Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis

doi:10.1097/CCE.0000000000001110

Meta-Analysis

. 2024 Jun 21;6(7):e1110.

doi: 10.1097/CCE.0000000000001110. eCollection 2024 Jul 1.

Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis

Shannon M Fernando^{1

2}, Alexandre Tran^{2

3

4}, Karim Soliman^{1

5}, Barbara Flynn¹, Thomas Oommen¹, Li Wenzhe⁶, Neill K J Adhikari^{1

2

3

4

5

6

7

8

9

10

11

12

13}, Salmaan Kanji^{2

3}, Andrew J E Seely^{2

3

4}, Alison E Fox-Robichaud¹⁰, Randy S Wax^{1

5}, Deborah J Cook^{10

11}, François Lamontagne^{12

13}, Bram Rochwerg^{10

11}

Affiliations

¹ Department of Critical Care, Lakeridge Health Corporation, Oshawa, ON, Canada.
² Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
³ Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁴ Department of Surgery, University of Ottawa, Ottawa, ON, Canada.
⁵ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
⁶ Department of Critical Care Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
⁷ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁹ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹⁰ Department of Medicine, Division of Critical Care, McMaster University, Hamilton, ON, Canada.
¹¹ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
¹² Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹³ Centre de Recherche du CHU de Sherbrooke, Sherbrooke, QC, Canada.

PMID: 38904978
PMCID: PMC11196076
DOI: 10.1097/CCE.0000000000001110

Meta-Analysis

Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis

Shannon M Fernando et al. Crit Care Explor. 2024.

. 2024 Jun 21;6(7):e1110.

doi: 10.1097/CCE.0000000000001110. eCollection 2024 Jul 1.

Authors

Affiliations

¹ Department of Critical Care, Lakeridge Health Corporation, Oshawa, ON, Canada.
² Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
³ Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁴ Department of Surgery, University of Ottawa, Ottawa, ON, Canada.
⁵ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
⁶ Department of Critical Care Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
⁷ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁹ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹⁰ Department of Medicine, Division of Critical Care, McMaster University, Hamilton, ON, Canada.
¹¹ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
¹² Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹³ Centre de Recherche du CHU de Sherbrooke, Sherbrooke, QC, Canada.

PMID: 38904978
PMCID: PMC11196076
DOI: 10.1097/CCE.0000000000001110

Abstract

Objectives: Although clinicians may use methylene blue (MB) in refractory septic shock, the effect of MB on patient-important outcomes remains uncertain. We conducted a systematic review and meta-analysis to investigate the benefits and harms of MB administration in patients with septic shock.

Data sources: We searched six databases (including PubMed, Embase, and Medline) from inception to January 10, 2024.

Study selection: We included randomized clinical trials (RCTs) of critically ill adults comparing MB with placebo or usual care without MB administration.

Data extraction: Two reviewers performed screening, full-text review, and data extraction. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool, and used Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates.

Data synthesis: We included six RCTs (302 patients). Compared with placebo or no MB administration, MB may reduce short-term mortality (RR [risk ratio] 0.66 [95% CI, 0.47-0.94], low certainty) and hospital length of stay (mean difference [MD] -2.1 d [95% CI, -1.4 to -2.8], low certainty). MB may also reduce duration of vasopressors (MD -31.1 hr [95% CI, -16.5 to -45.6], low certainty), and increase mean arterial pressure at 6 hours (MD 10.2 mm Hg [95% CI, 6.1-14.2], low certainty) compared with no MB administration. The effect of MB on serum methemoglobin concentration was uncertain (MD 0.9% [95% CI, -0.2% to 2.0%], very low certainty). We did not find any differences in adverse events.

Conclusions: Among critically ill adults with septic shock, based on low-certainty evidence, MB may reduce short-term mortality, duration of vasopressors, and hospital length of stay, with no evidence of increased adverse events. Rigorous randomized trials evaluating the efficacy of MB in septic shock are needed.

Registration: Center for Open Science (https://osf.io/hpy4j).

PubMed Disclaimer

Conflict of interest statement

Dr. Seely holds patents related to multiorgan variability analysis and has shares in Therapeutic Monitoring Systems. Dr. Cook is supported by a Canada Research Chair in Critical Care Knowledge Translation. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

**Figure 1.**
Flowchart summarizing evidence search and study selection.

**Figure 2.**
*Forest plots* depicting the efficacy of methylene blue versus placebo or usual care.

See this image and copyright information in PMC

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References

1. Singer M, Deutschman CS, Seymour CW, et al. : The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801–810 - PMC - PubMed
1. Rudd KE, Johnson SC, Agesa KM, et al. : Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 2020; 395:200–211 - PMC - PubMed
1. Evans L, Rhodes A, Alhazzani W, et al. : Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47:1181–1247 - PMC - PubMed
1. McIntyre WF, Um KJ, Alhazzani W, et al. : Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock: A systematic review and meta-analysis. JAMA 2018; 319:1889–1900 - PMC - PubMed
1. Sacha GL, Lam SW, Wang L, et al. : Association of catecholamine dose, lactate, and shock duration at vasopressin initiation with mortality in patients with septic shock. Crit Care Med 2022; 50:614–623 - PubMed

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[1] Singer M, Deutschman CS, Seymour CW, et al. : The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801–810 - PMC - PubMed

[2] Singer M, Deutschman CS, Seymour CW, et al. : The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801–810 - PMC - PubMed

[3] Rudd KE, Johnson SC, Agesa KM, et al. : Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 2020; 395:200–211 - PMC - PubMed

[4] Rudd KE, Johnson SC, Agesa KM, et al. : Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 2020; 395:200–211 - PMC - PubMed

[5] Evans L, Rhodes A, Alhazzani W, et al. : Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47:1181–1247 - PMC - PubMed

[6] Evans L, Rhodes A, Alhazzani W, et al. : Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47:1181–1247 - PMC - PubMed

[7] McIntyre WF, Um KJ, Alhazzani W, et al. : Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock: A systematic review and meta-analysis. JAMA 2018; 319:1889–1900 - PMC - PubMed

[8] McIntyre WF, Um KJ, Alhazzani W, et al. : Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock: A systematic review and meta-analysis. JAMA 2018; 319:1889–1900 - PMC - PubMed

[9] Sacha GL, Lam SW, Wang L, et al. : Association of catecholamine dose, lactate, and shock duration at vasopressin initiation with mortality in patients with septic shock. Crit Care Med 2022; 50:614–623 - PubMed

[10] Sacha GL, Lam SW, Wang L, et al. : Association of catecholamine dose, lactate, and shock duration at vasopressin initiation with mortality in patients with septic shock. Crit Care Med 2022; 50:614–623 - PubMed

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Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis

Affiliations

Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis

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Conflict of interest statement

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