Early Methylene Blue in the Microhemodynamics of Septic Patients

Evaluation of Early Methylene Blue in the Microhemodynamics of Septic Patients: a Feasibility Randomized Controlled Trial

The aim of the study is to evaluate the viability and feasibility of its protocol in order to conduct a larger clinical trial to assess whether methylene blue can improve patient-centered clinical outcomes such as mortality or length of hospital stay in septic shock patients.

One of the primary causes of high mortality in patients with septic shock is microcirculatory dysfunction related to vasodilation caused by excessive oxide nitric production. It has been shown that methylene blue, an old and safe drug that can reduce vasodilation by blocking nitric oxide pathways, is a vasopressor-sparing treatment in sepsis. Nevertheless, there is no evidence that methylene blue improves patient-centered clinical outcomes such as mortality. Understanding how early methylene blue affects the microhemodynamics of septic shock patients may lead to relevant clinical results that can improve their prognosis. So, the objective of the study is to evaluate the viability and feasibility of the study protocol for a larger clinical trial, assessing the effectiveness of early methylene blue in the microhemodynamics of septic shock patients, mainly through the capillary refill time measurement. For this purpose, a pilot study of an open-label, randomized, controlled and single-center clinical trial will be conducted, with two treatment arms: the intervention group (methylene blue plus standard treatment) and the control group (standard treatment). Fifty adult patients with septic shock within the first six hours of diagnosis will be included in this study. They will be randomized to either receive a methylene blue infusion or not. The randomization will be conducted using RedCap with a 1:1 ratio and variable block sizes. The primary outcome will be to assess the feasibility, which is defined as completing the study recruitment within the 12-month timeline and achieving protocol adherence of 90% or higher. Comparisons between groups for serially measured micro and macrohemodynamics parameters will be the secondary outcomes. Additionally, the incidence of adverse events related to methylene blue will be monitored.

Inclusion Criteria:

• Adult patients with a diagnosis of sepsis and persistent hemodynamic dysfunction despite adequate fluid resuscitation, requiring escalation of noradrenaline dose to maintain mean arterial pressure ≥65 mmHg, with prolonged capillary refill time or septic shock according to Sepsis-3 definition, within less than 6 hours of the diagnosis, will be eligible for the study.

Exclusion Criteria:

• Pregnant or breastfeeding patients;
• Patients with any withdrawal or withholding life-sustaining intervention;
• Cardiac surgery patients in the immediate postoperative period;
• Refractory septic shock, with a high propability of death within 24 hours;
• Personal or familiar history of glucose-6-phosphate dehydrogenase (G6PD) deficiency;
• Allergy to methylene blue, phenothiazines, or food dyes;
• Recent administration of linezolid (less than 14 days ago);
• Recent intake of serotonergic psychiatric medications (less than 2 weeks ago - with the exception of fluoxetine, which must be less than 5 weeks ago),
• Recent intake (less than 2 weeks ago) of monoamine oxidase inhibitors (MAOIs), such as rasagiline and selegiline.