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BJA Advance Access published online on January 27, 2006
British Journal of Anaesthesia, doi:10.1093/bja/ael009
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Accepted December 20, 2005

Laboratory Investigation

Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension

E. B. Lobato 1, T. Beaver 2, J. Muehlschlegel 3, D. S. Kirby 4, C. Klodell 2, and A. Sidi 3 *

1 Department of Anaesthesiology, Malcom Randall Veterans Administration Medical Center, Gainesville, FL, USA; Anaesthesia Service, Malcom Randall Veterans Administration Medical Center, Gainesville, FL, USA
2 Department of Surgery, University of Florida College of Medicine, FL, USA
3 Department of Anaesthesiology, Malcom Randall Veterans Administration Medical Center, Gainesville, FL, USA
4 Anaesthesia Service, Malcom Randall Veterans Administration Medical Center, Gainesville, FL, USA

* To whom correspondence should be addressed.
A. Sidi, E-mail: Asidi{at}anest.ufl.edu


  Abstract

Objectives. To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension.

Methods. Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FlOO2 of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 µg kg-1 of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube.

Results. Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil.

Conclusion. Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.

Keywords: complications, pulmonary hypertension; inhibitor, milrinone; inhibitor, sildenafil; phosphodiesterase inhibitors.
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