Even though MH is a rare complication of general anesthesia, the presented cases clearly demonstrate that this life threatening muscular hypermetabolism is still a relevant risk requiring immediate and consequent treatment by the responsible anesthesiologist to avoid serious harm to the patient.
After the first description of MH by Denborough numerous cases of fulminant MH as well as in vitro investigations had been published in the following years, identifying halothane and succinylcholine as potential MH triggering agents [10]. While the metabolic deterioration in the course of an MH crisis induced by halothane seems to be a direct consequence of an interaction with the sarcoplasmic ryanodine receptor, the pathophysiological mode of action of succinylcholine has remained unknown. For instance, in vitro succinylcholine increased halothane-induced muscular contractions of MHS patients, but no contracture could be observed after exposition to succinylcholine alone [11]. Even systemic application of succinylcholine could not reproducibly elicit an MH episode in susceptible swine [12, 13]. In humans, according to an evaluation of the North American MH Registry and a recently performed European multicentric study, succinylcholine triggered MH in absence of an inhalation anesthetic only in 0.7% or 1% respectively of the investigated cases [14, 15]. Since the definitively underlying mode of action of succinylcholine to elicit MH remains unclear so far, the pharmacological characteristics of this agent may enable a possible explanation of it’s role to induce MH. Following intravenous application succinylcholine activates the nicotinergic acetylcholine receptor and provokes a local depolarization of the cell membrane. The transient depolarization of voltage-gated receptors in combination with an influx of extracellular calcium via acetylcholine receptors could lead to a significant increase of intracellular calcium concentrations and after exceeding a certain threshold MH may occurs in affected individuals. In this context, muscular fasciculation and rigidity caused by succinylcholine was considered to be causal for MH. Consequently, a masseter spasm following succinylcholine was postulated to be an early sign of an imminent MH episode. However, specificity of this clinical sign is limited due to the subjective appraisal and the fact, that jaw tightness is a common side effect of succinylcholine, but only in half of the patients associated with MH susceptibility [16]. Similar results were obtained in our investigation. MH susceptibility was confirmed in only 50% of the suspected MH cases, where a succinylcholine-induced masseter spasm was noticed. Interestingly, histological examination of 1 MHEh patient who solely received succinylcholine revealed suspected myopathological finding. Although, neuromuscular disorders are common in MHE patients [17], it remains unclear, if these muscular alterations were responsible for the increased sensitivity to succinylcholine in this patient.
Generally, the likelihood of succinylcholine-induced MH seems to be extremely low, however there is little doubt, that combination with a volatile anesthetic potentiates the onset and the clinical symptoms of an MH event [18]. Remarkably, despite the possibly serious side-effects like MH, hyperkalemia or cardiac arrest, succinylcholine was actually applied to secure the airway in 79% of the referred patients. In part, this approach was reasonable due the higher risk of aspiration in case of trauma or abdominal surgery. However, according to published guidelines the use of the non-depolarizing muscle relaxant rocuronium and if needed followed by application of sugammadex to reverse the neuromuscular blockade might be an adequate alternative to avoid succinylcholine associated adverse effects [7, 19].
In contrast to succinylcholine, the impact of all inhalation anesthetics used in daily clinical routine in the development of an MH crisis is beyond dispute. However, dependent on the applied volatile anesthetic the time interval between induction of anesthesia and clinical symptoms of an MH episode seems to vary. For instance, Hopkins and colleagues reported, that in susceptible patients the onset of MH was statistically significant faster after halothane exposure compared to enflurane or sevoflurane [5]. Equally, fulminant MH episodes after isoflurane, sevoflurane or desflurane seem to occur with temporal delay [20, 21], while halothane may induce MH within minutes [5]. In MHS animals, similar results were seen after intramuscular injection of halothane or sevoflurane. The induced local hypermetabolic responses measured by local muscular lactate and carbon dioxide pressure increase were more distinct after halothane than after sevoflurane application [22, 23]. Furthermore, in vitro the effect on muscular contractures of MHS muscle bundles varies between halothane and modern volatile anesthetics at equivalent concentrations [24]. These different clinical appearances of MH following volatile anesthetic application might be caused due to differences in the calcium releasing potency of these diverse agents. For example, sarcoplasmic calcium release at cellular level was significant smaller after sevoflurane or desflurane exposure compared to equimolar halothane concentrations [25, 26]. In the analyzed anesthetic events of the present evaluation, MH episodes were induced by established MH triggers like halothane or isoflurane as well as by modern volatile anesthetics, e.g. sevoflurane or desflurane. Although, in the majority of the cases inhalation anesthetics were combined with succinylcholine and only in one case sevoflurane was applied solely, our findings emphasized the MH trigger potency of newer volatile anesthetics.
Beside masseter spasm cardiac arrhythmias are further early symptoms of imminent MH. Equally to a retrospective analysis from the United States, where the incidence was estimated 40% [14], in the presented investigation the occurrence of unexplained cardiac alterations was 42%. On closer examination the incidence of cardiac symptoms was even higher in the MHS group with either sinus tachycardia or tachyarrythmia as the leading signs.
The low incidence of testified metabolic acidosis might be attributed to the failure to obtain arterial blood gas analysis in the acute phase of the MH reaction or due to dantrolene pretreatment. For example, one patient’s blood gas analysis was performed not until the arrival on the intensive care unit and after treatment with dantrolene, showing an unremarkable blood acid status, while in contrast the intraoperative end-tidal carbon dioxide increased relevant to 56 mmHg in this patient. Overall, in only 37% of the MH suspected cases a blood gas analysis was conducted to verify the suspected diagnosis. This line of action is remarkable, since the presence of an acidosis supports the reasonable suspicion of MH in these cases.
Hyperthermia is a dramatic but often late sign of MH, reflecting the proceeding metabolic breakdown in affected individuals. Hence, temperature monitoring during general anesthesia is recommended if MH triggers are used, since in a couple of cases hyperthermia was the only sign of MH [14]. Fulminant MH episodes may be marked by a rapid increase in body temperature at a rate of 1-2°C every five minutes [27]. Stunningly, only in 11% of the suspected MH cases (1 MHS and 1 MHN) a remarkable hyperthermia with an increase in core temperature ≥ 38.5°C was noticed. The overall low incidence of core temperature rises in the presented study might be attributable to the initiated dantrolene treatment or the possible absence of temperature monitoring.
The pathological changes during MH crisis are based on an uncontrolled increase of myoplasmic calcium, resulting in an ongoing skeletal muscular contracture and loss of cellular integrity leading to hyperkalemia and rhabdomyolysis [28]. Although the surgical trauma itself might cause a significant increase in CK levels, postoperative unexplained excessive hyperCKemia should lead to a diagnostic workup to exclude MH susceptibility as underlying pathology. The reason for the remarkable CK increase up to 24.732 U/L in one of the MHN patients following succinylcholine remains unclear. A not yet diagnosed myopathy could not definitely be excluded, but based on the advanced age of the patient and the inconspicuous histological findings it seems very unlikely.
In contrast to the estimation, that nearly 70% of MH families carry mutations in the ryanodine receptor gene [29], the genetic prevalence of 27% in the analyzed MHS cases was overall low. Noteworthy, even if the Val4234Leu variant of one MHS patient has recently been mentioned in context of a novel exome sequencing method for MH relevant mutations [30], none of the detected genetic variants had been accepted as causative for MH according to the European MH Group database, which includes so far 31 approved mutations of the more than 200 identified ryanodine receptor gene variants [31]. However, it is important to mention, that absence of a causative mutation does not reliably exclude MH susceptibility. To confirm or exclude MH a muscle biopsy followed by an IVCT must be carried out in these patients [32].
After introduction of dantrolene in clinical use a causal treatment of MH has been available since the late 1970’s. The mode of action of this drug is based on inhibition of the sarcoplasmic reticulum calcium release without increasing the reuptake of calcium ions into the sarcoplasmic reticulum [33]. According to current guidelines application of dantrolene is an essential part in the treatment of an MH crisis [34, 35]. However, only 37% of the patients in the presented investigation received dantrolene for causal MH therapy. Nevertheless, the importance of consequent dantrolene treatment is absolutely clear [36], even if the hypermetabolic state in some of the presented cases was already terminated by discontinuation of MH trigger substances.
Once surviving fulminate MH episodes several reports documented severe complications, e.g. acute renal failure from rhabdomyolysis, DIC, congestive heart failure or intestinal ischemia due to the uncontrolled metabolic reaction and myocyte death [27]. Fortunately, the review of the medical records of the referred patients, did not detect any serious harms to the patients after an MH episodes, which importantly delayed recovery.
To draw conclusions about the likelihood of MH among the suspected incidents, the “Clinical Grading Scale” (CGS) established by Larach and colleagues assessed clinical and metabolic parameters, e.g. muscle rigidity, rhabdomyolysis, acidosis, increases in body temperature and cardiac arrhythmias [9]. The validity of the CGS may be reduced due to limited availability of complete data sets and hence, often does not satisfactorily correlate with the IVCT results [37]. The false negatives as well as the false positive diagnosis obtained by CGS calculation in our analysis are likely a result of the fragmentary available medical records. Thus, sole evaluation of the CGS seems not to be adequate to prove MH susceptibility.
Finally, anesthesiologists must be aware that uneventful previous general anesthesia does not exclude MH susceptibility [14]. For instance, two of the MHS patients reported a history of exposure anesthesia in the past. The reason why some patients develop MH after first exposition to MH triggering agents, while others do not, still remains unclear and might be explained by an individual cellular compensation mechanism lowering myoplasmic calcium concentrations.
