Comment on “The Role of Acetaminophen Use in Acute Kidney Injury Prevention in Cardiac Surgery: A Systematic Review and Meta-Analysis”

Dear Editor, We read with great interest the recent systematic review and meta-analysis by Ciconini et al.[1] titled “The Role of Acetaminophen Use in Acute Kidney Injury Prevention in Cardiac Surgery,” recently published in the Annals of Cardiac Anesthesia. The study provides important perspectives for the potential benefit of using acetaminophen to minimize postoperative acute kidney injury (AKI) after cardiac surgery; however, a few methodological concerns warrant discussion. First, the trials included showed significant heterogeneity of the doses, time of administration, and delivery of adenosine triphosphate (ATP), from pre-induction to post-bypass intravenous infusions. This variability makes the combined results challenging to interpret because the pharmacokinetics of acetaminophen may vary widely in cardiopulmonary bypass, and consequently, the results may lack generalizability.[2] Second, due to the complexity and severity of the underlying condition, cardiac surgical patients are commonly co-exposed to multiple nephrotoxic drugs such as NSAIDs, aminoglycosides, and loop-acting diuretics (contrast media also traditionally have been considered nephrotoxic, but recent studies have questioned their independent role, creating a cloud of doubt over it), each independently associated with perioperative renal damage. Even though there was an attempt to make statistical adjustments, the possibility of residual confounding would remain, consistent with perioperative nephrology literature that single-agent analyses might oversimplify the multifaceted and complex pathophysiology of AKI.[3] Lastly, the description of the safety results of the included studies was generally heterogeneous or incomplete. Systematic indication of hepatic events, transaminase increases, and systemic hemodynamic events related to IV acetaminophen was infrequent. Such underreporting is an issue, as incomplete harm data could result in a misleading report of safety.[4] Collectively, these considerations indicate that although the results of Ciconini et al.[1] are speculative, they should be taken in context. Mitigation of such limitations in future trials, with standardized dosing regimens, robust adjustment for nephrotoxic exposure, etc., would have increased the evidence supporting acetaminophen as a reno-protective intervention. Author contributions SZ: Conceptualization, manuscript writing and editing. MI and MR: Conceptualization and manuscript writing. Financial support and sponsorship Nil. Conflict of interest No conflict of interest.