Malignant Hyperthermia

Malignant hyperthermia (MH) is a life-threatening, autosomal-dominant pharmacogenetic disorder of skeletal muscle in which exposure to volatile inhalational anaesthetics and/or the depolarising muscle relaxant succinylcholine triggers an uncontrolled rise in intracellular calcium, producing a fulminant hypermetabolic crisis. It is a high-yield, must-know anaesthesia emergency because recognition is clinical, the antidote (dantrolene) is specific, and delay kills.

Definition & classification

MH is a subclinical myopathy — the patient is usually entirely normal until exposed to a triggering anaesthetic. The defect lies in excitation–contraction coupling, specifically in the calcium-release channel of the skeletal-muscle sarcoplasmic reticulum (SR).

Clinically it presents along a spectrum:

• Fulminant MH — the classic full-blown crisis (rigidity + hypermetabolism + acidosis + hyperthermia).
• Abortive / masseter spasm–only forms — isolated masseter muscle rigidity (MMR) after succinylcholine, which may or may not progress.
• MH-related syndromes — exertional rhabdomyolysis and exertional heat illness in MH-susceptible individuals (relevant because some present outside the operating theatre).

High-yield: MH is inherited as an autosomal dominant trait with variable penetrance and variable expressivity. A normal previous anaesthetic does NOT rule out susceptibility.

Associated conditions (NEET-favourite associations)

Condition	Relationship to MH
Central core disease	Strongest, definite association (same RYR1 gene)
Multiminicore disease	Associated (RYR1)
King–Denborough syndrome	Dysmorphic myopathy with high MH risk
Native American myopathy (STAC3)	Associated
Duchenne / Becker muscular dystrophy	Anaesthesia-induced rhabdomyolysis / hyperkalaemia — an MH-like reaction, NOT true MH
Myotonia / osteogenesis imperfecta	Older lists; weak/uncertain — not core associations

High-yield: Central core disease is the classic clinical condition tied to MH susceptibility — remember "core = RYR1 = MH."

Etiology & genetics

• The principal gene is RYR1 on chromosome 19q13.1, coding the ryanodine receptor type 1 (RyR1) — the SR calcium-release channel of skeletal muscle. Mutations account for ~50–70% of families.
• A minority involve CACNA1S (chromosome 1q, the alpha-1 subunit of the dihydropyridine receptor / L-type Ca²⁺ channel, DHPR) and rarely STAC3.
• Inheritance is autosomal dominant; >hundreds of RYR1 variants are described, so genetic testing has high specificity but limited sensitivity.

Triggering agents vs safe agents

Triggers (avoid)	Safe ("non-triggering")
All volatile agents: halothane, isoflurane, sevoflurane, desflurane, enflurane	Propofol, thiopentone, ketamine, etomidate
Succinylcholine (suxamethonium)	Nitrous oxide
	All opioids (fentanyl, morphine)
	All non-depolarising relaxants (vecuronium, rocuronium, atracurium, cisatracurium)
	Benzodiazepines, dexmedetomidine
	Local anaesthetics — esters and amides are all safe

High-yield: The two trigger classes are volatile anaesthetics + succinylcholine. Everything else commonly used (propofol, opioids, N₂O, non-depolarising blockers, all local anaesthetics) is SAFE. Regional/local anaesthesia is preferred when feasible.

Pathophysiology — the calcium story

Normal excitation–contraction coupling: depolarisation of the T-tubule activates the DHPR (voltage sensor), which signals the RyR1 to release Ca²⁺ from the SR → muscle contraction → SR Ca²⁺-ATPase (SERCA) pumps Ca²⁺ back, an ATP-consuming step → relaxation.

In MH, mutant RyR1 channels open abnormally and stay open when exposed to triggers:

Trigger exposure → uncontrolled RyR1 opening → massive sustained SR Ca²⁺ release → sustained muscle contraction (rigidity)

This sets off a self-amplifying hypermetabolic cascade:

1. Sustained myofibrillar contraction consumes ATP at a furious rate.
2. SERCA tries to pump Ca²⁺ back → even more ATP burned.
3. Aerobic + anaerobic metabolism surge → ↑↑ O₂ consumption, ↑↑ CO₂ production, heat generation.
4. ATP depletion + glycolysis → lactic acidosis (metabolic) plus CO₂ retention (respiratory) → mixed acidosis.
5. Energy failure damages the sarcolemma → rhabdomyolysis → leak of K⁺, myoglobin, CK into blood.
6. Result: hyperkalaemia, hyperthermia, mixed acidosis, hypercarbia, rhabdomyolysis, arrhythmias, DIC.

High-yield: The earliest and most sensitive sign is a rising end-tidal CO₂ (EtCO₂) that is unresponsive to increased minute ventilation. Hyperthermia is a late sign — do not wait for fever to act.

Clinical features

Onset may be within minutes of induction (especially with succinylcholine) or insidiously over hours. Features divide into early and late:

Early (hypermetabolic) signs

• Unexplained, rising EtCO₂ despite adequate ventilation (cardinal early sign).
• Tachycardia and unexplained tachypnoea (if spontaneously breathing).
• Masseter muscle rigidity (MMR) after succinylcholine — "jaws of steel"; may herald MH.
• Generalised muscle rigidity (a specific sign; sympathetic surge alone does not cause rigidity).
• Mixed respiratory + metabolic acidosis, hypoxaemia.
• Cardiac arrhythmias, labile/unstable blood pressure, sweating, mottling/cyanosis.

Late signs

• Rapidly rising core temperature — classically can rise ≥1–2 °C every 5 minutes, reaching ≥ 41–45 °C.
• Hyperkalaemia, dark/cola-coloured urine (myoglobinuria), markedly raised CK.
• Disseminated intravascular coagulation (DIC), acute kidney injury, cardiac arrest.

High-yield classic triad to recall: hyperthermia + muscle rigidity + acidosis — but in real time, unexplained ↑EtCO₂ + tachycardia + rigidity appear first.

Mnemonic for MH features — "Some Hot Tea Makes Patients Really Hyperthermic Always" → Suxamethonium/Sevoflurane trigger, Hypercarbia (↑EtCO₂), Tachycardia, Masseter spasm, Pyrexia (late), Rigidity, Hyperkalaemia, Acidosis.

Diagnosis

Intra-operative (clinical) diagnosis

MH is diagnosed clinically in theatre — there is no time to wait for confirmatory tests. The combination of unexplained hypercarbia, tachycardia, rigidity and rising temperature in a patient receiving triggers is sufficient to act. Arterial blood gas typically shows mixed acidosis with low PaO₂, high PaCO₂, base deficit, raised lactate.

The Clinical Grading Scale (Larach) assigns points across six categories — muscle rigidity, muscle breakdown (↑CK, myoglobinuria), respiratory acidosis (↑EtCO₂/PaCO₂), temperature rise, cardiac involvement, family history — to estimate the likelihood ("MH rank").

Confirmatory / susceptibility testing (electively, later)

Test	Notes
In-vitro Contracture Test (IVCT) / Caffeine–Halothane Contracture Test (CHCT)	GOLD STANDARD. Fresh muscle biopsy exposed to caffeine and halothane; MH muscle shows abnormal (exaggerated) contracture at low concentrations. Done at specialised centres on viable muscle.
Genetic testing (RYR1/CACNA1S)	Highly specific; positive result confirms susceptibility, but a negative result does not exclude MH (limited sensitivity). Useful for screening families once a proband mutation is known.

High-yield: The caffeine–halothane (in-vitro) contracture test on a muscle biopsy is the gold-standard diagnostic test for MH susceptibility. Genetic testing supplements but cannot replace it.

Management — the antidote and protocol

Treatment is a coordinated emergency. Call for help and the MH cart immediately.

Stepwise approach (memorise the order):

1. STOP all triggering agents (turn off volatile vaporiser; stop succinylcholine) and call for help.
2. Hyperventilate with 100% oxygen at high fresh-gas flows (≥10 L/min) to wash out volatile agent and blow off CO₂. Change to a non-triggering technique (e.g., propofol infusion). Do NOT waste time changing the breathing circuit/soda lime first.
3. Give DANTROLENE — the specific antidote: 2.5 mg/kg IV bolus, repeated every 5 minutes, titrated to effect (falling EtCO₂, HR, temperature), up to about 10 mg/kg (occasionally more).
4. Active cooling if hyperthermic: cold IV saline, surface cooling, cold lavage; stop cooling at ~38 °C to avoid overshoot hypothermia.
5. Treat hyperkalaemia: calcium (gluconate/chloride), insulin + dextrose, bicarbonate; treat acidosis.
6. Treat arrhythmias: standard antiarrhythmics — avoid calcium-channel blockers (verapamil + dantrolene → hyperkalaemia and cardiovascular collapse).
7. Maintain urine output (>1–2 mL/kg/hr) with fluids ± mannitol/frusemide to prevent myoglobinuric renal failure.
8. Monitor & support: core temperature, ABG, K⁺, CK, coagulation/DIC, urine myoglobin; ICU for ≥24–48 h (recrudescence in up to 25%).

Dantrolene essentials

• Mechanism: binds RyR1 and inhibits SR calcium release, decoupling excitation from contraction → relaxes the hypermetabolic muscle.
• Formulation: classic dantrolene sodium vials contain 20 mg dantrolene + 3 g mannitol, reconstituted in 60 mL sterile water — notoriously slow to dissolve (assign a dedicated person). Newer nanocrystalline (Ryanodex) 250 mg vials dissolve far faster.
• Side effects: muscle weakness, phlebitis (highly alkaline; give via large vein), respiratory weakness, hepatotoxicity with chronic use.

High-yield: Dantrolene is the drug of choice; first dose 2.5 mg/kg IV. Mechanism = inhibits calcium release from the sarcoplasmic reticulum via RyR1. Never give calcium-channel blockers with dantrolene.

High-yield: First action on suspecting MH = stop the trigger + 100% O₂ + hyperventilate, then dantrolene. Stopping the trigger precedes drug administration.

Complications

• Hyperkalaemia → ventricular arrhythmias / cardiac arrest (a leading cause of death).
• Rhabdomyolysis → myoglobinuria → acute kidney injury.
• Disseminated intravascular coagulation (DIC) — poor prognostic sign.
• Mixed acidosis, pulmonary oedema, cerebral oedema.
• Recrudescence (recurrence) within 24–48 h → mandatory ICU monitoring and continued dantrolene.
• Compartment syndrome from severe muscle swelling.

Key differentials

A rising temperature ± tachycardia under anaesthesia has several mimics — distinguishing them is a favourite exam theme.

Differential	Discriminating point
Neuroleptic malignant syndrome (NMS)	Caused by dopamine antagonists / antipsychotic withdrawal of L-dopa; onset over days; lead-pipe rigidity; treated with dantrolene + bromocriptine, NOT linked to anaesthetic triggers.
Serotonin syndrome	Serotonergic drugs (SSRIs, MAOI, tramadol); clonus, hyperreflexia, agitation; treat with cyproheptadine.
Thyroid storm	Tachycardia, fever, AF; rigidity absent; goitre/exophthalmos; no EtCO₂ surge of MH magnitude.
Phaeochromocytoma	Severe labile hypertension, sweating; no rigidity/hypercarbia signature.
Sepsis / inadequate anaesthesia / iatrogenic overheating	No rigidity, no disproportionate ↑EtCO₂; respond to usual measures.
Anaesthesia-induced hyperkalaemic rhabdomyolysis (DMD/BMD)	Sudden hyperkalaemic cardiac arrest after succinylcholine in a child with occult muscular dystrophy — an MH-mimic, treat hyperkalaemia, not always true MH.

High-yield: NMS and MH both respond to dantrolene, but NMS follows antipsychotics/dopamine blockade and has no anaesthetic trigger; serotonin syndrome is treated with cyproheptadine.

Anaesthetic management of a known MH-susceptible patient

• Prefer regional / local anaesthesia whenever possible.
• If GA needed, use a "clean"/trigger-free technique: propofol/TIVA, opioids, N₂O, non-depolarising relaxants; vapouriser removed, flush the anaesthetic machine with high-flow O₂ and fit new circuit/CO₂ absorbent (or use activated-charcoal filters).
• Dantrolene must be immediately available in any facility using volatile agents/succinylcholine.
• Routine prophylactic dantrolene is no longer recommended; vigilant monitoring (EtCO₂, temperature) suffices.

Recently asked / exam angle

• Most common first/earliest sign of MH → answer: rising end-tidal CO₂ (NOT fever).
• Drug of choice / mechanism → dantrolene; inhibits Ca²⁺ release from SR (RyR1); first dose 2.5 mg/kg.
• Gene & receptor → RYR1 on chromosome 19, ryanodine receptor; also CACNA1S (DHPR).
• Triggers → volatile agents + succinylcholine; N₂O and propofol are safe (one-liner MCQs).
• Gold-standard diagnostic test → caffeine–halothane (in-vitro) contracture test.
• Associated disease → central core disease.
• Which drug to avoid alongside dantrolene → calcium-channel blockers (verapamil).
• First step on suspecting MH intra-op → stop trigger, 100% O₂, hyperventilate.
• Image/clinical vignette: child develops masseter spasm ("jaws of steel") after suxamethonium → think MMR/MH.
• Differentiation grids: MH vs NMS vs serotonin syndrome (treatment-based discrimination).

Rapid revision

1. MH = autosomal dominant pharmacogenetic skeletal-muscle disorder; defect in RYR1 (chr 19) calcium-release channel.
2. Triggers = all volatile anaesthetics + succinylcholine; nitrous oxide, propofol, opioids, non-depolarisers and all local anaesthetics are safe.
3. Core defect = uncontrolled SR calcium release → sustained contraction → hypermetabolic crisis.
4. Earliest sign = unexplained rising EtCO₂ unresponsive to ventilation; fever is late.
5. Classic triad = hyperthermia + rigidity + (mixed) acidosis; masseter rigidity after sux is a warning.
6. Drug of choice = dantrolene (RyR1 inhibitor), 2.5 mg/kg IV, repeat q5min up to ~10 mg/kg.
7. First actions: stop trigger → 100% O₂ at high flow → hyperventilate → dantrolene.
8. Avoid calcium-channel blockers with dantrolene (risk of hyperkalaemia/collapse).
9. Treat hyperkalaemia, acidosis, arrhythmias; maintain urine output to prevent myoglobinuric AKI.
10. Gold-standard test = caffeine–halothane in-vitro contracture test on muscle biopsy; genetic testing is specific but not sensitive.
11. Strongest disease association = central core disease; King–Denborough syndrome also high risk.
12. Recrudescence in up to 25% → monitor in ICU 24–48 h; classic mimic differentials are NMS (dopamine blockers) and serotonin syndrome (treat with cyproheptadine).