The major complication of extracorporeal membrane oxygenation (ECMO) for the treatment of neonatal respiratory failure is bleeding related to heparinization. Systolic hypertension has emerged as another serious side effect in our experience. Thirty-eight of the first 41 newborns we treated with ECMO developed a systolic blood pressure greater than 90 mm Hg. The mean hypertension index (HI blood = hours greater than 90/hr on ECMO) was 0.17 +/- 0.16. Possible biochemical mediators were assayed in 17 patients. Plasma renin activity (PRA), aldosterone, epinephrine, norepinephrine, prostaglandin E2, thromboxane, and antidiuretic hormone were elevated. Angiotensin-converting enzyme (ACE) and prostacyclin were not elevated. Eighteen patients (44%) had intracranial hemorrhage (ICH), and 11 patients (27%) had clinically significant ICH. The HI was significantly (p less than 0.005) lower in those patients without ICH (0.11 +/- 0.01) than in those patients with ICH (0.25 +/- 0.04). PRA at hour 12, day 2, and day 3 was significantly higher (p less than 0.05) in patients experiencing ICH (62 +/- 42; 93 +/- 15; 73 +/- 30 ng/ml/hr) than in those without ICH (27 +/- 25; 14 +/- 8; 12 +/- 4 ng/ml/hr). An aggressive approach to medical management evolved that included hydralazine, nitroglycerine, and captopril, which protected against ICH. Two of 23 patients (9%) treated with the protocol sufferred clinically significant ICH, whereas nine of 18 patients (50%) treated before implementation of the protocol experienced ICH. The ACE inhibitor captopril was most effective in the control of hypertension. We conclude that systolic hypertension is common during neonatal ECMO, is associated with ICH, and is related to a high PRA. Aggressive management of hypertension during ECMO can reduce the incidence of ICH, and captopril is an important component of this aggressive medical management.