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Methylene blue as adjunctive therapy in septic shock: correct drug diluent derives optimal efficacy

Matters Arising to this article was published on 05 September 2023

The Original Article was published on 13 March 2023

We read with a great interest, the randomized controlled trial “Early adjunctive methylene blue in patients with septic shock” published by Ibarra-Estrada et al. in Critical care recently [1]. We would like to congratulate all the authors of the study for addressing such an important aspect in critical care and trying to answer the research question by conducting a randomized controlled trial.

The authors have concluded that the use of methylene blue (MB) within 24 h in patients with septic shock reduces the duration of vasopressor use, cumulative fluid balance, hospital and intensive care unit stay without significant adverse events as compared to placebo.

In methodology, authors mentioned that patients assigned to MB group received an intravenous (IV) infusion of 100 mg MB in 500 ml of 0.9% sodium chloride solution [1].

We would like to highlight that since MB is a hypotonic solution with osmolarity of about 10–15 mOsm/kg, dilution with 0.9% sodium chloride solution, could lead to precipitation of MB, as the presence of chloride (Cl) ions reduces the solubility of MB [2,3,4]. Precipitation of a drug in a solution can reduce its therapeutic efficacy due to drug inactivation, can occlude the infusion lines, may cause thrombophlebitis or rarely particulate embolization and multiple organ dysfunction [5].

Therefore, to avoid precipitation of MB in a solution and to improve its clinical efficacy without adversely affecting the patient, we suggest that MB should be diluted in either a sterile water or 5% dextrose solution before intravenous administration.

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  1. Ibarra-Estrada M, Kattan E, Aguilera-González P, Sandoval-Plascencia L, Rico-Jauregui U, Gómez-Partida CA, Ortiz-Macías IX, López-Pulgarín JA, Chávez-Peña Q, Mijangos-Méndez JC, Aguirre-Avalos G, Hernández G. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023;27(1):110.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Methylthioninium chloride 5mg/ml solution for injection. Last accessed on 24 July 2023.

  3. Safety Wires—Don’t dilute ProvayBlue in normal Saline. ISMP Nurse Advise ERR. Vol 15, Issue 5, 2017.

  4. Australian Product Information - Methylene Blue Injection PI V02. Last accessed on 24 July 2023.

  5. Benlabed M, Perez M, Gaudy R, Genay S, Lannoy D, Barthélémy C, Odou P, Lebuffe G, Décaudin B. Clinical implications of intravenous drug incompatibilities in critically ill patients. Anaesth Crit Care Pain Med. 2019;38(2):173–80.

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DD contributed to the conceptualization, supervision and writing—review and editing. PR was involved in writing—original draft and editing. AI assisted in the supervision, writing—review and editing. All authors have read and agreed to publish this version of the manuscript.

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Correspondence to Dilip Dubey.

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Dubey, D., Ray, P. & Imran, A. Methylene blue as adjunctive therapy in septic shock: correct drug diluent derives optimal efficacy. Crit Care 27, 337 (2023).

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