Methylene blue Versus Vasopressin as Second Line Vasopressor in Septic Shock- A Randomized Controlled Trial

Adult patients with septic shock requiring norepinephrine support of ≥0.2 µg/kg/min for a minimum of 30 minutes despite fluid resuscitation with a minimum of 20 ml/kg to maintain mean arterial pressure (MAP) ≥65 mm Hg will be randomly allocated into group M or V. Patients randomized to group M will receive a bolus of 1 mg/kg methylene blue over 15 minutes followed by an infusion of 0.25 mg/kg/hr. If there is improvement in MAP and the requirement of norepinephrine is reduced to <0.1 µg/kg/min, methylene blue infusion will be stopped. In case of worsening and norepinephrine requirement increases to > 0.4µg/kg/min, other vasopressors like vasopressin or adrenaline will be started as per ICU physician discretion in addition to methylene blue infusion. Methylene blue infusion will be continued for 96 hours or till the norepinephrine requirement reduces to <0.1 µg/kg/min whichever is earlier.  Patient randomised to group V will receive vasopressin infusion of 0.03 U/kg/hr. If there is improvement in MAP and the requirement of norepinephrine is reduced to <0.1 µg/kg/min, vasopressin infusion will be stopped. In case of worsening and norepinephrine requirement increases to > 0.4µg/kg/min, other vasopressor like adrenaline will be started and vasopressin dose titrated as per ICU physician discretion. Methylene blue or Vasopressin will be continued till the norepinephrine requirement reduces to <0.1 µg/kg/min. Beyond this period, the decision to continue methylene blue will be left to the discretion of the treating intensivist. Methylene blue will be discontinued if patient develops severe impairment in oxygenation (PaO2/FiO2 less than 100 mm Hg), KDIGO stage III acute kidney injury, haemolysis, or in patients in whom symptoms suggestive of serotonin syndrome. Apart from this, methylene blue will be discontinued at any point of time by the treating intensivist if it is felt that methylene blue therapy is harming the patient. Patients, in whom the study drug must be discontinued at any point of time for the above reasons, they will still be considered a part of study and data collection is continued. In case, if consent is withdrawn after enrolment, any intervention related to the study drug will be discontinued, and the patient will be omitted from analysis

The point of enrolment will be taken as time = 0. The following data sets will be recorded at the specified time intervals:

**a)**Enrolment data: Demographic and anthropometric data, ICU severity of illness scores, probable source of sepsis and volume of fluid received in the preceding 24 hours will be recorded at enrolment.

**b)**Organ function data: PaO2/FiO2, serum creatinine, bilirubin andSOFA score will be recorded at the time of enrolment and every 24 hours for 7 days. The average SOFA score will be taken as the primary outcome.

**c)**Hemodynamic data: Heart rate, MAP and vasopressor requirements will be recorded every 6 hours from enrolment up to 96 hours. CVP, cardiac index, SVRI, and fluid intake (sum of enteral and intravenous fluid intake) will be recorded every 12 hours from enrolment up to 96 hours.

d)     Oxygenation and micro-circulatory function data: Haemoglobin, arterial oxygen saturation (SaO2), ScvO2, peripheral oxygen extraction ration (O2ER), base excess (BE) and arterial lactate levels will be recorded every 12 hours from enrolment up to 96 hours

e)     Myocardial performance data: LVEF, E/e’ ratio and TAPSE will be recorded every 12 hours from enrolment up to 96 hours. TnI will be measured at enrolment and at 96 hours.

Patients will be followed up to 30 days after enrolment. Number of days on mechanical ventilation, need for renal replacement therapy, length of ICU stay, duration of survival and serious adverse events – including, but not limited to haemolysis, worsening hypoxemia, acute kidney injury, severe hepatic impairment will be recorded.