Tumor necrosis factor-alpha (TNF-alpha) release has been implicated in a sepsis-like syndrome following cardiopulmonary bypass (CPB). This also may be important in patients who have had a left ventricular assist device (LVAD) implanted. This report investigates the effect of reducing systemic blood flow on hemodynamic response, mixed venous oxygen saturation (SvO(2)), and the release of TNF-alpha. LVADs were implanted in 9 pigs. The aorta was clamped, and thus the LVAD flow represented the entire systemic blood flow. Plasma TNF-alpha in the femoral artery (FA) and superior mesenteric vein (SMV) was measured at baseline and following systemic blood flow changes. Simultaneously, hemodynamic parameters and oxygen saturation in the pulmonary artery (SvO(2)) were measured. Following reductions in systemic blood flow, plasma TNF-alpha increased gradually to a maximum level at a systemic blood flow of 20%. There was no significant difference between TNF-alpha levels in the SMV and the FA. There was a significant (p < 0.05) correlation between cardiac index, stroke volume index, and TNF-alpha. The SvO(2) decreased significantly (p < 0.05) at a systemic blood flow of 30 and 20%. A rise in TNF-alpha occurred when the SvO(2) was less than 75%. The data demonstrate that a reduction in systemic blood flow causes an increase in plasma TNF-alpha. This can lead to the development of a sepsis-like syndrome in a group of patients who already are hemodynamically compromised. While weaning short-term LVAD support, rapid diminution of the cardiac output and the pump flow must be avoided.