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Pulmonary blood flow during cardiac arrest and cardiopulmonary resuscitation (CPR) is <20% of normal, and transalveolar drug absorption is likely to be minimal. Animal and clinical CPR studies have not addressed the use of endotracheal (ET) epinephrine in doses currently recommended for adults (twice the intravenous dose). The purpose of this study was to compare the effects of ET and intravenous drugs on cardiac rhythm in the prehospital setting.A 3-yr (1995–1997) retrospective review of all cardiac arrests transported to a single, municipal teaching institution was performed.Patients >18 yrs in atraumatic cardiac arrest whose first documented field rhythm was asystole with time-to-definitive care of ≤10 mins (primary asystole) and patients found in ventricular fibrillation who developed postcountershock asystole (secondary asystole) were included. Patients were grouped according to route of drug administration (iv, ET, or no drug therapy) as well as rhythm (primary or secondary asystole). A positive response to drug therapy was defined as any subsequent rhythm other than asystole during continued prehospital resuscitation.A total of 136 patients met inclusion criteria. The following groups were defined: group 1, primary asystole/iv drugs (n = 39); group 2, postcountershock asystole/iv drugs (n = 39); group 3, primary asystole/ET drugs (n = 25); group 4, postcountershock asystole/ET drugs (n = 18); and group 5, primary or secondary asystole/no drug therapy (n = 15). Significant differences were not observed between groups with respect to age, gender, witnessed arrest, frequency of bystander CPR, or time-to-definitive care. The positive rhythm response rate was significantly greater in group 1 (64%) and group 2 (69%) (both p < .01) than in Group 3 (12%) or group 4 (11%). The response rate in the control group was 20% and not significantly different from either ET group. The intravenous groups also had a significantly greater rate of return of spontaneous circulation (17%) when compared with the ET groups (0%) (p = .005).We conclude that the currently recommended doses of epinephrine and atropine administered endotracheally are rarely effective in the setting of cardiac arrest and CPR.