BACKGROUND Multiple interventions have been tested in models of cardiopulmonary resuscitation (CPR) to optimize drug use, chest compressions, and ventilation. None has studied the effects of positive end-expiratory pressure (PEEP) on outcome. We hypothesized that because PEEP can reverse pulmonary atelectasis, lower pulmonary vascular resistance, and potentially improve cardiac output, its use during CPR would increase survival. METHODS Anesthetized Sprague-Dawley rats were exposed to 1 min of asphyxial cardiac arrest. Resuscitation was standardized and consisted of chest compressions, oxygen (Fio(2) 1.0), and IV epinephrine 30 microg/kg (Series 1) and 10 microg/kg (Series 2). Left ventricular function was assessed by echocardiography (Series 1), and animals were randomized to receive either 5 cm H(2)O PEEP or zero PEEP at commencement of CPR and throughout resuscitation. Survival was defined as the presence of a spontaneous circulation 60 or 120 min (Series 2) after initial resuscitation. RESULTS There were no baseline differences between the groups. In Series 1, administration of 5 cm H(2)O PEEP (Fio(2) 1.0 and 0.21) was associated with improved survival compared with zero PEEP (7/9 and 6/6 vs 0/9, P < 0.01 and <0.001, respectively). Application of 5 cm H(2)O PEEP (Fio(2) 1.0) increased left ventricular end-diastolic area, systemic oxygenation, and functional residual capacity. Use of PEEP during CPR did not adversely affect left ventricular systolic function or arterial blood pressure. The outcome differences were not due to increased oxygenation because the rank order of survival was 5 cm H(2)O PEEP (Fio(2) 1.0) approximately 5 cm H(2)O PEEP (Fio(2) 0.21) > zero PEEP (Fio(2) 1.0), whereas the rank order of Pao(2) was 5 cm H(2)O PEEP (Fio(2) 1.0) > 5 cm H(2)O PEEP (Fio(2) 0.21) approximately zero PEEP (Fio(2) 1.0). In an additional series in which epinephrine 10 microg/kg was used (Series 2), the survival was 100% with no beneficial effects of PEEP. CONCLUSION In asphyxial cardiac arrest in a small rodent model, continuous application of PEEP (5 cm H(2)O) during and after CPR had beneficial effects on survival that were independent of oxygenation and without adverse cardiovascular effects.