A 35-year-old male is undergoing elective abdominal surgery under general anesthesia with sevoflurane and succinylcholine. Fifteen minutes into the procedure, the anesthesiologist notices rapid rise in end-tidal CO₂, muscle rigidity, and core temperature climbing to 39.2°C. The structure marked **B** in the diagram (sarcoplasmic reticulum with RyR1) is suspected to be dysfunctional. Which of the following best explains the pathophysiology and immediate management in this patient?

Explanation

## Why option 1 is correct Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder caused by mutations in RYR1 (ryanodine receptor type 1), the calcium release channel on the sarcoplasmic reticulum. When triggered by volatile anesthetics (sevoflurane) and/or succinylcholine, the defective RyR1 cannot close properly, leading to uncontrolled and sustained calcium release from the SR into the cytoplasm. This causes prolonged muscle contraction (rigidity), massive heat generation, rhabdomyolysis (evidenced by rising CK and myoglobinuria), and hypercarbia—the most sensitive early sign. The clinical presentation in this case (rapid CO₂ rise, muscle rigidity, hyperthermia) is pathognomonic for MH. Immediate management includes discontinuation of triggering agents, hyperventilation with 100% oxygen, and IMMEDIATE dantrolene sodium administration (2.5 mg/kg IV bolus, repeated every 5 minutes up to 10 mg/kg), which directly blocks RyR1 and halts uncontrolled calcium release. Dantrolene has reduced MH mortality from ~80% to <5%. (Guyton & Hall 14e Ch 6; KD Tripathi 9e Ch 27) ## Why each distractor is wrong - **Option 2**: Defective DHPR (dihydropyridine receptor, the L-type Ca²⁺ channel on the T-tubule) would impair the initial depolarization signal transmission to the SR, resulting in FAILURE of muscle contraction (flaccid paralysis), not sustained rigidity and hyperthermia. This describes central core disease or other congenital myopathies, not MH. Calcium channel blockers are contraindicated in MH. - **Option 3**: Defective troponin C would prevent calcium binding to the thin filament regulatory protein, causing inability to initiate contraction (flaccid weakness) and hypothermia due to lack of muscle activity—the opposite of the clinical picture. Neuromuscular reversal agents are irrelevant to the pathophysiology. - **Option 4**: Defective SERCA pump (sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase) would impair calcium reuptake into the SR, causing delayed muscle relaxation but NOT the acute, severe, uncontrolled calcium release that drives the hypermetabolic crisis of MH. Cooling alone is insufficient without blocking the source of calcium release (dantrolene). **High-Yield:** RyR1 mutations → MH → uncontrolled SR Ca²⁺ release → dantrolene (RyR1 blocker) is life-saving; hypercarbia is the earliest clinical sign. [cite: Guyton & Hall 14e Ch 6; KD Tripathi 9e Ch 27]