Comment on “Intravenous Versus Inhaled Milrinone in Patients with Known Pulmonary Hypertension Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis

Dear Editor, We read with great interest the recent systematic review and meta-analysis by Kavanagh et al. titled “Intravenous Versus Inhaled Milrinone in Patients with Known Pulmonary Hypertension Undergoing Cardiac Surgery,” recently published in the Annals of Cardiac Anesthesia.[1] The authors compared IV and inhaled milrinone in patients with pre-existing pulmonary hypertension who were undergoing cardiac surgery. Their service deserves all credit based on the evidence available, as they have succeeded in praiseworthy attempt to shed light on important clinical points concerning the hemodynamic advantages and necessary doses regarding the safety of alternative routes during administration of milrinone among this critically ill cohort. Nevertheless, we would like to temperately point out some considerations that could improve the precision and interpretation of the data. First, the incorporated trials were heterogeneous with regard to the underlying etiology and severity of pulmonary hypertension, patient selection, types of cardiac surgery performed (coronary artery bypass grafting, valve surgery, congenital repairs), and the timing of outcome assessment. Cardiovascular measurements such as cardiac index or pulmonary artery pressure can vary unpredictably between cardiopulmonary bypass separation, induction, and postoperative ICU admission. Pooling such heterogeneous data without ample risk assessment creates an “average” effect that may not be clinically meaningful for any specific subgroup.[2] Subgroup and sensitivity analyses would, therefore, be essential to strengthen conclusions. Along with that, the reporting of adverse events in the reviewed studies was inconsistent. Inhaled milrinone may bring down systemic hypotension compared with intravenous administration, but complications such as bronchial irritation, arrhythmias, and rebound pulmonary hypertension have been described in perioperative settings. Without systematic reporting, there is a risk that the therapy seems safer than it actually is. This concern has also been raised in other perioperative pulmonary vasodilator trials where safety outcomes were either underpowered or incompletely captured.[3] Additionally, the presentation of results can be improved, as the forest plots and summary table do not provide all the essential key characteristics of the study, such as sample size, dosing regimen, and the timing of outcome measurement. The absence of this limits the reader from evaluating the clinical and methodological variability among studies completely. In line with PRISMA 2020 recommendations, visual summaries should facilitate the appraisal of heterogeneity and study quality at a glance.[4] Lastly, the authors characterize the findings as showing the “superiority” of inhaled milrinone, a terminology better suited to trials powered to test for true superiority. Given the heterogeneity and generally small scale of included studies, a more conservative phrasing to express this would be that there is “an association with positive clinical outcomes,” which does not downplay certainty yet makes it clear this phrase cannot denote strong evidence due to the widespread methodological differences among current prospective observational trials.[5] Authors contribution DR and SZ: Conceptualization, Manuscript writing and Editing. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.