Ondansetron-induced muscular contractures in malignant hyperthermia-susceptible individuals.
BACKGROUND
The 5-HT(3)-receptor antagonist ondansetron, commonly used to treat nausea and vomiting, was suspected of triggering malignant hyperthermia (MH) when a 5-year-old boy died after receiving a therapeutic dose of ondansetron. To evaluate a possible influence of ondansetron on the onset of MH, we investigated its effect on muscle specimens of MH-susceptible (MHS) and MH-nonsusceptible (MHN) individuals in vitro.


METHODS
Muscle bundles of 6 MHS and 10 MHN patients were incubated in a tissue bath with ondansetron at increasing concentrations (0.1 to 300 μg/mL). Changes in resting tension and twitch height were monitored continuously. Data are reported as median and interquartile range; Mann-Whitney U test for differences between the groups (P < 0.05).


RESULTS
Weight, length, initial resting tension, and twitch height of the muscle bundles did not significantly differ between the investigated groups. An increasing twitch amplitude after ondansetron application was observed in both groups. However, contractures developed only in MHS but not in MHN muscle at ondansetron concentrations of 50 μg/mL (MHS 2.5 [2.1 to 4.0] vs. MHN 0 [0 to 0] mN) and 100 μg/mL (18.0 [11.8 to 22.8] vs 0 [0 to 0] mN). At 300 μg/mL ondansetron, a muscular response was also observed in MHN (23.3 [20.1 to 40.1] vs 1.8 [0.3 to 4.9] mN).


CONCLUSIONS
Ondansetron induced contractures in skeletal muscle bundles in vitro. The effect was significantly higher in MHS than in MHN muscle. Because the necessary concentration of ondansetron exceeded the therapeutic plasma levels by a minimum of 500 times, a trigger potency in vivo seems unlikely.
Department of Anaesthesia and Critical Care, University of Wuerzburg, Wuerzburg, Germany.
Stephan
S
Johannsen
Norbert
N
Roewer
Frank
F
Schuster
D000328:Adult; D004198:Disease Susceptibility / Q000139:chemically induced / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics / Q000503:physiopathology; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D017294:Ondansetron / Q000009:adverse effects / Q000494:pharmacology*; D009924:Organ Culture Techniques; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology*
D058831:Serotonin 5-HT3 Receptor Antagonists; D017294:Ondansetron