Malignant Hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. A genetically susceptible patient exposed to a volatile anaesthetic agent or suxamethonium develops a hypermetabolic crisis, and although the anaesthetist manages it, the surgeon at the table has to recognise it, support the resuscitation, and know which of their own patients carry the risk. It remains a core basic-science viva topic in fellowship examinations worldwide.

How common. About 1 in 100,000 adult anaesthetics involving volatile agents, and higher in children at about 1 in 30,000. Males are affected more often; a higher muscle mass amplifies the hypermetabolic response.

Mortality. Before dantrolene, 70-80% of crises were fatal. With prompt dantrolene, mortality is now under 5%.

Why it matters in orthopaedics. Long cases, tourniquet use and repeated doses of suxamethonium raise the risk, and a tourniquet may also mask or delay recognition of limb rigidity. Patients with Duchenne and Becker muscular dystrophy carry an elevated MH-like risk through a distinct mechanism with an overlapping crisis, and they may be undiagnosed when they present for surgery; neuromuscular scoliosis patients are a high-risk group.

Post-operative analgesia. Opioids are safe and regional techniques are preferred.

Normal excitation-contraction coupling. Depolarisation of the motor endplate activates dihydropyridine receptors (DHPR) on the T-tubule membrane. These couple mechanically to the ryanodine receptor type 1 (RYR1), the major calcium release channel of the sarcoplasmic reticulum (SR) in skeletal muscle, which opens briefly to release Ca2+. SERCA pumps then actively sequester the calcium back into the SR and the fibre returns to baseline.

The defect. In MH-susceptible individuals a mutated RYR1 is hyper-responsive to triggering agents: volatile anaesthetics and suxamethonium cause prolonged, uncontrolled Ca2+ release. Everything that follows comes from that one event: sustained myofibrillar contraction (rigidity), massive ATP consumption, and a hypermetabolic cascade producing heat, CO2, lactate and potassium.

Triggers. All volatile agents - sevoflurane, desflurane, isoflurane, halothane and enflurane - and suxamethonium. The agents that are safe are listed under Management.

Genetics. Susceptibility is inherited as an autosomal dominant trait with variable penetrance: each child of a carrier has a 50% chance of inheriting the variant, but many carriers never have a crisis. RYR1 on chromosome 19q13.2 accounts for approximately 70% of cases; over 400 variants have been identified and approximately 30 are causally linked to MH, the most common pathogenic variants being R614C, G2434R, R2163C and T2206M. CACNA1S on chromosome 1q32.1 encodes the DHPR alpha-1 subunit that links the voltage sensor to RYR1 opening, and accounts for approximately 1% of cases.

Muscle histology and the RYR1 spectrum. Routine H+E staining of MH-susceptible muscle shows no diagnostic features; susceptibility is confirmed by contracture testing or genetics, covered under Investigations. The same channel defect can also present as a myopathy or as a crisis with no anaesthetic at all, and each association is examinable:

• Central core disease - a myopathy caused by RYR1 mutations and strongly associated with MH susceptibility; the key exam link
• Multi-minicore disease - another RYR1-related myopathy with MH risk
• King-Denborough syndrome - a rare congenital RYR1-related myopathy with strong MH susceptibility and a characteristic dysmorphism (short stature, webbed neck, low-set ears, ptosis, pectus deformity, cryptorchidism, skeletal abnormalities); a recognisable syndromic flag that the child is at high anaesthetic risk
• Awake and exertional phenotypes - certain RYR1 variants predispose to exertional heat illness or heat stroke, and to exertional, statin-related or fever-related rhabdomyolysis, with no anaesthetic trigger

A personal or family history of unexplained exertional collapse, heat stroke or recurrent rhabdomyolysis should therefore raise the possibility of underlying MH susceptibility and prompt the same trigger-free anaesthetic precautions. Together these define a continuum of RYR1-related disease in which one channel defect manifests as myopathy, anaesthetic MH, exertional crises, or any combination of them.

Patterns of presentation. Not every episode follows the textbook cascade. The picture ranges from a mild abortive episode that settles once the trigger is withdrawn, which must still be investigated for susceptibility, to a fulminant crisis within minutes.

Differential diagnosis. In the acute crisis, treat for MH first: giving dantrolene to a patient who turns out not to have MH is far safer than delaying it in a true crisis.

The early signs, in the first minutes. A rising EtCO2 with no change in the ventilation settings is the most sensitive and specific early sign, and the one that should start treatment. Unexplained tachycardia follows and is often the first vital sign to change, peak airway pressures rise as the chest wall stiffens, a spontaneously breathing patient becomes tachypnoeic, and a blood gas shows a mixed respiratory and metabolic acidosis.

Masseter rigidity after suxamethonium is the sentinel event: jaw stiffness that prevents intubation. It may be isolated or the prodrome of a full crisis, so abandon the intubation attempt, switch to a non-triggering technique and monitor closely.

The late signs, at 10-60 minutes. These are the signs of an established crisis.

• Generalised skeletal muscle rigidity of the trunk and limbs
• Hyperthermia, with core temperature rising up to 1-2 degrees Celsius every 5 minutes and able to exceed 40 degrees
• Falling SpO2 from increased oxygen consumption
• Dark, cola-coloured urine from myoglobinuria
• Ventricular tachycardia or fibrillation from hyperkalaemia
• Skin mottling, sweating, cyanosis

During the crisis. MH is a clinical diagnosis and treatment never waits for a result; the intraoperative tests confirm and track it. Continuous end-tidal CO2 monitoring, where a rapid rise is diagnostic; core temperature at an oesophageal, nasopharyngeal or bladder site; an arterial blood gas for the metabolic and respiratory acidosis, the hyperkalaemia and a rising lactate; and an ECG for arrhythmia detection, with the peaked T-waves of hyperkalaemia.

Over the following hours. Send serum CK at baseline and then serially, serum and urine myoglobin, since myoglobinuria indicates ongoing muscle destruction, a coagulation profile of fibrinogen, D-dimer and INR for DIC surveillance, and creatinine and urea for acute kidney injury. The expected values and what each means are in the laboratory table above.

Confirming susceptibility, weeks later. The in vitro contracture test (IVCT) is the gold standard. Strips of fresh (not frozen) muscle, typically from the vastus lateralis, are taken by open biopsy under local anaesthetic in a specialised centre and exposed to halothane and caffeine in the laboratory under the European MH Group protocol; a positive contracture confirms susceptibility. The caffeine-halothane contracture test (CHCT) is the North American MH Group equivalent, built on the same principle.

Genetic testing sequences RYR1 and CACNA1S from a blood sample and identifies the causative variant in approximately 70% of cases. It is increasingly used first-line in families where a known pathogenic variant exists: once a variant is found, the family can be screened without biopsy, and a positive test in a first-degree relative of a confirmed MH survivor is sufficient to label that person MH-susceptible.

The principle. Stop the trigger, give dantrolene, and treat what the muscle releases. Dantrolene is the only specific treatment for MH and the goal is to break the hypermetabolic cascade with it as rapidly as possible, while supportive care deals with the heat, the potassium and the myoglobin.

Dantrolene. It works by directly inhibiting RYR1-mediated calcium release from the sarcoplasmic reticulum; it does not act centrally. It causes mild muscle weakness but not full paralysis. Newer formulations such as Ryanodex reconstitute in much smaller volumes, which dramatically speeds administration.

The MH-susceptible patient. Known susceptibility means a trigger-free anaesthetic on a trigger-free machine, and the anaesthetist must be informed before the operation. All volatile agents are avoided and suxamethonium is absolutely contraindicated. The safe agents:

• Propofol, given as total intravenous anaesthesia (TIVA), the standard safe hypnotic
• All opioids: fentanyl, morphine, remifentanil
• Non-depolarising relaxants: rocuronium, atracurium, vecuronium
• Nitrous oxide
• Local anaesthetics: lidocaine, bupivacaine, ropivacaine
• Benzodiazepines

Regional anaesthesia (spinal, epidural or peripheral nerve block) is the safest technique for MH-susceptible patients undergoing orthopaedic procedures, because it avoids all triggering agents entirely. Where a general anaesthetic is needed, the machine is prepared as follows.

After the crisis. The patient stays in ICU for 24-48 hours at minimum because the crisis can return: recrudescence typically occurs within 6-24 hours. During that time the CK is trended, since a falling CK indicates resolution, urine output is kept above 1 mL/kg/hour to protect the kidneys, temperature is watched for secondary fever spikes, and compartment pressures are measured if a limb swells severely from rhabdomyolysis.

Long-term follow-up. Every survivor needs:

• Referral to an MH specialist centre for susceptibility testing
• Genetic counselling for an autosomal dominant condition, with RYR1/CACNA1S testing offered to all first-degree relatives
• A MedicAlert bracelet once susceptibility is confirmed
• Future anaesthesia by TIVA or regional technique only
• A report to an MH registry, which contributes to the global epidemiological data

Each complication below is a downstream effect of the crisis; the table pairs it with its risk factors and its management.

What decides the outcome. Time to dantrolene. Given within 10 minutes of symptom onset it is associated with near-zero mortality, and every 10-minute delay significantly increases mortality; the table sets out what each delay costs. The best prognosis belongs to early recognition from the rising EtCO2, immediate dantrolene, a young healthy patient and the abortive form. The worst belongs to delayed recognition, a fulminant presentation, extreme hyperthermia above 41 degrees, a pre-existing myopathy and limited dantrolene availability.