ARTICLE: Ibarra-Estrada M, Kattan E, Aguilera-Gonzalez P, et al. Early adjunctive methylene blue in patients with septic shock: a randomized control trial. Crit Care. 2023;27(1):110.
OBJECTIVE
To assess whether early adjunctive methylene blue reduced time to vasopressor discontinuation in patients with septic shock
BACKGROUND
Methylene blue (MB) is an adjuvant medication used frequently in cardiopulmonary bypass for vasodilatory shock. However, there is not substantial research for its use in septic shock. Surviving Sepsis Campaign guidelines recommend early multimodal treatment for sepsis and initiation of vasopressors for shock to improve organ perfusion.1 Norepinephrine is often the first-choice vasopressor, but high doses increase the risk of adverse tachyarrhythmias, myocardial dysfunction, or peripheral ischemia.2 Additionally, systematic reviews have recognized that higher exposures to catecholamine vasopressors are associated with an increased risk of multi-organ failure and death in septic shock.3 Using multiple agents could offset the deleterious effects of sepsis (e.g., endothelial dysfunction leading to increased vascular permeability) while minimizing the toxicity of individual agents.
MB has the potential to reduce vascular dysregulation through inhibition of inducible nitric oxide (NO) synthase and its cascade of effects, thus restoring vasoregulation in conditions of NO upregulation such as sepsis.4 One small randomized controlled trial (RCT) in the early 2000s showed promising results including that MB counteracts myocardial depression, maintains oxygen transport, and reduces concurrent adrenergic support while having no significant adverse effects on selected organ function variables.5 The authors of this RCT aimed to provide more recent evidence to assess the benefits of early adjunctive MB to reduce vasopressor use in patients with septic shock.
DESIGN
This study was a parallel, double-blinded randomized controlled trial at a MICU in an academic hospital in Mexico from March 2017 through July 2022. Patients with septic shock were randomly assigned to receive MB or placebo in addition to norepinephrine. Patients assigned to the MB group received an IV infusion of 100 mg of MB in 500 mL of 0.9% sodium chloride solution over 6 hours once daily for a total of three doses. Patients assigned to the control group received the same dose of 500 mL of 0.9% sodium chloride without MB.
Both groups received:
- Vasopressin 0.03 IU/min if norepinephrine dose reached ≥ 0.25 mcg/kg/min. It was progressively withdrawn by 0.005 IU/min each hour only after complete discontinuation of norepinephrine
- Hydrocortisone continuous infusion at 200 mg/day. It was withheld within 6 hours after discontinuation of all vasopressors without taper
- Evaluation of volume responsiveness at least 3 times each day as long as vasopressors were needed
INCLUSION CRITERIA
- Age > 18 with septic shock as defined by sepsis-3 criteria:
- Highly suspected or confirmed infection
- Requiring norepinephrine to maintain MAP > 65 mmHg
- Serum lactate > 2 mmol/L after adequate fluid resuscitation
EXCLUSION CRITERIA
- Greater than 24 hours since initiation of norepinephrine
- Pregnancy
- High probability of death within 48 hours
- Concurrent hemorrhagic, obstructive, or hypovolemic shock
- Pending damage control surgery
- Major burn injury
- Personal or familiar history of glucose-6-phosphate dehydrogenase deficiency
- Allergy to methylene blue, phenothiazines, or food dyes
- Recent intake (4-weeks) of SSRIs
- Refusal of the patient or decision maker to participate
- Patients with COVID-19 infection
PRIMARY OUTCOME
Time to vasopressor discontinuation at 28 days, defined as discontinuation of all vasopressors for at least 48 consecutive hours
SECONDARY OUTCOMES
- Vasopressor-free days at 28 days
- All-cause mortality at 28 days
- Serum lactate levels
- Days on mechanical ventilator
- Length of stay in ICU and hospital
- The change in serum creatinine, bilirubin, AST/ALT, PaO2/FiO2 ratio and ejection fraction (EF) after intervention
KEY RESULTS
Ninety-two patients were enrolled with ninety-one included in the analysis: 45 patients assigned to the MB group and 46 to the control group. One patient in the control group died before receiving the 3rd dose with all other patients receiving a complete course of treatment. The median age of patients was 46, 60% were men, 46% presented with AKI, and a majority were placed on mechanical ventilation. The most common sources of sepsis were pulmonary (49.5%) followed by intra-abdominal (38.5%). Baseline characteristics were the same between the two groups. No other vasopressors (e.g., phenylephrine, epinephrine) or inotropes (e.g., milrinone, dobutamine) were used.
Primary outcome
-
The MB group had a shorter time to vasopressor discontinuation vs the control group (69 hours vs 94 hours; p<0.001)
Secondary outcomes
- In comparison to the control group, the MB group had:
- One more day of vasopressor free days at day 28 (p=0.008)
- Lower cumulative fluid balance by 741 mL (p=0.001)
- Shorter ICU length of stay by 1.5 days (p=0.039)
- Shorter hospital length of stay by 2.7 days (p=0.027)
- Lactate levels within the first three days, days on mechanical ventilation, and mortality at 28 days were similar between the two groups
- There were no significant changes in EF, PaO2/FiO2 ratio, serum creatinine, bilirubins and liver aminotransferases between groups
- The most common adverse effect was green-blue discoloration of urine noted in 93% of patients in the MB group. They also had higher maximum methemoglobin saturations (2.9% vs 0.5%, p<0.001) vs the control group, though these levels were still far from the clinically relevant threshold of 10%
LIMITATIONS
- Single-center study
- Since most patients were identified to be in septic shock in other departments prior to admission to the ICU, there were natural delays to initiation of MB which might be more beneficial early in the course of resuscitation
- Exclusion of patients with COVID-19
- Urine discoloration and frequent monitoring of methemoglobin levels made it difficult to maintain blinding
EM TAKE-AWAYS
Methylene blue led to earlier vasopressor discontinuation and shorter ICU and hospital lengths of stay in patients with septic shock in this RCT, though this did not translate to a decrease in mortality. Consider its use early in patients with septic shock who have escalating pressor requirements.
REFERENCES
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017:43(3);304-377.
- Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–247.
- Richards-Belle A, Hylands M, Muttalib F, et al. Lower versus higher exposure to vasopressor therapy in vasodilatory hypotension: a systematic review with meta-analysis. Crit Care Med. 2023;51:254–66.
- Puntillo F, Giglio M, Pasqualucci A, et al. Vasopressor-sparing action of methylene blue in severe sepsis and shock: a narrative review. Adv Ther. 202;37:3692-706.
- Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001;29:1860–7.