Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization

Abstract

inhaled milrinone administered before cardiopulmonary bypass (cpB) reduces the severity of pulmonary hypertension during cardiac surgery. However, milrinone pharmacokinetics has not been determined for this route of administration. the objective of this study was to investigate inhaled milrinone dosing in vitro and early plasma concentrations in vivo after jet and mesh nebulization. twelve pulmonary hypertensive patients scheduled for cardiac surgery were randomized to receive milrinone (5 mg) by inhalation before CPB using a jet or mesh nebulizer. In vitro experiments were conducted to determine the inhaled dose delivered with either jet or mesh nebulization. In vivo experiments involved hemodynamic monitoring and blood samples drawn from patients for the first 15 min after the end of inhalation to determine early plasma concentrations. After mesh nebulization, the mean in vitro inhaled dose was almost 3-fold higher compared to jet nebulization (46.4% vs 16.6% for mesh and jet, respectively; mean difference, 29.8%; 95% CI, 14.1 to 45.5; P = 0.006). Consistent with this, the early plasma concentrations in vivo were also 2-3 fold higher after mesh nebulization (P = 0.002-0.005). After inhalation (jet or mesh nebulization), milrinone early plasma concentrations remained within the therapeutic range. no systemic hypotension was reported in our patients. Intravenous milrinone, a phosphodiesterase inhibitor and inodilator, has been extensively used in cardiac surgery for the treatment of pulmonary hypertension (PH), particularly during difficult separation from cardiopulmonary bypass (CPB) 1-4. An important drawback of intravenous milrinone is its association with systemic hypotension 5-7. To avoid this side effect, inhalation has been proposed as an alternative therapeutic route of administration for milrinone 8-10. Pulmonary drug delivery presents advantages such as rapid absorption, high bioavailability, and high local concentrations 11. Consequently, a hypothesis was put forward in the past decade that inhaled milrinone administered prior to CPB would have a protective effect against the exacerbation of PH in cardiac surgical patients 12,13 by minimizing CPB-related inflammation 14 , preventing pulmonary endothelial dysfunction 15 , and facilitating separation from CPB 16. More recently, a multicenter randomized controlled trial demonstrated the clinical efficacy of inhaled milrinone in reducing the degree of PH; however, it was not associated with a reduction in difficulty separating from CPB 17. Several factors could explain those results, including suboptimal drug delivery 18. Nebulizers are commonly used drug delivery devices in aerosol therapy for patients with pulmonary diseases. These devices operate by converting liquid formulations into fine breathable droplets. There are three types of nebulizers: jet, ultrasonic and mesh 19. Apart from four clinical studies using ultrasonic 9,14 or mesh nebulizers 17,20 , jet nebulizers have been the standard drug delivery devices for inhaled milrinone in adult cardiac ...

Inhaled versus intravenous milrinone in mitral stenosis with pulmonary hypertension

“…Milrinone has a rapid onset of action and has been proven in many studies to be effective in decreasing PAP after surgery. 16 , 17 Although the effect of inhaled milrinone lasts for only 20 to 30 min, 8 , 9 after cessation of inhalation, our findings indicate that the effect is sufficient to prevent an acute post-CPB rise in PAP. In our study, milrinone inhalation led to a significant reduction in systolic pulmonary artery pressure, MPAP, PVRI, and PVRI/SVRI ratio despite a decrease in SVRI, ultimately resulting in an increase in CI.…”

“…In the iMil group, there was a higher total milrinone dose, but with a jet nebulizer, the plasma level achieved by a 5-mg dose is 100 ng·mL −1 which is way below the intravenous bolus dose of 50 µg·kg −1 that increases the plasma level to 600 ng·mL −1 . 17 So, we gave a lower dose in the iMil group with a better effect.…”

Inhaled pulmonary vasodilators: a narrative review

“…In addition, routine use of inhaled milrinone and iloprost before initiation of CPB and at chest closure is associated with reduced postoperative iNO trope use (191). And aerosolized milrinone with mesh nebulization improved with almost a 3-fold higher deposition compared to jet nebulization (192). Furthermore, inhaled milrinone after LVAD implantation proved to be well-tolerated, feasible, improved hemodynamics, pharmacokinetics, and was less expensive (193).…”

In Vitro Evaluation of a Vibrating-Mesh Nebulizer Repeatedly Use over 28 Days

“…The advantages of vibrating-mesh nebulizers over the jet and other ultrasonic nebulizers include less noise, effective concentration, and minimal temperature changes that make it suitable for temperature-sensitive drugs. Vibrating-mesh nebulizers are predominantly used in clinical trials involving mechanical ventilation and newly developed medications [ 2 , 3 , 5 , 6 , 7 , 8 ].…”

“…Particle sizes (measured using eFlow, Pari Ltd., Starnberg, Germany) were very similar; however, aerosol generation was inconsistent owing to clogging by drug. There are several papers by investigators, as well as the manufacturer demonstrating device performance in a number of clinical applications with a wide range of formulations [ 3 , 5 , 6 , 7 , 8 ]. The intellectual property portfolio is largely focused on physical attributes of the technology, such as the number, shape and configuration of apertures, and the composition of both the mesh, the key components of the aerosol generator, as well as the design and function of the medical reservoir.…”