Norepinephrine formulation itself does not constitute heterogeneity in shock trials

Critical Care Wieruszewski and Bauer Critical Care (2025) 29:439 https://doi.org/10.1186/s13054-025-05720-0 Open Access M AT T E R S A R I S I N G Norepinephrine formulation itself does not constitute heterogeneity in shock trials Patrick M. Wieruszewski1,2* and Seth R. Bauer3,4 We read with great interest the recent systematic review by McDonald et al. in which they evaluate the available clinical trial evidence regarding the impact of vasopressor selection on renal outcomes in septic shock and provide guidance for the future of trial design in this arena [1]. We agree with the authors that norepinephrine salt formulations are an important issue in shock research, but for different reasons. Specifically, we would like to comment on their statements that “the type of formulation can impact the actual effect of norepinephrine” and that this “represents an important cause of heterogeneity” to bring clarity to the issue. The issue surrounding norepinephrine salt formulations has garnered significant interest over the last four years [2]. Central to this issue is the physiochemical necessity for norepinephrine to be processed into a conjugated salt preparation, without which, intravenous administration to humans would be physically impossible [3]. Hence, several different preparations of norepinephrine (including tartrate, bitartrate, and hydrochloride salts) are available for clinical use worldwide [4]. Importantly, the salt components of these products are biologically inactive ingredients, thus regardless of which formulation is used, the pharmacological activity of molecular norepinephrine (and by extension, its vasoconstrictive potency) is the exact same across all products [5]. Simply put, the formulation of norepinephrine used has no impact on its clinical effect. This comment refers to the article available online at https://doi.org/ 10.1186/s13054-025-05573-7. *Correspondence: Patrick M. Wieruszewski Of the 17 randomized trials McDonald et al. identified, they found just one reported which formulation of norepinephrine was used in the trial [6]. However, that report simply stated the product used in the trial was norepinephrine bitartrate. This leaves the very important detail of how the trial reported norepinephrine doses to be ambiguous. The manner in which norepinephrine doses are reported is what contributes to heterogeneity between studies and obscures evidence interpretation, not the description of the formulation utilized [7]. Indeed, an official statement from the European Society of Intensive Care Medicine and Society of Critical Care Medicine recommended reporting all norepinephrine doses in research publications in its base form (molecular norepinephrine), regardless of which salt formulation is used [8]. Taken altogether, while many different norepinephrine formulations are available for use across the world, they all contain the same pharmaceutically active norepinephrine molecule and thus exert the same clinical effect. The specific formulation that is used is less important, and rather, emphasis must be placed on how norepinephrine doses are reported. Clarity surrounding how issues related to norepinephrine salt formulations are discussed is critical for the future of trial design, evidence interpretation and synthesis, and application of research findings to patient care. 1 Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA 2 Department of Pharmacy, Mayo Clinic, Rochester, MN, USA 3 Department of Pharmacy, Cleveland Clinic, Cleveland, OH, USA 4 Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Wieruszewski and Bauer Critical Care (2025) 29:439 Page 2 of 2 Acknowledgements Not applicable. Author contributions PMW and SRB conceived the content, drafted the manuscript, and edited the manuscript. All authors read and approved the final version. Funding Supported by the National Institutes of Health, National Institute of General Medical Sciences (SRB: K08GM147806). The funding source had no role in study design; data collection, analysis, or interpretation; writing the report; or the decision to submit the report for publication. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests PMW received consulting fees from Wolters Kluwer/UpToDate and Viatris Inc. SRB reports no potential competing interests. Received: 6 October 2025 / Accepted: 11 October 2025 References 1. McDonald R, Burns M, Wong A, Smith C, Ostermann M, Hutchings S. The effects of vasopressor choice on renal outcomes in septic shock: a systematic 2. 3. 4. 5. 6. 7. 8. review of randomised trials as a guide for future research. Crit Care. 2025;29:417. https://doi.org/10.1186/s13054-025-05573-7. D’Andria Ursoleo J, Bottussi A, Khanna AK, Leone M, Wieruszewski PM, Monaco F. Norepinephrine pharmacolexicology: a chronological review of dose reporting and the implications of salt formulations. Intensive Care Med. 2025;51:1664–73. https://doi.org/10.1007/s00134-025-08053-2. Wieruszewski PM. Norepinephrine dosage: the details go beyond a grain of salt. Intensive Care Med. 2023;49:714–5. https://doi.org/10.1007/s00134-02 3-07077-w. Leone M, Goyer I, Levy B, Dünser MW, Asfar P, Jentzer JC. Dose of norepinephrine: the devil is in the details. Intensive Care Med. 2022;48:638–40. https://do i.org/10.1007/s00134-022-06652-x. Wieruszewski PM, Khanna AK. Norepinephrine salt formulations are not a matter of pharmacologic potency. Intensive Care Med. 2024;50:1179–80. http s://doi.org/10.1007/s00134-024-07451-2. Lauzier F, Levy B, Lamarre P, Lesur O (...truncated)