Malignant hyperthermia and the otolaryngologist. (Original Article).

Abstract

Malignant hyperthermia is a rare disorder that can occur in patients who are sensitive to certain agents used in general anesthesia. The treatment of malignant hyperthermia has not changed over the years, but prevention strategies have evolved. These strategies include an increased emphasis on how patients are managed prior to a surgical procedure, on the selection of the particular anesthetic agent, and on postoperative vigilance. Susceptible patients who undergo simple excisions or a low degree of surgical stress can receive treatment safely in the office or ambulatory surgery center and be discharged the same day, provided that all known triggering agents are avoided. For more extensive procedures that cause a moderate level of surgical stress to susceptible patients, facilities for managing malignant hyperthermia should be readily available. Susceptible patients who undergo high-stress invasive procedures should be hospitalized. Routine preoperative prophylactic drug administration, even with dantrolene, is no longer considered necessary for any susceptible patients. All local anesthetics--including lidocaine, which had been previously contraindicated--are now considered to be safe for use in patients who are susceptible to malignant hyperthermia. In this article, we review the prevention, diagnosis, and management of malignant hyperthermia. We also report our experience in anesthetizing a patient who had a history of malignant hyperthermia--a case that illustrates the uncertainty that can complicate the management of such patients.

Introduction

Malignant hyperthermia is a rare disorder that can occur in patients who are sensitive to certain agents used in general anesthesia. Although malignant hyperthermia has been well described in the literature, there continue to be conflicting recommendations from different sources regarding its prevention. In this article, we review the past and current concepts pertinent to malignant hyperthermia, with particular emphasis on otolaryngologic practice, especially in the outpatient setting. The recommendations based on current data here are meant to serve only as a guide. Each surgeon must assess the circumstances of each individual patient in any given situation before proceeding on a course of action. As more is learned about malignant hyperthermia, guidelines for preoperative considerations and treatment can be expected to evolve. In addition to reviewing the prevention, diagnosis, and management of malignant hyperthermia, we also report our experience in anesthetizing a patient who had a history of malignant hyperthermia--a case that illustrates the uncertainty that can complicate the management of such patients.

Case report

A 42-year-old man came to our center with a longstanding history of nasal obstruction. He had previously undergone surgery to repair a cleft lip and palate. Examination revealed the presence of a severe left septal deformity, bilateral concha bullosas, and markedly enlarged turbinates. We initially decided to perform a septoplasty and abilateral endoscopic resection of the concha bullosas. However, during the patient's visit, he brought to our attention the fact that he had a history of an adverse reaction to anesthesia. Three decades earlier he had experienced a fever as high as 40[degrees] C, convulsions, and facial swelling following the administration of general anesthesia during jaw surgery. He had not experienced any reaction to general anesthesia during two previous surgical manipulations. An anesthesiology consult was obtained, and the patient was cleared for surgery at our ambulatory surgery center. Of note, no muscle biopsy was obtained.

On the morning of surgery, however, several issues were raised regarding the patient's safety. A question arose as to the wisdom of performing surgery on a patient with a probable history of malignant hyperthermia at an ambulatory surgery center that was not equipped with intensive care unit capabilities. Another issue concerned the fact that anesthetic support was to be provided by a certified registered nurse anesthetist rather than an anesthesiologist. After much discussion and angst, we proceeded with the procedure as planned. No prophylactic measures were taken other than to use known nontriggering anesthetic agents. The operation was completed without incident, and the patient was discharged home later that day.

Discussion

Although malignant hyperthermia did not occur in our patient, this case illustrates the uncertainty that can complicate the management of patients who have a history of this disorder. Indeed, much controversy and confusion attend to malignant hyperthermia and its diagnosis, its triggering factors, and its clinical manifestations.

Although heat stroke as a postoperative complication has been described since 1900, (1-3) it was not until 1962 that Denborough et al (4) first established a link between malignant hyperthermia and anesthesia and identified the familial pattern of this condition. Mortality was originally estimated to be nearly 80%, but since the introduction of the skeletal muscle relaxant dantrolene (the only specific drug indicated for the treatment of malignant hyperthermia) in 1975, mortality has been reported to be less than 10%. (5,6)

Susceptibility and incidence. Susceptibility to malignant hyperthermia is known to be the result of abnormal calcium metabolism in the skeletal muscle fiber. It is also known to be an inherited autosomal-dominant condition of variable penetrance. However, the precise culprit has proved to be elusive, as genetic analysis has demonstrated heterogeneity. Linkage to the ryanodine receptor gene, the dihydropyridine membrane calcium channel, and the second-messenger inositol polyphosphate system has been found, but not consistently. (1,7) Linkage to chromosomes 1, 3, 5, 7, 17, and 19 has been discovered, but such genetic heterogeneity precludes a DNA-based diagnosis. (1,2,5,6)

The incidence of malignant hyperthermia is estimated to be 1 in 15,000 children and 1 in 20,000 to 50,000 white adults. (1,5,8) Fulminant malignant hyperthermic crises occur in 6.5% of all cases; the calculated incidence of these crises is 1 in 84,000 following the administration of volatile anesthetics and 1 in 62,000 following the administration of succinylcholine. (1,8)

The best way of determining a patient's susceptibility to malignant hyperthermia is the personal and family history, although an estimated 21% of patients who experience malignant hyperthermia had undergone at least one previous uneventful anesthetic procedure (as had our patient). (8) Another much less practical means of identifying susceptibility is the in vitro muscle contraction test, which is the only objective means available for identifying a presymptomatic predisposition to malignant hyperthermia. (6,8,9) Only 10 centers in the United States perform this test (a list of these centers can be obtained by telephoning the Malignant Hyperthermia Association of the United States at [800]986-4287 or by visiting its Web site at www.mhaus.org). A sample of the quadriceps femoris muscle is obtained by open biopsy and analyzed. (1) The patient must travel to a designated testing site because the test must be completed within 5 hours of the biopsy. (8) Its reported sensitivity is 95 to 99% and its specificity is 78 to 93.6%. (1) The only contraindications to this test are age less than 4 years and weight less than 20 kg.

Although it is not mandatory to obtain a biopsy for all patients who have a history suggestive of malignant hyperthermia, all patients should be considered to be susceptible until proven otherwise. (9) Furthermore, given the autosomal-dominant pattern of malignant hyperthermia, any family history of this disorder automatically presumes susceptibility in all family members unless proven otherwise by the in vitro muscle contraction test. (8,9) Again, it might be worthwhile to consult an anesthesiologist before operating on any patient with a possible susceptibility. A preoperative measurement of the patient's creatine kinase (CK) level is not recommended. (1,9)

Perioperative preventive measures. In the past, patients with a history of malignant hyperthermia were treated with the utmost caution preoperatively as well as postoperatively, regardless of whether any adverse event had occurred during anesthesia. Prophylactic medications were administered, and patients were admitted for routine postoperative observation. Even routine office dental procedures were denied these patients for fear that they would trigger an attack. (10)

Today, other pre-, intra-, and postoperative precautions are recommended for susceptible patients. (1) For example, the anesthesia machine must be decontaminated, especially any part of it that might have come into contact with a volatile anesthetic. The breathing circuit must be flushed with fresh oxygen at a rate of 10 L/min for 10 minutes, and fresh soda-lime canisters should be installed. Sufficient amounts of dantrolene should be readily available, although current opinion holds that premedication with dantrolene is obsolete. (1,5,9) Finally, of course, the patient must be appropriately monitored.

Potent inhalational anesthetics are known triggers of malignant hyperthermia, and they should be avoided in susceptible patients (table). (1,8,9) Although there is controversy as to whether succinylcholine and other depolarizing muscle relaxants alone increase the risk of malignant hyperthermia, it is generally accepted that the combination of a volatile anesthetic and succinyicholine does increase the risk. (2) Thus it follows that depolarizing muscle relaxants should be avoided in favor of nondepolarizing neuromuscular blocking drugs, which are considered to be safe in susceptible patients. Barbiturates (e.g., thiopental), etomidate, and propofol are all considered to be safe intravenous anesthetic agents. (2) It is unclear whether phenothiazines trigger malignant hyperthermia, but they can cause neuroleptic malignant syndrome, which is characterized by hyperthermia but which has a different pathophysiology and treatment. (9) However, malignant hyperthermia triggered by phenothiazine alone has never been ve rified. (2)

Amide local anesthetics, which include the commonly used agent lidocaine, were at one time contraindicated in susceptible patients because they can induce in vitro muscle contracture. (1, 2, 5) However, the doses needed to cause such contractures are extremely high. All local anesthetics are now considered to be safe in susceptible patients. In fact, in centers where the in vitro muscle contraction test is performed to test for malignant hyperthermia, physicians use the amide local anesthetic prilocaine.

Although there is no firm clinical evidence that catecholamines trigger malignant hyperthermia, the use of epinephrine remains controversial. Even though catecholamines are not flatly contraindicated, surgeons are urged to use caution. (1) It is believed that the sympathetic dysfunction seen in malignant hyperthermia might be a secondary phenomenon rather than a primary triggering event. Therefore, if epinephrine is deemed necessary, no more than 0.04 mg should be administered. (10)

The act of waking a patient from anesthesia should be carried out in a relaxed and quiet atmosphere because stress might induce malignant hyperthermia, although the concept of stress as a trigger is controversial. (1, 3) Following minor surgery, an observation period of only 3 to 6 hours prior to discharge is appropriate; following major surgery, 24 hours in the intensive care unit is recommended. (8, 9) In itself, a history of susceptibility to malignant hyperthermia does not warrant hospital admission following an uneventful surgery. (8)

In 1992, Haas et al proposed three preventive guidelines for dentists who treat susceptible patients. (10) A similar set of recommendations for dermatologic surgeons was published by Murray et al in 1999. (5) With some modifications, both sets of guidelines can also be applied to otolaryngology practice:

* Nonstressful treatment (simple excisional surgery) can be carried out in the clinic on an outpatient basis.

* More extensive procedures that carry a moderate amount of stress can be carried out in an outpatient setting, provided that the surgeon has ready access to a facility that is equipped to manage malignant hyperthermia if need be. It might also be worthwhile to obtain an anesthesiology consult for risk assessment.

* More invasive and more stressful procedures must be performed in a facility that has an active protocol for managing malignant hyperthermia. An anesthesiology consult might be required, and the procedure might have to be performed in an inpatient hospital setting that has intensive care capabilities.

Haas et al placed particular emphasis on the importance of stress factors that can induce malignant hyperthermia. (10) Factors such as the patient's degree of apprehension, the length of the procedure, and the amount of trauma that is involved are key elements in assessing the risk of malignant hyperthermia in susceptible patients.

Signs and symptoms. When malignant hyperthermia does occur, it is characterized by multiple nonspecific signs and laboratory values that evolve over time during and after exposure to anesthesia. These signs and symptoms are related to skeletal muscle hypermetabolism and ultimate breakdown. The Onset of malignant hyperthermia can occur within 10 minutes or several hours following the administration of anesthesia. (2,8) The speed of onset is dependent on a combination of variables, including the type of drug that triggered the attack, the concentration of the drug, and a patient's unique calcium homeostasis physiologic variables.

Early signs and symptoms of malignant hyperthermia include masseter muscle rigidity (following succinylcholine administration), tachypnea, tachycardia, arrhythmias, a rising end-tidal carbon dioxide level, an increase in minute ventilation, and a hot soda-lime canister. Subsequent signs include cyanosis, cutaneous flushing, a rising core body temperature, hyperkalemia, and acidemia.

The first manifestation of malignant hyperthermia might be masseter spasm, which is often more pronounced in children. The incidence of masseter spasm is 1% following halothane and succinylcholine administration. (1) As a result, many anesthetists reserve succinylcholine for use during induction only under special circumstances in children. (8) Several studies have shown that as many as 50% of patients who experienced masseter spasm were later found to be prone to malignant hyperthermia. (1,3,6) Moreover, an episode of trismus that lasts longer than 90 seconds and prevents laryngoscopy and intubation is classified as masseter muscle rigidity and must be regarded as pathologic. (1,3,6) The onset of masseter muscle rigidity is an indication to immediately discontinue anesthesia and admit the patient for overnight observation for evidence of malignant hyperthemia. (3,9) Transient trismus alone does not confirm malignant hyperthermia, but generalized rigidity is a definitive sign, and treatment should be initiate d promptly.

Late signs are ominous. They include generalized muscle rigidity, prolonged bleeding, dark urine, oliguria, an increase in CK level, and myoglobinuria. In a fulminant crisis, the patient's core temperature can rise at a rate of 1[degrees]C every 5 minutes up to, and even above, 42[degrees]C; in rare cases, however, actual hyperthermia might be absent. (1,8) Even with aggressive treatment, end-stage malignant hyperthermia can result in death. Therefore, prompt diagnosis and early treatment are important, but the diagnosis can be difficult in view of the nonspecific nature of some of its signs and symptoms and the extensive differential diagnosis. The differential diagnosis includes, but is not limited to, inadequate anesthesia or analgesia, an improper breathing circuit, sepsis, hypoxia, hypercapnia, iatrogenic hyperthermia, heat stroke, the presence of radiologic contrast material in the central nervous system, anaphylaxis, pheochromocytoma, thyroid storm, cerebral ischemia, neuroleptic malignant syndrome, an d other muscular diseases. (2,6,11) Several reviews have been published that provide more detail on the signs and symptoms of malignant hyperthermia. (1,2,6,8,11)

Management. While preoperative considerations have evolved over time, the management of patients in the midst of a developing malignant hyperthermic crisis has not changed significantly over the years. Malignant hyperthermia is treated on multiple fronts. (1,2,8) In addition to the immediate termination of a volatile anesthetic, other management steps include the commencement of mechanical ventilation with 100% oxygen at a flow rate greater than 10 L/min, normalization of metabolic derangements, and a lowering of body temperature with topical ice or ice-water lavage. Dantrolene can also be started at the recommended dosage of 2.5 mg/kg administered intravenously every 5 minutes up to a total dose of 10 mg/kg until symptoms abate. In some circumstances, the total dose can be as high as 20 mg/kg. (5) Following the stabilization of a hyperthermic crisis, the patient must be admitted to the intensive care unit for observation because malignant hyperthermia has been reported to recur in 25% of patients. (12)

Table

The safety of selected drugs in patients susceptible to malignant
hyperthermia

Do not use (trigger agents)

Cyclopropane
Depolarizing muscle relaxants (e.g., succinylcholine)
d-Tubocurarine
Ether
Methoxyflurane
Rapid intravenous potassium
Volatile inhalational anesthetics (desflurane, enflurane,
  halothane, isoflurane, sevoflurane)

Use cautiously

Catecholamines
Haloperidol
Phenothiazines (chlorpromazine, prochlorperazine)

Safe to use

Anticholinergics
Anticholinesterases
Barbiturates
Benzodiazepines
Calcium
Droperidol
Etomidate
Ketamine
Local anesthetics
Narcotics
Nitrous oxide
Nondepolarizing muscle relaxants
Nonsteroidal anti-inflammatory drugs
Propofol

References

(1.) Wappler F. Malignant hyperthermia. Eur J Anaesthesiol 2001;18:632-52.

(2.) Hopkins PM. Malignant hyperthermia: Advances in clinical management and diagnosis. Br J Anaesth 2000;85:118-28.

(3.) Kaplan RF. Clinical controversies in malignant hyperthermia susceptibility. Anesthesiology Clinics of North America 1994;12:537-51.

(4.) Denborough MA, Forster JF, Lovell RR, et al. Anaesthetic deaths in a family. Br J Anaesth 1962;34:395-6.

(5.) Murray C. Sasaki SS, Berg D. Local anesthesia and malignant hyperthermia: Review of the literature and recommendations for the dermatologic surgeon. Dermatol Surg 1999;25:626-30.

(6.) Denborough M. Malignant hyperthermia. Lancet 1998;352:1131-6.

(7.) MacLennan DH, Duff C, Zorzato F, et al. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 1990;343:559-61.

(8.) Karlet MC. Malignant hyperthermia: Considerations for ambulatory surgery. J Perianesth Nurs 1998;13:304-12.

(9.) Malignant Hyperthermia Association of the United States, 2002. www.mhaus.org.

(10.) Haas DA, Young ER, Harper DG. Malignant hyperthermia and the general dentist: Current recommendations. J Can Dent Assoc 1992;58:28-33.

(11.) Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771-9.

(12.) Redmond MC. Malignant hyperthermia: Perianesthesia recognition, treatment, and care. J Perianesth Nurs 2001;16:259-70.

From the Division of Otolaryngology--Head and Neck Surgery, Department of Surgery, Duke University Medical Center, Durham, N.C.

Reprint requests: Christopher Chang, MD, Duke University Medical Center, DUMC Box 3805, Durham, NC 27710. Phone: [phone]; fax: [phone]; e-mail: [e-mail]