This report describes an initial experience applying warm glutamate/aspartate substrate-enriched blood cardioplegic solution to resuscitate hearts in 14 patients with witnessed perioperative arrest. Ten patients were in stable hemodynamic condition in the catheterization laboratory (n = 3) or intensive care unit when sudden irreversible fibrillation developed. It progressed to electromechanical arrest in six patients. In patients with preoperative or postoperative arrest, conventional cardiopulmonary resuscitation and defibrillation were unsuccessful and extracorporeal circulation was started 22 to 150 minutes after arrest. The left ventricle was vented, the aorta clamped, and warm (37 degrees C) aspartate/glutamate blood cardioplegic solution was given at a rate of 150 ml/min for 20 minutes. All bypass grafts were open with good flows in patients who had had coronary bypass, and coronary bypass was done in the three patients who had preoperative arrest. Eleven of 14 hearts resumed normal sinus rhythm after aortic unclamping, only two electrocardiographically proved infarctions occurred, and 13 patients had complete hemodynamic recovery with improved ejection fraction. Three patients died: one of progressive cardiogenic shock, another of mediastinitis, and the third of irreversible neurologic damage. Eleven patients were discharged from the hospital and are well after a follow-up period between 3 and 9 months. We conclude that witnessed perioperative arrest with intractable ventricular fibrillation should be treated aggressively by administering cardiopulmonary resuscitation during prompt transfer to the operating room for total vented bypass and delivery of warm substrate-enriched blood cardioplegic solution. This treatment may salvage hearts thought to be damaged irreversibly and may be a feasible approach to intractable witnessed cardiac arrest, provided cardiopulmonary resuscitation maintains satisfactory cerebral perfusion pressure.