatine kinase. Dantrolene sodium binds to RYR1, causing it to favor the closed state, thereby reversing the uninhibited flow of calcium into the sarcoplasm.
(Figure from Litman et al, 2005)
Many individuals present to a preoperative area in preparation for surgery with either a known history of a hypermetabolic episode, or a family history of MH-susceptibility, without any prior definitive testing, namely the caffeine-halothane contracture test. Consequently, if a patient presents with either a known or suspected MH-susceptibility, the key treatment is prevention by anesthetizing with non-triggering agents.
Prevention should start with a thorough anesthesia history including questions about prior adverse reactions to anesthetics in the patient, or in family members. However, a negative history is not reliable in ruling out MH-susceptibility. In one study, only 6.5% of patients had a family history of MH. Furthermore, almost half of patients who develop acute MH were found to have prior uneventful episodes to triggering agents.
MHAUS recommends anesthetizing patients using anesthesia machines which are free of residual halogenated anesthetics. This is achieved by either using a dedicated anesthesia machine for MH-susceptible patients, or by flushing halogenated anesthetics from an anesthesia machine before use. Several investigators have found that many of the newer anesthesia machines require significantly longer flush times than older machines. Gunter et al described a procedure using an activated charcoal filter adjunct which can effectively remove residual sevoflurane to a concentration <5 ppm within 10 min, as opposed to 2 hours using conventional flushing procedures. In addition, depolarizing muscle relaxants, such as Succinylcholine must be avoided.
Treatment of MH
The key to treatment is discontinuation of triggering agents, administration of 100% oxygen, and immediate administration of dantrolene. Institution of active cooling methods should be done if the patient is hyperthermic. Hyperventilation at two to three times the predicted minute ventilation can help reverse the acidosis. If the surgery cannot be stopped, then anesthesia can be maintained with opioids, sedatives, and non-depolorazing muscle relaxants.
Dantrolene binds to ryanodine receptors (RYR1), directly inhibiting sarcoplasmic calcium release. This in turn reverses the hypermetabolic effects of the triggering agents. There are two accepted dosing guidelines for dantrolene, one produced by European Sources (ES), and the other from the Malignant Hyperthermia Association of the United States (MHAUS). The following guidelines below are recommended by MHAUS: Dantrolene 2.5 mg/kg IV bolus, to be repeated until signs of MH are reversed. This is then followed by 1 mg/kg every 6 hours, or 0.25 mg/kg/hr infusion for at least 24 hours. Schumacher et al found that the MHAUS recommendations led to fluctuating plasma concentrations due to the 6 hour maintenance boluses. Consequently, they recommended starting a continuous infusion approximately 5 hours after the initial bolus or boluses to avoid these fluctuations.
As known susceptible patients are not exposed to anesthetic triggering agents, prophylactic treatment with dantrolene is not recommended. Dantrolene has a host of side effects, including muscle weakness, dizziness, drowsiness, tachyarrhythmia, nausea, vomiting, and allergic reactions, which limit its use to MH susceptible patients.
Following an acute event, a determination can be made of whether the event represents a true acute MH episode by using the MH clinical grading scale, devised by Larach et al(Table 1).
Table 1. Clinical Grading Scale to Estimate the Likelihood that an MH episode has occurred (Table from Rosenberg et al, 2002)
This article presents a case report of a patient with a known history of Malignant hyperthermia and describes the necessary precautions taken to prevent an acute MH hypermetabolic crisis. In addition, an overview of the pathophysiology, prevention and management of MH has been reviewed. Malignant hyperthermia is an inherited muscle disorder characterized by a hypermetabolic crisis initiated by triggers such as inhalational anesthetic agents or depolarizing muscle relaxants. Individuals susceptible to MH can have detrimental perioperative consequences, and rarely death, if not properly identified and treated. The key to anesthetic management of MH is prevention of an acute crisis by avoidance of triggering agents in anesthesia machines, either by flushing a machine of volatile agents, or using a dedicated "clean" machine. Treatment of an acute crisis centers on discontinuation of the triggering agents, immediate administration of dantrolene, and reversal of metabolic/electrolyte derangements. Due to advances in detection of hypercarbia, as well as prompt treatment with dantrolene, the mortality associated with acute MH has dropped from historic rates of 70% to less than 5%.