We read with great interest the recent paper by Liang et al. who conclude that their meta-analysis indicated an association between metformin (MET) use prior to admission and lower mortality in septic adult patients with diabetes mellitus [1]. We would like to make some comments. Nearly half of critically ill patients, especially those with septic shock, have or develop acute kidney injury (AKI), and 20–25% need renal replacement therapy (RRT) within the first week of their admission [2]. Because of its low molecular weight and minimal protein binding, metformin is equally (highly) eliminated by ultrafiltration (convection) and dialysis (diffusion). Furthermore, its large volume of distribution within a two-compartment pharmacokinetic model implies that metformin may be more effectively cleared by prolonged RRT. This was corroborated by Keller et al., who showed a dramatic reduction of metabolic acidosis and metformin plasma concentrations within the first 24 h after initiating CRRT in patients with MET-induced lactic acidosis, followed by normalization on the second day in all subjects [3]. Although we do not know the exact rate of CRRT in both arms [1], it may well be that one group had more CRRT than the other, particularly the metformin group. For instance, in the study of Doenyas-Barak et al., which had a huge impact on the conclusions of this meta-analysis, the use of RRT was higher in the MET-treated population (38.6 vs. 21.2%, p = 0.13) [1, 4]. Accordingly, we suspect that the observed difference in mortality rate may be due to the more frequent use of RRT in the MET-treated population. A protective effect of RRT has already been suggested by Peters et al., who found that despite higher illness severity, the mortality rate in patients with MET-associated lactic acidosis treated with intermittent hemodialysis (IHD) was no different to that of non-dialyzed subjects [5].
Acknowledgements
We would like to thank Dr. Melissa Jackson for critical review of the manuscript.
Abbreviations
- MET
Metformin
- AKI
Acute kidney injury
- RRT
Renal replacement therapy
- IHD
Intermittent hemodialysis
- CRRT
Continuous renal replacement therapy
Authors’ contributions
PMH, SR, and DDB designed the paper. All authors participated in drafting and reviewing. The authors read and approved the final version of the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare to have no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Patrick M. Honore, Email: Patrick.Honore@CHU-Brugmann.be
Aude Mugisha, Email: Aude.Mugisha@CHU-Brugmann.be.
Luc Kugener, Email: Luc.Kugener@CHU-Brugmann.be.
Sebastien Redant, Email: Sebastien.Redant@CHU-Brugmann.be.
Rachid Attou, Email: Rachid.Attou@CHU-Brugmann.be.
Andrea Gallerani, Email: Andrea.Gallerani@CHU-Brugmann.be.
David De Bels, Email: David.DeBels@CHU-Brugmann.be.
References
- 1.Liang H, Ding X, Li L, Wang T, Kan Q, Wang L, Sun T. Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies. Crit Care. 2019;23(1):50. doi: 10.1186/s13054-019-2346-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit. Crit Care. 2018;22(1):188. doi: 10.1186/s13054-018-2112-z.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Keller G, Cour M, Hernu R, Illinger J, Robert D, Argaud L. Management of metformin-associated lactic acidosis by continuous renal replacement therapy. PLoS One. 2011;6:e23200. doi: 10.1371/journal.pone.0023200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Doenyas-Barak K, Beberashvili I, Marcus R, Efrati S. Lactic acidosis and severe septic shock in metformin users: a cohort study. Crit Care. 2016;20:10. doi: 10.1186/s13054-015-1180-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert PE, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care. 2008;12:R149. doi: 10.1186/cc7137. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Not applicable.