Inhaled milrinone for pulmonary hypertension in high-risk cardiac surgery: silver bullet or just part of a broader management strategy?

Abstract

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are common and potentially devastating conditions in patients undergoing cardiac surgery. The prevalence of PH and elevated pulmonary vascular resistance (PVR) in patients with aortic stenosis and regurgitation is 15-30% and C 25%, respectively, and at least 40% in patients with mitral stenosis.1 In certain patients with pulmonary venous hypertension due to valvular cardiac disease, the elevated PVR persists or is slow to regress after valve replacement/repair as a result of remodelling of the pulmonary circulation.2 Preoperative PH is associated with prolonged mechanical ventilation, greater duration of hospital stay, and increased operative and long-term mortality.3 This is likely a consequence of the relationship between PH and the development of perioperative RV failure, a condition that, even with early recognition and treatment, has high morbidity and greater than 30% mortality. 4,5 Despite the critical importance of perioperative PH and RV dysfunction, there is a paucity of high-quality clinical trials addressing the perioperative management of these conditions.Milrinone, a phosphodiesterase-3 inhibitor, acts by augmenting cyclic adenosine monophosphate signalling to induce pulmonary and systemic vasodilation and to increase cardiac contractility -i.e., an inodilator.2,6 Inhaled milrinone (iMil) has attracted attention in view of the preferred route of administration in the setting of PH and RV dysfunction. There is a reduction in systemic vasodilation with this approach when compared with the intravenous route, and there is evidence to suggest that iMil has superior ability to mitigate pulmonary endothelial dysfunction during cardiopulmonary bypass (CPB). 7Lamarche et al. published retrospective data suggesting that the incidence of difficult weaning from CPB was reduced when iMil was administered before vs after CPB. 6 Until now, however, there has been a lack of prospective randomized-controlled trials evaluating the utility of iMil in this setting.In this issue of the Journal, Denault et al. present an important multicentre randomized-controlled trial examining a unique strategy for the management of perioperative PH and RV dysfunction.8 They posed the question: does prophylactic treatment with iMil before CPB facilitate separation from CPB in patients with preoperative PH? The authors studied 124 well-matched adult patients undergoing elective high-risk cardiac surgery with baseline mean pulmonary artery (PA) pressure [ 30 mmHg or a PA systolic pressure [ 40 mmHg. Patients were randomized to receive a single dose of either iMil (5 mg) or placebo through an in-line ultrasonic mesh nebulizer after induction of anesthesia. Detailed hemodynamic measurements and echocardiographic data were collected.

Perioperative approach to precapillary pulmonary hypertension in non-cardiac non-obstetric surgery

“…Milrinone is commonly available for intravenous (i.v.) administration, but also in inhaled form [50]. Inhaled milrinone decreases mPAP, PVR, transpulmonary gradient (TPG) and PVR/ systemic vascular resistance ratio during surgery, as well [51].…”

Pulmonary Hypertension in an Oncologic Intensive Care Unit

“…Longer-acting analogues of prostacyclin (iloprost and treprostinil) can be administered through nebulization [10]. Inhaled milrinone has also been studied alone as well as in combination with inhaled prostacyclin in the context of cardiovascular surgery, but it is not widely used at this time [6,16,34]. Sildenafil, a phosphodiesterase-5 inhibitor, can be used in treating acute cardiogenic RV shock from PH [22].…”

The link between pulmonary hypertension and adverse renal transplant outcome may be renal venous hypertension

“…[ 4 ] This likely explains the benefit to the acute treatment of RV dysfunction with pulmonary vasodilators and other inotropic agents that can reduce the RA pressure and improve renal function. [ 5 ] Hence, although the circulating vasoactive substances that can lead to pulmonary hypertension could theoretically result in renal vasoconstriction, the main problem may not be the arterial flow to the kidney but rather the venous outflow from the kidney, which can similarly cause an ischaemic injury due to low transmural organ blood flow.…”