Inhibition of cAMP phosphodiesterase by milrinone improves cardiac recovery after deep hypothermic circulatory arrest

Introduction

Perioperative cardiac dysfunction may be related to inadequate myocardial protection during cardiopulmonary bypass (CPB) and associated procedures. Many intrinsic and extrinsic factors may act directly on vessels or indirectly by release of vasoactive metabolites to alter vascular tone and myocardial function during reperfusion. Milrinone, by inhibiting cAMP-specific phosphodiesterase enzymes in both cardiac and vascular smooth muscle, is a powerful inotrope and vasodilator, but has little effect on systemic arterial blood pressure. The purpose of the study was to investigate the effect of milrinone administration on recovery of left ventricular (LV) function and systemic haemodynamics after deep hypothermia and CPB in rabbits.

Method

Fourteen New Zealand White rabbits (3.5 ± 0.5 kg body weight) underwent CPB and deep hypothermic cardiopulmonary arrest (DHCA) for 1 h. LV function and systemic haemodynamics were compared between a control group (n = 7) and a treatment group of animals (n = 7) that received a loading dose of milrinone (50 μg/kg body weight) before the onset of circulatory arrest, followed by slow release (0.5 μg/kg pody weight per min) during reperfusion. LV and haemodynamic measurements were taken before surgical interventions and at 2 h after reperfusion.

Results

There were no statistical differences in baseline values between the two groups. Perioperative treatment with milrinone resulted in better recovery of LV function (max+dP/dt: 1206 ± 149 versus 1043 ± 134 mmHg/s [P < 0.05]; LV stroke work index: 41 ± 2 versus 33 ± 2 gxm/m² [P < 0.05]) and significant changes in systemic haemodynamics (cardiac index: 3.1 ± 0.1 versus 2.2 ± 0.2 l/min per m² [P < 0.05]; pulmonary artery pressure: 13.2 ± 1.6 versus 18.6 ± 3.8 mmHg [P < 0.05]; pulmonary vascular resistance: 550 ± 70 versus 1020 ± 110 dyns/cm⁵ per m² [P < 0.01]), with no significant change in mean arterial pressure, despite higher plasma cAMP levels (19 ± 2 versus 12 ± 1.1 pmol/ml).

Conclusion

These data indicate that milrinone administration acutely improves systemic haemodynamics and has beneficial effects on recovery of myocardial function after deep hypothermic ischaemia. Milrinone and related drugs warrant further investigation in the treatment of vascular tone and ischaemia-reperfusion deterioration after CPB and DHCA.