Inotropic and vasoactive drug treatment of interleukin 2 induced hypotension in sheep

The side effects associated with recombinant interleukin 2 administration, including systemic hypotension and a vascular leak syndrome, may limit therapy before reaching maximum doses of this innovative and promising treatment for cancer. In an attempt to reverse this hypotension without decreasing cardiac output and systemic oxygen delivery (DO2), we studied several inotropic agents, dobutamine, dopamine, amrinone, CaCl2, and a pure alpha-adrenergic vasoconstrictor, methoxamine. These were administered singly or in combination to sheep with chronically implanted arterial and pulmonary artery catheters following 24 h of 3 x 10(5) units/kg recombinant interleukin 2. Compared to baseline values, 24 h of recombinant interleukin 2 infusion caused a significant increase in cardiac output from 4.4 +/- 0.9 (SD) to 5.0 +/- 0.6 liters/min, a significant fall in systemic vascular resistance (SVR) from 21 +/- 7 to 15 +/- 5 units, a decrease in mean systemic blood pressure (SBP) from 88 +/- 9 to 78 +/- 6 mm Hg, and a decrease in left ventricular stroke work from 51.5 +/- 8 to 49 +/- 6 gram meters (P less than 0.05) without any change in DO2. Dopamine, dobutamine, and CaCl2 returned SBP to baseline values by increasing cardiac output without increasing SVR. Methoxamine increased SBP by increasing SVR, but cardiac output decreased significantly. A combination of 12 micrograms/kg/min of dopamine and 2 to 3 mg of methoxamine infused over 15 min resulted in an increase in SBP, cardiac output, and SVR to baseline values while maintaining DO2 and oxygen consumption (VO2). We suggest that this latter combination would be appropriate for clinical use since it returns physiological parameters to normal.