Key result
Midazolam significantly improved the recovery of cardiovascular parameters and autonomic function following acute organophosphate intoxication, an effect that was enhanced by the addition of allopregnanolone.
Why the study?
Combined midazolam and allopregnanolone terminates organophosphate-induced seizures more effectively than midazolam alone, but concerns exist regarding potential increased risks of adverse cardiovascular events.
Does combined treatment with midazolam and allopregnanolone improve cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with DFP compared to midazolam alone or no treatment?
Does combined treatment with midazolam and allopregnanolone improve cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with DFP compared to midazolam alone or no treatment?
In a rat model of acute organophosphate intoxication, the combination of midazolam and allopregnanolone improved recovery of cardiovascular and autonomic function better than midazolam alone.
Combination enhanced CV recovery after DFP intoxication in rats without raising adverse events; leaves open clinical translation for OP poisoning.
Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.
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Pan et al. (2024) studied Acute organophosphate intoxication. Midazolam with or without allopregnanolone vs. No treatment or midazolam alone was evaluated on Recovery of cardiovascular parameters and heart rate variability. Midazolam significantly improved the recovery of cardiovascular parameters and autonomic function following acute organophosphate intoxication, an effect that was enhanced by the addition of allopregnanolone.
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