Hot on the Trail of “I know it when I see it!”

This issue of the journal presents four articles dedicated to the subject of malignant hyperthermia (MH).1–4 MH is classically defined as a pharmacogenetic sensitivity to volatile anesthetics and succinylcholine (depolarizing skeletal muscle relaxant) that results in a potentially lethal syndrome of runaway hypermetabolism that is manifested by a mixed respiratory and metabolic acidosis, hypercarbia, tachycardia, and very high fevers.5 Left untreated, both symptomatically, and specifically with dantrolene, this syndrome will progress to frank rhabdomyolysis, with resultant myoglobinuria and renal failure, cardiovascular instability, disseminated intravascular coagulation, and eventual death. Only 2 of the 5 genes associated by linkage analysis with MH susceptibility are known: MHS1, the type 1 ryanodine receptor (Protein:RYR1; gene:ryr1 = 50% to 70% of patients), and MHS5, the skeletal muscle isoform of the dihydropyridine receptor (Protein:DHPRs; Gene:cacna1s = 1% of patients), while the identity of the 3 others remains unknown.5 The DHPRs is the voltage sensor in the transverse tubule of skeletal muscle that senses sarcolemmal depolarization during skeletal muscle excitation-contraction-coupling (ECC), and RYR1, the primary Ca2+ release channel present in the sarcoplasmic reticulum responsible for the contraction-inducing Ca2+ flux,6,7 is the target of the excitatory DHPRs signal during ECC. MH-causing mutations in these 2 proteins result in a volatile anesthetic-induced, uncontrolled rise in skeletal muscle Ca2+, hypermetabolism, and acidosis, that will ultimately lead to the adverse outcomes described above.8 Since the clinical presentation of MH has no pathognomonic signs, our clinical diagnosis is, at best, a highly educated guess; so much so, that in 1994, Larach and colleagues9 gathered to develop a clinical grading scale (CGS) that would allow, via retrospective analysis, a more robust determination of the likelihood of any particular clinical event resembling MH to be categorized as such. This remains the clinical standard today. While, as a goal, prospective identification of all MH-susceptible patients via biological testing would be ideal, this remains an elusive objective. Contracture testing (caffeine-halothane contracture test [CHCT] in North America; in- vitro contracture test [IVCT] in Europe, with similar but not identical protocols using halothane and caffeine as agonists) is an invasive, expensive, biological assay, that requires excised, physiologically viable skeletal muscle for pharmacological assays, is done at only 5 sites in North America (see: http://www.mhaus.org/testing/centers) and requires patient travel to these sites for the test to be done. Genetic testing for causative mutations in the 2 known genes that confer MH susceptibility, described above, are not consistently valuable. The major drawbacks of the genetic testing at our present state of knowledge include the fact that a negative answer is not informative and does not confer release from clinical concern, since there are (at least) 3 other causative genes that cannot yet be tested for, and that variants present in ryr1 and cacna1s have to be proven to be causative by segregating with MH susceptibility in at least 2, unrelated families. While over 300 variants in ryr1 that have been identified to date, only 31 have been determined to be causative (see: http://www.emhg.org/genetics/mutations-in-ryr1/ for a list of these mutations and the criteria used to determine causation. Accessed December 5, 2014.). Identification of a ryr1 variant in a patient with suspected MH is still clinically uninformative unless causation criteria are met. Despite all our molecular advances in ryanodine receptor and MH research over the past decade, and they are formidable, we still don’t know what exactly MH is, nor do we have an easy and specific method of preemptively identifying all patients who are susceptible to developing MH. As a community of caring physicians, we anesthesiologists are dedicated to accumulating as much knowledge about MH as we can, at least to try and develop clinical profiles of susceptibility and to attempt to simplify functional testing that might replace invasive contracture testing. In North America, garnering of comprehensive clinical knowledge about MH is very difficult because there are no governmental structures tasked with maintaining a database on adverse anesthetic events, and there are no statutes mandating reporting of all cases of suspected MH, either in the United States or Canada. In the United States, the North American Malignant Hyperthermia Registry (NAMHR, http://www.mhreg.org/) was established in 1987 as a site to collect data on MH and be a resource for epidemiologic research. In Canada, the Malignant Hyperthermia Investigation Unit (MHIU, http://pie.med.utoronto.ca/MH/) was established at Toronto General Hospital as a site both for contracture and genetic testing, as well as a repository for clinical information on cases of MH in that country. In both countries, reporting is voluntary, and, as can be seen from the Methods section of these articles, complete clinical information is often lacking. Research queries using these databases face serious methodological problems that are difficult to overcome. The primary drawback to registry-based studies is bias, which may be grouped into 3 categories: selection bias, information bias, and confounding.10 Selection bias deals with how the population under study was selected to be in the registry. With voluntary reporting of patients to MH registries, selection of cases to report will be affected by provider desire to report, economics of reporting, culture of reporting, and other factors that have not yet been described that make the reported populations nonrepresentative of the total population of affected patients or potential reporters. Information bias results from measurement error and missing data, the latter being a significant problem in voluntary reporting databases such as the MH registries in the United States and Canada. Measurement error is the difference between the measured value and the true value of a variable. Misclassification is the most common measurement error. Since classification of a patient as MH susceptible (MHS) depends either on a clinical grading scale that is partially subjective or on a contracture test cutoff value that is a surrogate for a true MH event, potential for misclassification is significant. Confounding is due to extrinsic factors that are not directly in an outcome’s causal pathway, but due to factors that are associated with both the predictor and the outcome in a tangential, i.e., non-causative, but statistically significant way, and can induce distortion in the data. Since we do not know what MH really is, and we are measuring general (patho)physiological and clinical characteristics of patients via intraoperative monitoring and laboratory tests or postevent questionnaires, the potential for confounding is great. Despite the caveats, these databases remain the only repositories of any information on patients who may have developed MH, whether during an anesthetic or otherwise. With appropriate caution, clinically useful information may be extracted for general dissemination. Three of the 4 manuscripts presented in this issue attempt to do so. Using the CGS as a guide to determining which patients likely had MH, Nelson and Litman1 present, for the first time, an examination of the clinical characteristics of pediatric patients registered in the NAMHR database. Trisecting the 264 recorded individuals by age into groups of from 0 to 24 months, 25 months to 12 years, and 13 to 18 years, these authors found that there was no predisposing family history of MH or untoward anesthetic reactions in the entire population. This is a very unusual finding for a syndrome that is described as having autosomal dominant transmission, is unexplained by the data in the manuscript, and may be representative of multiple forms of reporting bias.10 It is interesting, to note that the authors found that, in descending order of frequency, the triad of sinus tachycardia, hypercarbia, and rapidly rising temperatures were the most common findings, and reported most often in the oldest group of patients. The youngest group of patients was the most likely to have higher lactic acid levels and lower peak creatinine levels. The latter findings might be explained by the lower glycogen stores and smaller muscle mass to be found in infants relative to teenagers, which would theoretically result in a more rapid transition to anaerobic metabolism and myocyte dysfunction and death during hypermetabolic crisis. Despite the latter findings, there were, no MH-associated deaths reported among affected infants, while there were 6 deaths in the middle group and 4 among the teenagers. One would think that infants would be more fragile than older children and, hence, have a greater mortality. These results may, again, reflect both reporting bias and the insufficient numbers of patients to capture the true incidence of death, because there were only 35 patients in the infant group, but 163 in the middle group and 66 in the teenage group. Recrudescence occurred in approximately 14% of patients across all the age groups, and 2 of the recorded deaths were in patients who experienced recrudescence. Surprisingly, there were no deaths reported in the years between 1960 and 1989, yet there were 5 deaths reported in each of the 2 decades following. It is highly unlikely that MH was less deadly prior to 1990 than it was in following years. Reporting bias is very likely at work here, makes all rank order findings suspect, and should be a warning to those trying to read exactness into these findings (Board question trawlers, beware!). Yet we need to be aware that MH can trigger even in infants, that they too have the potential to die from MH11 unless treated appropriately with dantrolene (even if the evidence has not been deposited with the NAMHR database), and that symptoms will be similar across the pediatric population, though skin mottling may be more common in the infant population. There have always been intimations in the literature that there are differences in the ability of the various anesthetics to trigger MH, with halothane being the most potent.8 Recently, Migita et al.12 examined 147 cases (1990–2009) in the Japanese MH database for cases characterized as “very likely” or “almost certain” (by CGS score) for offending volatile anesthetics (sevoflurane vs isoflurane both, in the absence of succinylcholine). By examining outcome, CGS score, and time from induction to onset of MH, the authors attempted to rank volatile anesthetic potency in triggering MH, yet they were unable to find any differences between these volatile anesthetics. The North American experience, however, seems to be different. In this issue, Visoiu et al.2 present their analysis of 477 cases in the NAMHR and find that halothane is the most potent volatile anesthetic in triggering MH, followed by, in descending order, sevoflurane, desflurane, and isoflurane, as measured by time of induction to time of first presenting sign of MH. Differences between the 2 studies can be attributed to differing populations (Japan versus North America), differing number of patients, and some form of reporting bias. It is unclear whether the differences between the 2 populations are meaningful, but what is certain is that all volatile anesthetics in use today can trigger MH. Visoiu et al.2 report that masseter muscle spasm was the most common first sign of MH, and one supposes that this occurred with the use of succinylcholine, which, as has been noted before,8 decreases the time to diagnosis with all anesthetics. Surprisingly, these authors note that signs of MH have, on the average, appeared later in the course of an anesthetic since the year 1998 than prior to this year. Since there is no known biological mechanism that could remotely account for such a finding, we must resort to attributing these differences to changes in reporting biases, changing provider knowledge base and situational awareness over time and, most likely, the possible decreased use of succinylcholine among anesthesia providers in the post-1998 period. This last is likely due to the “Black Box” warning promulgated by the Food and Drug Administration in the late 1990s regarding drug-induced rhabdomyolysis and hyperkalemic cardiac arrest in children with Duchenne Muscular Dystrophy associated with the use of succinylcholine (see: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/008453s027lbl.pdf; accessed August 29, 2013). The manuscript by Riazi et al., however,3 offers a more integrated approach to the study of the clinical characteristics and epidemiology of MH. The Malignant Hyperthermia Investigation Unit in Toronto is a centralized testing unit for all of Canada, and as such, was able to amass a modest database of 129 proband-survivors of MH whose MHS status was confirmed by caffeine-halothane contracture testing and/or a positive genetic test performed in-house, and whose anesthetic records were available for examination. The database was queried for demographics, clinical signs, laboratory findings, outcomes, and treatment. Young men dominated the sample at 61.2%, 13.2% had uneventful prior anesthetics, 6.2% of cases occurred in the postanesthesia care unit, and no cases occurred after discharge from this unit. In agreement with Nelson and Litman,1 the most frequent clinical signs in the Canadian population were the triad of hyperthermia, hypercarbia, and sinus tachycardia. While 20.1% of patients in this series experienced complications, particularly renal dysfunction, complication rates increased to ≥30% if treatment with dantrolene was delayed by >20 minutes from the time the first sign of MH was noted. Clearly, aggressive and early treatment with dantrolene is what reduces morbidity and potential lethality, and lends credence to the sentiment among anesthesia providers that if one suspects that an MH event is evolving, one should begin treatment with dantrolene even before one is confident of the diagnosis of MH. Delaying treatment in a case of MH has far more ominous ramifications than unnecessary treatment with dantrolene, since the side effects of dantrolene are rarely serious.13 Most significantly for anesthetic practices, both this study and that of Visoiu et al.2 document an aggregate of 34 cases of MH triggered by succinylcholine alone, laying to rest any controversy whether this drug is capable of triggering MH by itself. Whether MHS patients will trigger on first exposure to succinylcholine or, as with volatile anesthetics,14 may require multiple exposures to the drug, has not been answered by this study. In addition, Riazi and colleagues3 do not address the clinical characteristics of those patients who were suspected of having an MH reaction during anesthesia but proved to be normal on contracture testing. It will be important to determine, if possible, whether there are any intraoperative or preoperative clinical characteristics which could be used to distinguish between patients who are normal versus MHS, even if they have a reaction that could be construed as MH. Finally, this series of articles addresses the need for functional surrogate analyses that would allow the preoperative prediction of MH susceptibility. In this issue of Anesthesia & Analgesia, Schiemann et al.4 use targeted, MH-mutation “hot-spot” ryr1 DNA sequencing techniques to identify MH mutations in 3 New Zealand families. Two mutations (R2355W, present in 2 of the families, and V2354M, present in 1 family) were previously known and segregated with MH susceptibility in the 3 families. Since mutations require functional analysis to be considered as MH-causative, the authors (a) used the IVCT (classic surrogate test) results and correlated these with the genetics in family pedigrees to determine MHS segregation, and (b) used B-cell lines derived from affected patients and normals to determine the extent of agonist-induced, RYR1-mediated, Ca2+ flux as a functional measure of susceptibility to MH, a technique originally pioneered by Girard et al.15, and by Sei et al.16 Using 4-chloro-m-cresol (4-CmC) as RYR1 agonist, the authors demonstrate that B-cells containing either mutation noted above are more sensitive to drug-induced Ca2+ fluxes than B-cells derived from normal patients. Since the R2355W mutation is present in 2 families, the authors propose this as a causative mutation and suggest that the V2354M mutation is also causative but awaits a similar finding in another, unrelated family, before such a designation is canonized. The V2354M mutation in RYR1 was recently published as a novel, MH-associated RYR1 mutation in the North American population,17 so this mutation likely will be classified as MH-causative, as well. These surrogate functional data would be wonderful if they correlated 100% with other surrogate functional data, as well. Unfortunately, they do not. For example, family member CII:6 is genetically normal at the ryr1 locus being examined, but is MH equivocal by IVCT. While clinically he would be treated as MHS, in reality it is possible he is not MHS unless there is a second locus that segregates along with the locus examined that might make him MHS. Yet B-cells derived from this patient should respond normally to 4-CmC by the criteria set forth in this assay. Furthermore, there are no data supporting the use of 4-CmC to replace caffeine in either of the contracture test protocols alluded to above. Indeed, there are data to suggest that 4-CmC is not as pharmacologically discriminative of MH susceptibility as caffeine in a skeletal muscle myotube Ca2+ release assay.18 If a drug is not as reliable a discriminator in the classic contracture test, which is not perfect, can we rely on it in a secondary surrogate test that has not truly been to replace that classic really do not yet know whether RYR1 or variant status in B-cells is to that in skeletal muscle as to an to MH susceptibility from There is a difference between an that is a research in and one to be an epidemiologic The of the of the findings in these manuscripts is of the fact that the we have in the of MH, the and of RYR1 and with the the clinical and characteristics of those susceptible to MH, and the mechanism by which dantrolene is likely to we still do not know what MH our of MH are changing to that of a metabolic syndrome that a pharmacogenetic syndrome at one and a muscle and/or MH at the other individuals with the latter with changes that we know about unless they if they do does the know to these individuals to a aware who can the and care to the of that of the advances of the past decades have identified pathognomonic about have any into the of that potentially the hypermetabolism of skeletal muscle during an MH and we have still not identified the 3 other genes that are reported to with MH susceptibility. we are able to specifically the characteristics of MH metabolism and all the genes that confer susceptibility, we will have of developing tests capable of susceptibility to MH or intraoperative that to be MH from those that really need to the that pharmacogenetic MH. are yet in the in in versus regarding the possible or that might be in the noted that while he may not be able to exactly what know it too to with the clinical diagnosis of MH during a suspected event is not on pathognomonic data but on an often of to the of and database that will this into an of greater and epidemiologic and allow for greater This the data and the the This manuscript was

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