Cardiopulmonary effects of phosphine poisoning: A preliminary evaluation of milrinone

Highlights: • Milrinone (600 μg/kg) nominally improved survivability following phosphine exposure. • Dose-lethality curve for phosphine inhalation remained largely unchanged. • Phosphine exposure induced increased respiratory drive, regardless of treatment. • Behavioral signs of phosphine intoxication were unaffected by milrinone. • QRS elongation was reversed in milrinone-pretreated animals. Exposure to phosphine (PH₃) presents with a host of diverse, non-specific symptoms that span multiple organ systems and is characterized by a high mortality rate. While a comprehensive mechanism for PH₃ poisoning remains inconclusive, prior studies have implicated cardiac failure and circulatory compromise as potential pathways central to PH₃-induced mortality. In this study, milrinone (MLR), a phosphodiesterase-3 inhibitor used to treat cardiac failure, was investigated as a potential countermeasure for PH₃ poisoning. Lethality, physiological responses, and behavioral changes were evaluated in telemetrized female rats pretreated with water (sham) or one of three doses of MLR (40, 200, or 600 μg/kg) and exposed to PH₃ (660 ppm for 25–40 min; 16,500–26,400 ppm × min). Animals receiving prophylactic administration of 600 μg/kg of MLR had nominally improved survivability compared to sham animals, although median lethal concentration-time and time of death did not differ substantially between treatment groups. Changes in respiration and behavior induced by PH₃ appeared largely unaffected by MLR pretreatment, regardless of dose. Conversely, MLR pretreatment alleviated some aspects of PH₃-induced cardiac function impairment, with slight dose-dependent effects observed for cardiac contractility, mean arterial pressure, and QRS duration. Together, these results illustrate the importance of circulatory compromise in PH₃ poisoning and highlight the potential viability of MLR as a potential countermeasure option or part of a countermeasure regimen when administered prophylactically at 600 μg/kg.