95 Safety and Efficacy of Dantrolene Sodium (250 mg/5 mL) in Patients With Exertional Heat Stroke

Abstract

Exertional heat stroke (EHS) is a rare, life-threatening condition that may affect anyone performing intense physical activity, especially in a hot environment. Morbidity and mortality persist despite aggressive cooling. EHS is a leading cause of death in young athletes and non-combat-related deaths in the military. EHS affects outdoor workers, firefighters, and people performing intense physical activities in hot weather. Severe hyperthermia and CNS dysfunction are hallmark features; rhabdomyolysis, renal failure, liver damage, and coagulation abnormalities are common and as many as 1/3 of survivors have long-term neurologic deficits despite the use of aggressive cooling. The study objectives were to evaluate the safety and efficacy of dantrolene sodium 250 mg/5 mL (DS) for injectable suspension for the treatment of EHS, administered as an adjunct to standard body cooling (SBC). This was a randomized, 2-arm, parallel, open-label study evaluating DS plus SBC compared to SBC alone in patients with EHS. EHS was defined as a core body temperature ≥40.0°C, impaired level of consciousness (LOC)(Glasgow Coma Scale, GCS score <13), and tachycardia. SBC was defined as efficient body cooling plus supportive measures. Patients were randomized 1:1 (n=17 per group). The primary endpoint was the cumulative incidence of recovery of LOC defined as a GCS score ≥13 at ≤90 minutes postrandomization. Secondary efficacy endpoints included calculated cooling rates and rectal temperature values. Safety and tolerability were assessed. The modified intent-to-treat (mITT) population excluded patients with endotracheal intubation at baseline, which made full assessment of GCS unfeasible. The study was conducted in a real-world emergency medicine setting. Due to the rareness and unpredictable nature of EHS, the study was designed to evaluate clinically meaningful outcomes and not powered for statistical significance. Demographics and baseline characteristics were balanced between the treatment groups. A total of 61.8% of patients were male. Mean age was 40.7 years (range 18-45). Mean baseline rectal temperature was 41.4°C; mean baseline GCS score was 6. Ten patients required rapid sequence intubation on presentation. More patients in the DS plus SBC group met the primary endpoint vs SBC alone (29.4% [CI: 10.31, 55.96] vs 11.8% [CI: 1.46, 36.44]). Patients in the DS plus SBC arm cooled faster. The median time to first rectal temperature ≤ 38°C in ≥75% of subjects in the mITT population was 125 min for the DS group vs 195 min for SBC alone. Safety and tolerability findings were similar in both groups. No treatment-emergent adverse events were reported as treatment related or led to discontinuation in either group. SAEs were reported for 11.8% of patients in each group. Seven patients (20.6%) experienced at least 1 SAE, with similar proportions across the 2 groups (DS plus SBC: 23.5%; SBC alone: 17.6%). This well-conducted, randomized, controlled clinical trial demonstrated that DS is safe and well tolerated in subjects with EHS and is consistent with the known, well-characterized safety profile in currently approved indications. DS in addition to SBC demonstrated greater clinically meaningful improvement in neurologic function vs SBC alone. Patients treated with DS in the ITT population were 3 times more likely to achieve recovery in their LOC; whereas, the mITT population were 6 times more likely to achieve recovery.