Safety in numbers: how do we study toxicity of spinal analgesics?

MALIGNANT hyperthermia (MH) is probably the only medical syndrome that can only be caused by the administration of anesthetic agents. Because it is almost uniformly fatal if not rapidly diagnosed and treated, it would be a significant improvement for anesthesia risk management if we could reliably predict or confirm MH susceptibility. The mechanism of MH appears to be a defect in skeletal muscle excitation–contraction coupling. In 50% of patients, MH has been associated with one of 20 or more mutations in the type 1 ryanodine receptor (RyR1), the skeletal muscle sarcoplasmic reticulum Ca release channel, and in one family it was associated with a mutation in the 1s-dihydropyridine receptor, the slow voltage gated calcium channel in the sarcolemma. However, in the remaining 50% of patients it has not yet been linked to any genetic locus. This seriously limits our ability to use genetic testing methods. The diagnosis of MH is still a result of a clinical event, and these events are associated with variable symptoms. There have been efforts to grade these events and to make the diagnosis based on a clinical score, but it would be very desirable to have a simple laboratory test that could predict or confirm MH susceptibility with a high level of confidence. Over the years, there have been many diagnostic tests that have been proposed to predict MH susceptibility. However, only the caffeine, caffeine–halothane, and 4 chloro-m-cresol (4-CmC) contracture tests (Caffeine Halothane Contracture Test [CHCT] in North America and In Vitro Contracture Test [IVCT] in Europe) have withstood the test of time. The CHCT is not perfect, but it has had a high degree of correlation with genetic testing in the small, clinically selected population of individuals susceptible to MH. Nevertheless, contracture testing requires a large surgical muscle biopsy and, although readily available in Europe, is performed at a decreasing number of centers in the United States. A less invasive test that could be easily performed at any center and would be at least as reliable as the CHCT would obviously be very desirable. In this issue of ANESTHESIOLOGY, there are two new tests proposed by Sei et al. and Klingler et al. that are “noninvasive” and appear to correlate well with both the CHCT and genetic testing. If the results of these preliminary studies are confirmed, the new tests may well prove to be a useful adjunct to the diagnosis of MH susceptibility. If not, they still suggest new paths to be explored in the direction of this “holy grail. ” Sei et al. had previously demonstrated the existence of RyR1 in B lymphocytes. Girard et al. demonstrated that B lymphocytes from patients susceptible to MH produced more interleukin 1 in response to caffeine and 4-CmC than those from patients who were not susceptible to MH. Based on these findings and the recent findings of others, Sei et al. hypothesized that Ca homeostasis in B lymphocytes is altered in individuals who are susceptible to MH and proposed that this could be the basis for a noninvasive diagnostic blood test. The current study by Sei et al. shows that Ca release induced by caffeine and 4-CmC in cells from individuals susceptible to MH is greater than that in patients with normal CHCT test results (MH susceptibility negative) and that in normal control subjects who did not undergo CHCT testing. This suggests that Ca regulation may be altered in B lymphocytes, and that this malfunction is related to the mutation of RyR1. In addition, on average, the MH-susceptible cells show a lower threshold for 4-CmC than controls. The finding that the caffeine response can be abolished by treatment with EGTA or Ca -free media was unexpected, since caffeine induces its pharmacologic action in the vast majority of cells not by facilitating the entry of Ca from the extracellular space, but by releasing Ca from intracellular stores. This will require further study. However, the lack of a clear-cut point between the responses from cells that are susceptible to MH and those that are not, which is probably related to the heterogeneity of the MH phenotype, limits our ability to discriminate between patients who are and are not susceptible to MH. It will also be necessary for Sei et al. to determine whether this test will have any value for use in patients who do not have a mutation of the RyR1, since B lymphocytes have not been shown to express the other proteins thought to be important for skeletal excitation–contraction coupling or MH. While these factors limit the current utility of this test for diagnosing MH susceptibility, we look forward to This Editorial View accompanies the following articles: Sei Y, Brandom BW, Bina S, Hosoi E, Gallagher KL, Wyre HW, Pudimat PA, Holman SJ, Venzon DJ, Daly JW, Muldoon S: Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes. ANESTHESIOLOGY 2002; 97:1052–8; and Klingler W, Baur C, Georgieff M, LehmannHorn F, Melzer W: Detection of proton release from cultured human myotubes to identify malignant hyperthermia susceptibility. ANESTHESIOLOGY 2002; 97:1059–66.