Pharmacokinetic/pharmacodynamic relationship of pulmonary administration methods for milrinone : a translational approach

Following weaning from cardiopulmonary bypass (CPB), the cardiac surgery patients undergoing a procedure are often faced with the pulmonary reperfusion syndrome which may lead to pulmonary hypertension condition which, in turn, is likely to precipitate right ventricular dysfunction. Milrinone, a phosphodiesterase type 3 inhibitor (PDEIII) is used, among others, to facilitate CPB weaning in patients by reducing the severity of pulmonary hypertension through vasodilation. Milrinone is typically given intravenously. However, this mode of administration is frequently associated with systemic hypotension which may require administration of vasoactive agents. Administration of milrinone throughnebulization has therefore been developed, targeting the lungs directly and avoiding systemic hypotension. In case of emergency, milrinone may even be injected directly into the trachea or even possibly atomized intratrachealy. In this thesis we will describe an experimental protocol where the administration of milrinone through inhalation was studied. Unfortunately, experimental protocols during surgeries requiring CPB are often challenging due to time and procedural constraints. Indeed, the signal-to-noise ratio makes it difficult to isolate the effect of a specific intervention. The effect of the other administered medications and the physical stress of surgery may result in potentially incomplete or biased pharmacological studies. This aspect is the basis of the first portion of the thesis. The identification and and the quantification of the surgical manipulation artifacts on our main biomarker, the mean systemic pressure over the mean pulmonary pressure, was our first objective. In our first study, following our experimentation, we witnessed a 30- 50% changes on systemic pressures and these changes were twice those observed on pulmonary pressures for the same artefact. Pooled durations of all effects on both mAP and mPAP averaged 4.5±2.5 min (n=152). These changes fully justified the creation of a new model due to the potential biais of the artefacts. Secondly, as nebulization is a novel way to administer milrinone, the pharmacokinetic-pharmacodynamics (PK-PD) relationship has not been completely characterized. Even less information is available for the emergency routes. Milrinone targets PDEIII in vascular smooth muscle, thus the local antihypertensive effect of milrinone is most likely to occur at the level of muscular arteries alongside the tracheobronchial tree. We studied four methods of administration: simple jet (SJ), vibrating mesh (VM) nebulization, intratracheal instillation (ITI) and atomization (ITA). In addition, the optimal pulmonary deposition and absorption site for maximum local effect remains as of yet unknown. We have strived to identify the factors influencing the lung deposition of milrinone through nebulization and part of the work discussed in this thesis is aimed at characterizing the amount of milrinone deposited on the various sections of the tracheobronchial tree by the mentioned methods. Through in and ex vivo studies we have investigated the differences in efficacy of the two nebulization methods. We have found each method to generate a significantly different deposition pattern and as such, influencing lung deposition. Our results show that VM targets the lower airways and alveoli, whereas SJ targets preferably the higher and middle airways. Our study also shows a higher inhaled dose for VM but surprisingly a better dose-related efficacy for SJ. Indeed, in addition to a better oxygenation, our study shows, as demonstrated by the acetylcholine-induced relaxation IC50, a 20 times higher sensitivity and a 25% higher maximum relaxation following simple jet nebulization. Subsequently, following the development of a pulmonary hypertension model devoid of surgical manipulations and, by association, artefacts, we have determined a urinary-dose-corrected PK/PD relationship for the nebulization and emergency methods of milrinone administration. We explored the methods of intratracheal bolus and atomization and compared their efficacy to those of nebulization. This study shows a lower EC50 of milrinone impact and an almost 40% increase of the mean systemic arterial pressure over mean pulmonary arterial pressures ratio following simple jet adminstration. The information obtained by these studies offers the potential to aid clinicians in making a more informed judgment in the use of milrinone.

Keyphrases: milrinone, inhalation, intratracheal, nebulizer, pharmacokinetics, pharmacodynamic, pulmonary hypertension, cardiopulmonary bypass, cardiac surgery, in vivo