Canadian Journal of Anesthesia, Vol 24, 678-694, Copyright © 1977 by Canadian Anesthesiologists' Society

The Caffeine Test of Isolated Human Muscle in Relation to Malignant Hyperthermia

¹ Departments of Pharmacology and Anaesthesia, Faculty of Medicine, University of Toronto

1. Pharmacological tests of isolated fibers of skeletal muscle proved to be a means of clarifying the occurrence of certain genetic defects.

2. Muscle specimens from 74 subjects were investigated. Of these, 14 had recovered from an episode of malignant hyperthermia (MH), an often fatal complication of general anaesthesia which is known to occur on the basis of a genetic predisposition. The others were 25 relatives of MH patients, and 35 subjects unrelated to malignant hyperthermia.

3. The tests consisted in measuring the contracture tensions of isolated fibres of skeletal muscle when exposed to various concentrations of caffeine, once in the presence, once in the absence of the anaesthetic agent halothane. The method is described in detail.

4. Muscle specimens which in the presence of halothane required more than 1.3 millimolar concentration of caffeine to produce a tension increase of 1 gram were defined as controls. The 45 control data thus defined were normally distributed. Age, sex, type of muscle, and size of the specimen did not account for individual difference within this control population. The control group did not contain any MH patient who had developed rigidity during the attack. On the other hand, it did contain all but one of the specimens from MH-unrelated subjects.

5. The acceptance of the control data as a standard left a deviant group of 29 subjects. This group could be subdivided according to the caffeine-contracture in the absence of halothane.

All those MH patients who had displayed some rigidity during their attack were in this deviant group; they were characterized by high sensitivity to caffeine. The deviant group included two subjects who had suffered an MH episode without rigidity; they differed from all others by a high resistance to caffeine contracture and thereby seemed to represent a separate category of MH which could not be further analyzed during the studies reported here.

The deviant group contained 10 relatives of MH patients who differed in their caffeine response from the patients themselves. Hence there are at least three kinds of relatives of MH patients: those that are indistinguishable from patients, those that fall into the control group, and an intermediate group. One of the MH-unrelated subjects reacted like an intermediate, suggesting that this represents a defect which is not rare in the general population.

6. When these data were seen in the context of family groups, there was evidence of a recessively inherited predisposition to malignant hyperthermia. However, part of the data were also compatible with the repeatedly published evidence of dominant inheritance of this predisposition. Since multigenic inheritance appears to be excluded, the simplest genetic models which can reasonably account for the observations are either a two-gene case or the assumption of one gene locus with three alleles. Improvement of the test methods or an increase of the data base should allow a choice between genetic theories.