Diazepam inhibits organophosphate-induced central respiratory depression.
OBJECTIVE
Current evidence suggests that mortality from acute organophosphate (OP) poisoning is partially mediated through central nervous system (CNS) respiratory center depression (CRD). However, the exact mechanism of OP-induced CRD is unknown. In these studies, the authors investigated the hypothesis that OP-induced CRD is the result of overstimulation of CNS respiratory centers.


METHODS
Wistar rats received prophylaxis with either normal saline (controls), atropine, the peripherally acting anticholinergics glycopyrrolate (GLYC), ipratropium bromide (IB), or the CNS respiratory center attenuator diazepam. To determine if a dual CNS/peripheral cholinergic mechanism is responsible for animal death, two additional groups received combination treatment with diazepam plus either IB or GLYC. All treatments were completed 5 minutes before OP with subcutaneous dichlorvos. Differences in 10-minute and 24-hour mortality were assessed by the Fisher exact test.


RESULTS
Dichlorvos poisoning resulted in profound fasciculations without obvious seizure in all cohorts. In controls and animals treated with peripherally acting anticholinergics, fasciculations were followed by sedation and respiratory arrest (0% 10-minute survival in all cohorts). In contrast, pretreatment with either atropine or diazepam significantly improved 10-minute survival (100% and 44%, respectively). Although GLYC or IB afforded no protection when given alone, when delivered in conjunction with diazepam, the combination significantly improved survival (both groups 88% at 24 hours), suggesting a dual CNS/pulmonary muscarinic mechanism of lethality.


CONCLUSIONS
The central respiratory depressant diazepam paradoxically attenuates organophosphate-induced respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning.
Dickson
Eric W
EW
Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA. eric_dickson@uiowa.edu
Bird
Steven B
SB
Gaspari
Romolo J
RJ
Boyer
Edward W
EW
Ferris
Craig F
CF
D000818:Animals; D003975:Diazepam / Q000627:therapeutic use*; D007306:Insecticides / Q000633:toxicity*; D023421:Models, Animal; D009125:Muscle Relaxants, Central / Q000627:therapeutic use*; D009943:Organophosphorus Compounds; D011446:Prospective Studies; D051381:Rats; D017208:Rats, Wistar; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality
D007306:Insecticides; D009125:Muscle Relaxants, Central; D009943:Organophosphorus Compounds; D003975:Diazepam