Malignant HyperthermiaEdit

Malignant hyperthermia (MH) is a rare but life-threatening pharmacogenetic disorder of skeletal muscle that is triggered in susceptible individuals by certain anesthetic agents and, in some cases, by depolarizing muscle relaxants such as succinylcholine. When exposed to these triggers, MH causes an uncontrolled rise in intracellular calcium, leading to a hypermetabolic state that can progress rapidly to profound hyperthermia, acidosis, rhabdomyolysis, and organ failure if not treated promptly. Since the introduction of specific antidotes and improved monitoring, mortality from MH crises has fallen dramatically, but the condition remains a critical concern for anesthesia teams and genetic counselors alike.

MH is generally inherited in an autosomal dominant pattern with incomplete penetrance, meaning that not all carriers develop clinically evident crises, and environmental triggers largely determine whether an episode occurs. The most common genetic contributor is mutations in the ryanodine receptor type 1 gene RYR1, which encodes a calcium channel in the sarcoplasmic reticulum of skeletal muscle. Other genetic contributors include mutations in CACNA1S and several other loci, reflecting substantial genetic heterogeneity within this condition. The concept of malignant hyperthermia susceptibility (MHS) refers to individuals who harbor pathogenic variants and who are at risk when exposed to triggering anesthetics, even if they have not yet experienced an actual crisis.

Pathophysiology

The pathophysiology of MH centers on abnormal calcium handling in skeletal muscle. In susceptible individuals, trigger agents such as volatile anesthetics (for example isoflurane, sevoflurane, or desflurane) and the depolarizing muscle relaxant succinylcholine cause the mutated ryanodine receptor to release large amounts of calcium from the sarcoplasmic reticulum into the cytoplasm. This sustained calcium elevation drives continuous muscle contraction and a relentless rise in metabolic rate. The consequences include rapid heat production, hypercapnia, acidosis, electrolyte disturbances (including hyperkalemia), rhabdomyolysis, and, if not addressed, multi-organ failure. The clinical picture can evolve within minutes and requires immediate recognition and intervention.

Triggers and clinical presentation

Triggers: The classic triggers are the volatile anesthetics and succinylcholine used during anesthesia. Other stressors, including severe heat or exertional stress in susceptible individuals, may provoke similar cellular responses in some cases, though exposure to anesthesia remains the primary clinical trigger in most reported crises.
Presentation: Early signs include unexpected rise in end-tidal CO2, tachycardia, muscle rigidity, acidosis, and eventually marked hyperthermia. Laboratory findings often show metabolic acidosis, hyperkalemia, elevated creatine kinase, and myoglobinuria as the episode progresses.

Diagnosis and testing

Intraoperative recognition: MH is a clinical emergency. An anesthesia team relies on sudden hypermetabolism in the setting of exposure to triggering agents to initiate treatment, even before laboratory confirmation.
Diagnostic testing: The definitive laboratory tests are the caffeine-halothane contracture test (Caffeine-halothane contracture test) or the in vitro contracture test (in vitro contracture test) performed on muscle biopsy samples in specialized labs. These tests classify individuals as MH susceptible or non-susceptible. Genetic testing for pathogenic variants in RYR1 and other MH-associated genes is increasingly used as a non-invasive complementary approach, though a negative genetic test does not completely exclude susceptibility due to genetic heterogeneity.
Preoperative assessment: A detailed personal and family history of adverse reactions to anesthesia, particularly episodes involving hyperthermia or muscle rigidity, remains an important screening method. In at-risk families, genetic counseling and targeted testing can inform perioperative planning.

Management and treatment

Acute crisis management: Immediate steps include stopping triggering agents, cooling the patient, and administering a rapid dose of the antidote dantrolene, which reduces calcium release from the sarcoplasmic reticulum. The dosing and escalation are guided by clinical response and local protocols, with continued monitoring and supportive care (airway management, ventilation, hemodynamic support, electrolyte correction, and management of acidosis).
Supportive care: Aggressive cooling (ice packs, cooling blankets, cooled IV fluids), ensuring adequate oxygenation, treating acidosis with appropriate buffers, and addressing hyperkalemia and potential arrhythmias are essential components of care. Serial laboratory testing tracks progress and helps guide ongoing treatment.
Prevention and preparedness: The availability of dantrolene in operating rooms, regular MH drills for anesthesia teams, and clear protocols for rapid escalation are central to reducing mortality. Preoperative strategies emphasize the use of non-triggering anesthesia whenever possible and meticulous documentation of MH risk in medical records. Genetic counseling can be valuable for families with known pathogenic variants to inform future anesthesia planning and family risk.

Epidemiology and population considerations

MH is considered a rare disorder, with reported incidences varying by population, surveillance methods, and exposure to triggering anesthetics. The risk is not understood to be strongly linked to race or ethnicity, and clinical vigilance should be maintained across populations. Public health and hospital policy responses emphasize preparedness—ensuring staff training, trigger avoidance when possible, and rapid access to dantrolene—over broad, population-wide screening, given the current balance of costs and predictive value.

Controversies and policy debates

Screening strategies: A longstanding debate centers on whether universal preoperative genetic screening for MH susceptibility is cost-effective or clinically valuable. Proponents of targeted testing argue that it should focus on families with known pathogenic variants and those with a suggestive personal or family history, given the incomplete penetrance and genetic heterogeneity. Opponents point to logistical and ethical considerations, including cost, privacy, and the risk of false reassurance from negative tests.
Resource allocation and preparedness: Hospitals must decide how to allocate limited resources for MH preparedness, including maintaining adequate stocks of dantrolene and ensuring staff training. Some policymakers argue for standardized national protocols and support for regional MH centers, while others emphasize local flexibility to manage budgets and supply chains. The core objective is to minimize mortality and morbidity while avoiding unnecessary expenditures.
Diagnostic pathways: The use of genetic testing versus functional testing (IVCT/CHCT) raises questions about sensitivity, specificity, and accessibility. Genetic testing can miss variants outside known MH-associated genes, while functional tests require specialized laboratories. Balancing these options involves considerations of cost, turnaround time, and patient-family counseling.
Clinical recognition and differentiation: In acute care, distinguishing MH from sepsis, thyroid storm, pheochromocytoma, or other hypermetabolic states can be challenging. Advocacy for standardized recognition training and decision-support tools is common across policy discussions, with debates about how best to implement such tools in diverse hospital settings.