Malignant Hyperthermia, Susceptibility To, 1

Alternative Names

  • MHS1
  • MHS
  • Hyperthermia of Anesthesia
  • Hyperpyrexia, Malignant
  • MH
  • King Syndrome
  • King-Denborough Syndrome
  • Hyperpyrexia
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WHO-ICD-10 version:2010

Injury, poisoning and certain other consequences of external causes

OMIM Number

145600

Mode of Inheritance

Autosomal dominant

Gene Map Locus

19q13.2

Description

Malignant hypothermia is a potentially lethal, rare, pharmacogenetic skeletal muscle disorder characterized by a hypermetabolic reaction in response to all volatile anesthetics and depolarizing muscle relaxants. Patients display no signs or symptoms under normal conditions, although they may be associated with a subclinical myopathy. However, under the effect of an anesthetic, severe muscle contraction, and a rapid rise in body temperature, up to 40.5 degrees Celsius, is observed. Consumption of oxygen and production of carbon dioxide is increased, and so is the activity of the sympathetic nervous system. Other symptoms include, sore muscles, tachycardia, hypertension, cyanosis, metabolic acidosis, myogobinuria, and breakdown of muscle fiber (rhabdomyolysis). The latter symptom is especially dangerous, since the degraded muscle fibers tend to move into circulation, and block the structures of the kidney, causing kidney failure, evidenced by dark brown urine.

The patient's clinical signs under administration of anesthesia are enough to diagnose malignant hyperthermia. Additionally, the patient also shows elevated levels of creatinine phosphokinase, potassium, uric acid, and phosphate in the blood, and myoglobin in the urine. To test for susceptibility to MH, a Halothane caffeine test may be undertaken. This test can be especially useful for patients with a family history of MH or unexplained death during anesthesia, and are planning to undergo surgery themselves. The test involves placing a small muscle strip of the patient in a solution containing an anesthetic and monitoring for force of contraction. Moreover, genetic susceptibility tests that analyze the ryanodine receptor (RYR1) gene are also available for patients at risk. Once a susceptibility status is confirmed, the best strategy would be to avoid generalized anesthesia during surgery. In cases where hyperthermia has set in, antipyretic medications may be given to bring down the fever, in addition to medications to maintain kidney function.

World incidence data for malignant hypothermia are not available. However, a recent survey in Canada estimated that the disease occurs in 1 in every 14,000 live births.

MH has been shown to be transmitted in an autosomal dominant fashion. At least five different genetic loci have been implicated in the manifestation of this disease, of which the gene most commonly seen to be mutated, and the best characterized is the Ryanodine Receptor 1 gene (RYR1) on chromosome 19. The ryanodine receptor protein, seen on the sarcoplasmic reticulum (SR) of muscle cells, is responsible for enabling muscle contraction by releasing calcium from the SR. In MH, defects in the RYR1 gene diasble the closing mechanism of the receptor protein, leading to excessive release of calcium ions. Large amount of energy is wasted (and heat produced) in getting these calcium ions back into the SR. The muscle damage occurs principally due to the depletion in energy.

Molecular Genetics

MH has been shown to be transmitted in an autosomal dominant fashion. At least five different genetic loci have been implicated in the manifestation of this disease, of which the gene most commonly seen to be mutated, and the best characterized is the Ryanodine Receptor 1 gene (RYR1) on chromosome 19. The ryanodine receptor protein, seen on the sarcoplasmic reticulum (SR) of muscle cells, is responsible for enabling muscle contraction by releasing calcium from the SR. In MH, defects in the RYR1 gene diasble the closing mechanism of the receptor protein, leading to excessive release of calcium ions. Large amount of energy is wasted (and heat produced) in getting these calcium ions back into the SR. The muscle damage occurs principally due to the depletion in energy.

Epidemiology in the Arab World

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Other Reports

Bahrain

Kooheji (1988) reported on three Bahraini nationals who developed malignant hyperthermia under general anesthesia. The first case was that of an 18-year old male, who underwent surgery for excision of a bony swelling in his right ear in 1971. The patient had had no previous anesthetic history. He was premedicated with atropine 0.6mg, and induced into anesthesia with sodium thiopentone 300mg and suxamethonium 75mg. Anesthesia was maintained with 2% halothane and 60% nitrous oxide in oxygen. At the end of the surgery, which lasted 45 minutes, the patient developed tachycardia and high fever (108 degrees F), which was diagnosed as MH, and he was treated with 100% oxygen, IV fluids, cooling, and intravenous administration of sodium bicarbonate. Although the temperature dropped down to 96 degrees F after three hours, the patient arrested an hour later and died. This patient was the first case of MH in the Gulf Cooperation Council countries. Interestingly, a daughter of one of the female relatives of this patient developed MH during a surgery for repair of a congenital cardiac defect in USA in 1982. MH susceptibility was confirmed in her case, by muscle contracture tests. Another case reported by Kooheji (1988) was that of an 18-month old Bahraini child, who was slated for cytoscopy, circumcision, and orchidopexy. Previous minor surgeries undergone by this patient had resulted in pyrexia lasting for three days. He was, therefore considered an anesthetic risk. Pethidine 10mg and atropine 0.3mg was administered to him 50 minutes prior to induction with althesin 1ml. Anesthesia was maintained with 50% nitrous oxide in oxygen and 2% halothane. Forty five minutes after induction, curare 2mg was administered and the patient was manually ventilated using nitrous oxide: oxygen 4:4 litres/minute. At the end of the 2-hour long operation, neostigmine 0.4mg and atropine 0.2mg were administered. The patient then showed an increase in his pulse rate (180-200 beats/minute) and rectal temperature (40.6 degrees C), rigid limbs, tachypnoea, and masseteric spasm. He was diagnosed with malignant hyperthermia, and treated with cooling using ice packs, 100% oxygen, and sodium bicarbonate. Over the next 45 minutes, his temperature and pulse rate dropped to 38 degrees C and 160 beats/min, respectively. In the recovery room, his pulse rate further stabilized. However, he still required cooling to correct his body temperature. Although in the next 36 hours, he again developed pyrexia, 48 hours later, he was apyrexial, and in a normal conscious state. [Kooheji AJ. Malignant hyperthermia. Bahrain Med Bull. 1988; 10(3):148-51.]

Lafi and Farhoud (1998) reported a four-year-old child who was scheduled for surgery because he had left communicating hydrocele. General anesthesia was given with difficult intubation due to master muscle spasm. Immediately post intubation, the patient developed fever which reached 40 degrees Celsius. Arterial blood gases showed pH: 7.05 mmol, PO2: 44 mmHg and PCO2: 70 mmHg, and malignant hyperthermia was diagnosed. All anesthetic gases were stopped and a different anesthesia system was used. Foley's urethral catheter was fixed and drained red colored urine. Hematogram revealed Hb 10mg%, blood platelets 233000/cumm.S.Na 133 mEq/L, Ca 6 mEq/L, K 6.7 mEq/L and CPK 75800 U/L. Three hours after giving him eighty ml of 10% D/W intravenously in addition to 1.2 units simple insulin, the child's temperature returned to normal (37 degrees Celsius). [Lafi MIO, Farhoud AM. Malignant Hyperthermia. J Bahrain Med Soc. 1998; 10(2):105-6.]

Saudi Arabia

Radwan et al. (1985) report a Saudi child with of a case of malignant hyperthermia. MH was probably triggered by response to Halothane. The diagnosis was suspected by the clinical signs of tachycardia, severe rigidity, cyanosis and rising temperature. The case was successfully managed by vigorous cooling, dantrolene sodium and diuresis. In 1994, Ahmed and Usman described a 32 year old healthy male patient who had an acute episode of a malignant hyperthermia-like syndrome due suxamethonium and halothane anesthesia during a tendon repair operation to his right thumb. Dantrolene therapy rapidly reversed the life threatening signs.

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