Dose-effect relationships of prostaglandin E1 in severe endstage chronic heart failure.
Prostaglandin E1 is a potent vasodilator in severe chronic heart failure. To evaluate the time sequence and magnitude of prostaglandin E1's hemodynamic effects a dose finding study was performed in 24 patients. Right heart catheterization was performed and prostaglandin E1 was administered via a central venous line in incremental doses of 2.5, 10, 20, 30 and 40 ng/kg/min, each dose, lasting 15 min before hemodynamic evaluation. The first significant change was a approximately 20% decrease in systemic vascular resistance index accompanied by a approximately 18% increase in cardiac index at an infusion rate of 2.5 ng/kg/min of prostaglandin E1, which was sustained at 5 ng/kg/min in all patients. A dose response-curve with cumulative doses ranging from 2.5 to 25 ng/kg/min of prostaglandin E1 was established in a subset of 14 patients due to 10 drop-outs at lower dosages. At 2.5 and 5 ng/kg/min of prostaglandin E1, cardiac index increased by 18% (p < 0.05) and peripheral resistance decreased by 18% (p < 0.01). These changes were sustained up to a maximal dose of 25 ng/kg/min, which was tolerated by all patients in this group. At 15 and 20 ng/kg/min of prostaglandin E1 a significant decrease in blood pressure of -4 mmHg (p < 0.05) was observed which was reversed at the next dose step. In a second analysis maximal tolerated dosages of prostaglandin E1 were evaluated in all 24 patients (group A, 26 +/- 2 ng/kg/min), and in two subsets using a maximum tolerated dose of 20 ng/kg/min as a cutpoint (B: 14 patients, 34 +/- 2 ng/kg/min; C: 10 patients, 15 +/- 2 ng/kg/min) Then the respective peak dosages were halved for continuous infusion through 12 hours. In the acute study pulmonary capillary wedge pressure (by A: -11%, p < 0.01; B: -4%, p < 0.01; C: -22%, p < 0.01) and systemic vascular resistance (by A: -32%, p < 0.0001; B: -25%, p < 0.001; C: -43%, p < 0.001) decreased significantly in all three groups and cardiac index increased (by A: +38%, p < 0.0001; B: +33%, p < 0.0001; C: +59%, p < 0.0001). In the chronic study these changes were sustained. Furthermore, mean arterial pressure (by A: -14%, p < 0.0001; B: -13%, p < 0.001; C: -13%, p < 0.05), right atrial pressure (by A: -36%, p < 0.0001; B: -36%, p < 0.01; C: -30%, p < 0.01), pulmonary artery pressure (by A: -16%, p < 0.0001; B: -16%, p < 0.01; C: -19%, p < 0.01) and pulmonary vascular resistance (by A: -28%, p < 0.01; B: -31%, p < 0.01; C: -25%, p < 0.01) were significantly reduced after 12 hours.


CONCLUSIONS
These results demonstrate potent hemodynamic effects of low-dose prostaglandin E1 in severe heart failure. While systemic effects appear rapidly, a slow onset of the pulmonary effects was observed.
Stanek
B
B
Department of Cardiology, University of Vienna, Austria.
Pacher
R
R
D000328:Adult; D000368:Aged; D000527:Alprostadil / Q000008:administration & dosage* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000494:pharmacology
D014665:Vasodilator Agents; D000527:Alprostadil