Therapeutic efficacy of oral pirbuterol in severe chronic congestive heart failure: Acute hemodynamic and long-term ambulatory evaluation

Abstract

Development of effective orally administered cardiotonic agents for sustained ambulatory therapy of severe chronic congestive heart failure (CHF) is currently of considerable clinical interest. Thus we evaluated temporal cardiocirculatory responses to the new ingestible beta-adrenergic receptor agonist pirbuterol (PBL) (0.4 mg/kg) by cardiac catheterization and limb plethysmography in 10 patients with coronary disease and severe CHF refractory to digitalis and diuretics. PBL considerably improved left ventricular (LV) dysfunction during the 6-hour period of hemodynamic monitoring: control lowered cardiac index (CI) of 1.7 L/min/m 2 rose to 2.6 (p < 0.001) at 1 hour, 2.4 (p < 0.005) at 3 hours, and was 2.2 (p < 0.001) at 6 hours; control excessive LV filling pressure (LVFP) of 24 mm Hg fell to 19 (p < 0.005) at 1 hour, 18 (p < 0.005) at 3 hours, and was 22 mm Hg (p < 0.05) at 6 hours. Concomitantly, peak heart rate (HR) increment (6 bpm) was minimal, mean arterial blood pressure (MAP) decrement was only 10 mm Hg, total systemic vascular resistance (TSVR) declined, forearm venodilation occurred, and rate · pressure product of myocardial oxygen consumption was unaltered. Further, hemodynamic actions of PBL were compared with intravenously administered dobutamine (DBA) in nine patients with CHF. Both agents produced similar effects on LV pump function: CI was markedly augmented from 1.8 to 2.6 L/min/m 2 (p < 0.005) by DBA and from 1.8 to 2.9 L/min/m 2 (p < 0.001) by PBL, and stroke work index was increased from 19 to 27 gm · m/m 2 (p < 0.005) by DBA and from 20 to 29 gm · m/m 2 (p < 0.005) by PBL. However, although DBA did not change (p > 0.05) MAP and LVFP, PBL modestly diminished MAP from 83 to 75 mm Hg (p < 0.02) and moderately decreased LVFP from 23 to 18 mm Hg (p < 0.005). DBA reduced TSVR 22% from 2049 to 1582 dynes · sec · cm −5 (p < 0.001), whereas PBL reduced TSVR 42% (p < 0.05 vs DBA), from 2068 to 1150 dynes · sec · cm −5 (p < 0.001). During extended ambulatory therapy (0.4 mg/kg three times daily) with PBL orally, scintigraphic LV ejection fraction rose from 0.25 to 0.29 (p < 0.01). Concomitantly, treadmill exercise duration increased from 267 to 366 seconds (p < 0.001), and New York Heart Association functional class improved from 3.5 to 2.4 (p < 0.01). Thus PBL orally has DBA-like beneficial hemodynamic effects on LV pump function but causes greater fall in TSVR consistent with combined inotropic and peripheral vasodilator actions of this oral beta-receptor agonist. Of importance, salutary hemodynamic responses to PBL orally were maintained for prolonged duration of 6 hours following single dose. Further, during sustained ambulatory PBL therapy substantial augmentation of LV function and exercise capacity was observed and resulted in marked amelioration of CHF symptomatology.