Skip to main content

Irrespective of the degree of hyperlactatemia, similar lactate levels were associated with a lower mortality rate in metformin users compared with non-users: beware of confounders!

We read with great interest the article by Posma et al. who reported that early lactate levels were strongly associated with mortality and, irrespective of the degree of hyperlactatemia, similar lactate levels were associated with a lower mortality rate in metformin (MET) users compared with MET non-users [1]. We would like to make some comments. In their observational study, MET users were more often treated with mechanical ventilation, inotropes or vasopressors, and between 3 and 20% of patients received renal replacement therapy (RRT) [1]. 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 [2]. This was corroborated by Keller et al. [3] who showed a dramatic reduction of metabolic acidosis and plasma metformin concentrations within the first 24 h after initiating continuous renal replacement therapy (CRRT) in patients with MET-induced lactic acidosis, followed by normalization on the second day in all subjects. The finding that MET users more often require RRT has already been reported in other studies. For instance, in a study by Doenyas-Barak et al. [4], 38.6% of the MET-treated population received RRT, as compared to 21.2% of the cohort of patients not treated with MET. 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 been suggested by Peters et al. [5] who found that despite higher illness severity, the mortality rate in patients with MET-associated lactic acidosis treated with intermittent hemodialysis was no different to that of non-dialyzed subjects. It would be extremely interesting to know the correction rate of MET and lactate after initiation of RRT in the MET group of Posma et al.

Availability of data and materials

Not applicable.

Abbreviations

MET:

Metformin

RRT:

Renal replacement therapy

CRRT:

Continuous renal replacement therapy

References

  1. 1.

    Posma RA, Frøslev T, Jespersen B, et al. Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study. Ann Intensive Care. 2020;10(1):36. https://doi.org/10.1186/s13613-020-00652-0.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Calello DP, Liu KD, Wiegand TJ, et al. Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the Extracorporeal Treatments in Poisoning Workgroup. Crit Care Med. 2015;43:1716–30. https://doi.org/10.1097/CCM.0000000000001002.

    Article  Google Scholar 

  3. 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. https://doi.org/10.1371/journal.pone.0023200.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 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. https://doi.org/10.1186/s13054-015-1180-6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Peters N, Jay N, Barraud D, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care. 2008;12:R149. https://doi.org/10.1186/cc7137.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Melissa Jackson for critical review of the manuscript.

Funding

None.

Author information

Affiliations

Authors

Contributions

PMH, SR, DDB designed the paper. All authors participated in drafting and reviewing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Patrick M. Honore.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Honore, P.M., Barreto Gutierrez, L., Kugener, L. et al. Irrespective of the degree of hyperlactatemia, similar lactate levels were associated with a lower mortality rate in metformin users compared with non-users: beware of confounders!. Ann. Intensive Care 10, 148 (2020). https://doi.org/10.1186/s13613-020-00766-5

Download citation