Contents
Introduction
Rare life-threatening pharmacogenetic disorder of skeletal muscles that presents as an exaggerated hypermetabolic response to volatile anesthetic agents and depolarizing muscle relaxants.
History:
From the beginning of the 20th century, there have been numerous case reports of anaesthesia-associated deaths related to perioperative hyperthermia. However, it was not until 1960, when Denborough et al defined MH as an independent syndrome, that the link between deaths attributed to general anaesthesia and a genetic predisposition was postulated. In 1975, with the introduction of dantrolene as a specific ryanodine receptor antagonist, a causative treatment became available and the mortality rate for acute MH crisis decreased from approximately 70–80% to about 5%. Based on in vitro detection of halothane-induced and caffeine-induced contractures in skeletal muscle specimens from MHS individuals, the first diagnostic procedure was developed to distinguish between MHS and MH-non-susceptible (MHN) patients independently of a previous symptomatic MH event.
Following these observations, a standardized protocol for in vitro contracture testing was published by the European Malignant Hyperthermia Group in 1984, and a modified protocol was introduced by the North American Malignant Hyperthermia Group 3 years later. After MH-associated mutations in the ryanodine receptor gene were identified, guidelines for genetic testing allowing diagnosis of MH susceptibility in selected patients were published by the European Malignant Hyperthermia Group in 2001 and are still under development as more causative mutations become apparent.
Aetiology
Genetic factors:
Autosomal dominant inheritance with variable penetrance.
- RYR1 gene (Ryanodine receptor-1) mutation (common)
- CACNA1S gene (calcium voltage-gated channel subunit alpha 1) mutation (less common)
Triggering agents:
In an MH crisis, the triggering agent induces prolonged opening of functionally altered ryanodine receptors, resulting in uncontrolled release of calcium from the sarcoplasmic reticulum and ongoing muscle activation presenting as rigidity.
- All volatile halogenated inhalational anaesthetics: Halothane, enflurane, isoflurane, desflurane, sevoflurane
Associated conditions:
- Central core myopathy (AD): Hypotonia in infancy, delay in motor development and lower limb muscle weakness
- Multi-mini core myopathy (AR): Hypotonia, delay in motor development, muscle weakness mainly in lower limbs, and musculoskeletal abnormalities
- King-Denborough syndrome (AR): Hypotonia at birth, mild proximal muscle weakness, delay in motor development, joint hyperextensibility and dysmorphic facial features including ptosis, low-set ears and high arched palate, micrognathia, malar hypoplasia, hypertelorism, along with palmar simian line, pectus excavatum, winging of scapulae, lumbar lordosis and thoracic scoliosis
- Native American myopathy (AR): STAC3 mutations predispose them to develop MH provoked by anesthesia, therefore depolarizing muscle relaxants and volatile anesthetics must be avoided
Pathophysiology
Functionally altered calcium release channels cause dysfunction of intracellular calcium homeostasis and uncontrolled calcium release from the sarcoplasmic reticulum, which may lead rapidly to a fatal hypermetabolic state known as MH crisis.
Clinical features
Early manifestations:
The episodes of MH can occur during anesthesia or in the early postoperative period. Rapid onset of symptoms is predominantly seen following succinylcholine administration, a potent depolarizing anesthetic agent.
- Rise in end-tidal carbon dioxide (ETCO) (earliest diagnostic sign)
- Masseter spasm
- Generalized muscular rigidity (50%–80%)
- Tachycardia (>80%)
- Hypercapnia
- Hypoxia
- Combined metabolic-respiratory acidosis
Marked hyperthermia (HALLMARK)
Increase in core temperature of 1–2 °C every five minutes. Severe hyperthermia with core temperature higher than 44 °C can lead to a significant increase in oxygen consumption, carbon dioxide production, vital organ dysfunction, and disseminated intravascular coagulation (DIC).
- Uncontrolled hypermetabolism: Leading to respiratory and metabolic acidosis
- Rhabdomyolysis leading to hyperkalemia & myoglobinuria
- Acute renal failure (due to rhabdomyolysis)
- Congestive heart failure
- Bowel ischemia
- Compartment syndrome (secondary to profound muscle swelling)
Case study:
Diagnosis
Muscle biopsy and subsequent observation for contraction in muscle after treating it with caffeine and halothane:
gold standard diagnostic test for malignant hyperthermia
- In-Vivo Contracture Test (IVCT): Developed by European Malignant Hyperthermia Group (EMHG)
- Caffeine-Halothane Contracture Test (CHCT): Developed by North American Malignant Hyperthermia Group (NAMHG)
Genetic testing:
- RYR1 mutations or other associated genetic variants associated with MH
Differential diagnosis:
- Inadequate depth of anaesthesia
- Sepsis
- Insufficient ventilation or spontaneous breathing
- Malfunction of anaesthesia machine
- Anaphylactic reaction
- Pheochromocytoma
- Thyroid crisis
- Neuromuscular disease
- CO2 increase due to laparoscopic procedure
- Drug intoxication
- Serotonin syndrome
- Malignant neuroleptic syndrome
Management
The critical element in the treatment of MH is immediate dantrolene administration. Once an MH episode is suspected, all triggering agents must be discontinued and the patient hyperventilated with 100% oxygen with non-triggering anesthetic agents utilized for patient care and surgery should be ended as soon as possible.
