The response of patients with chronic severe heart failure to extended infusions (greater than or equal to 48 hours) of milrinone was evaluated in a multicenter, baseline-controlled, phase III efficacy and safety trial in 189 patients in the United States. Milrinone was given as loading and maintenance infusions according to one of four dose regimens. An effective response was defined as greater than or equal to 20% increases in cardiac index or decreases in pulmonary wedge pressure. All loading doses (range, 37.5 to 75 micrograms/kg/10 min) were effective short term, and maximum response occurred at 15 minutes. For the three effective regimens, cardiac index increased initially (at 15 minutes) by 24% to 42%, and pulmonary wedge pressure decreased by 24% to 33%. Systemic vascular resistance was reduced by 15% to 31%. The maximal acute response was effective in 99% of individual patients. During maintenance therapy, effective responses were seen at infusion doses of 0.375, 0.50, and 0.75 micrograms/kg/min, whereas an infusion of 0.25 micrograms/kg/min was ineffective. During 2 days of maintenance therapy, cardiac index remained augmented by 34% to 39% for the low and intermediate doses and by 44% to 73% for the high-dose infusion regimen. Pulmonary wedge pressure decreased an average of 18% on day 1 and 30% on day 2. Systemic vascular resistance was reduced by 20% to 25%, and stroke work index was augmented by 21% to 58%. Symptomatic improvement was common during intravenous milrinone therapy for symptoms of dyspnea (61% response), orthopnea (63%), edema (62%), and fatigue (40%). Improvement occurred more frequently in those with worse baseline functional indexes and in those with greater hemodynamic responses to therapy. Safety and tolerance were exceptionally good for these patients with advanced heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)