MALIGNANT HYPERTHERMIA IN CRITICALLY ILL PATIENTS

Abstract

Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic

disorder of skeletal muscle calcium regulation associated with

uncontrolled skeletal muscle hypermetabolism. Manifestations of

malignant hyperthermia (MH) are precipitated by certain agents, either

conventional such as depolarizing muscle relaxant (specifically,

succinylcholine) or even volatile anesthetics (e.g. isoflurane), and also

can be triggered by certain newly discovered drugs including

(serotonergic drugs, phosphodiesterase type III inhibitors, statins,

ondansteron, methylene blue, tetracaine).

The triggering substances release calcium stores from the

sarcoplasmic reticulum and may promote entry of calcium from the

myoplasm, causing contracture of skeletal muscles, glycogenolysis, and

increased cellular metabolism, resulting in production of heat and excess

lactate. Affected individuals experience: acidosis, hypercapnia,

tachycardia, hyperthermia, muscle rigidity, compartment syndrome,

rhabdomyolysis with subsequent increase in serum creatine kinase (CK)

concentration, hyperkalemia with a risk for cardiac arrhythmia or even

arrest, and myoglobinuria with a risk for renal failure. MH may occur in

the early postoperative period and can recur in the intensive care unit in

following 24 to 48 hours. Without proper and prompt treatment with

dantrolene sodium, mortality is extremely high.

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Malignant hyperthermia in critically patients Summary

A clinical grading scale helps determine if a malignant hyperthermia

(MH) episode has occurred. Contracture testing, the standard diagnostic

test for MH since the mid-1970s, relies on the in vitro measurement of

contracture response of biopsied muscle to graded concentrations of

caffeine, halothane, and other calcium-releasing agents. To date, two

genes predisposing to MHS have been identified; four additional loci

have been mapped, but the genes have not been identified. MHS1 is

associated with mutations in RYR1, encoding ryanodine receptor type 1;

MHS5 is associated with mutations inCACNA1S, encoding a skeletal

muscle calcium channel. Up to 70% of MHS is caused by mutations

in RYR1 and about 1% results from mutations in CACNA1S.

Early diagnosis of MHS is essential for better prognosis and lower

mortality and morbidity. Successful treatment of an acute episode of MH

includes discontinuation of the triggering agents (e.g. succinylcholine);

administration of dantrolene sodium intravenously; surface and

intravenous and body cavity cooling with cold solutions for hyperthermic

individuals; and treatment of metabolic abnormalities.

Affected individuals who display extreme hyperthermia are at risk for

disseminated intravascular coagulation; therefore, a coagulation profile

should be obtained on all individuals experiencing fulminant MH.

Prevention of primary manifestations: Avoidance of triggering agents

(e.g. succinylcholine, volatile anesthetics as isoflurane)). Concerning to

the other drugs recently discovered to be implicated as triggers of MH

including (serotonergic drugs, phosphodiesterase type III inhibitors,

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Malignant hyperthermia in critically patients Summary

statins, ondansteron, methylene blue, tetracaine), There is no convincing

evidence to support the restriction of these drugs in MH-susceptible

patients.

Malignant hyperthermia susceptibility (MHS) is inherited in

an autosomal dominant manner. Most individuals diagnosed with MHS

have a parent with MHS; however, the parent may not have experienced

an episode of MH. The proportion of individuals with MHS caused by de

novo mutations is unknown. Each child of an individual with MHS has a

50% chance of inheriting the disease-causing mutation.