EFFECT OF EARLY USE OF METHYLENE BLUE AND VASOPRESSIN ON THE DOSE OF NORADRENALINE FOR MANAGEMENT OF SEPTIC SHOCK:A RANDOMIZED CONTROL STUDY

HYPOTHESIS

In adult patients with septic shock does methylene blue compared to vasopressin reduces noradrenaline requirement and increase blood pressure?

4. AIMS AND OBJECTIVES:

Dose estimation of Noradrenaline in micrograms/Kg/min after 6, 12 and  24 hours of starting the methylene blue/vasopressin infusion to maintain a Mean Arterial Pressure above 65 mm of Hg.

To measure the change in Serum Lactate levels after 6, 12 and 24 hours of starting the vasopressor infusion.

To evaluate the change in SOFA score after 6, 12 and 24  hours of starting the vasopressor infusion.

To observe the change in SOFA score at the time of discharge from ICU.

Primary outcome

To study the dose of Norepinephrine required to achieve target MAP(65-70mm of Hg) after 6,12and 24  hours of starting the infusion.

Secondary outcome

Duration of vasopressor requirement.

Changes in lactate level at 6,12 and 24 hours after starting the infusion.

Urine output in ml per hour at 6,12 and 24 hours after starting of infusion.

Mortality during the ICU stay after starting Methylene blue or Vasopressin.

Changes in the Sequential Organ Failure Assessment (SOFA) score after 6,12 and 24  hours of starting vasopressor infusion.

5. MATERIAL AND METHODS

Study setting: Department of Anaesthesiology and Critical Care, AIIMS, Jodhpur

Study design: Prospective, Open Label, Randomized Control single blinded Study.

The study will be carried out after approval from Institutional Ethics Committee and relative’s informed consent. The participants will be recruited and randomized with the help of computer generated random number method. The group allocation numbers will be concealed in a sealed opaque envelopes that will be opened just before starting the vasopressor. Once the noradrenaline requirement is more than 0.2 mcg/kg/min -Group 1 will receive  of methylene blue 1mg/kg bolus over 30 minutes followed by 0.5mg/kg infusion over 6 hours. Group 2 will receive vasopressin 0.04 units/kg/min for 6 hours.

If the maximum dose of noradrenaline (3mcg/kg/min) is reached, drug will be considered as failure and will be managed as per the standard ICU guidelines of using multiple vasopressors in Septic shock patients.

Inclusion criteria-

Patients older than 18 years diagnosed with septic shock during their ICU stay whose relatives give informed consent for the study will be considered for enrolment.

Within 24hrs of septic shock

Exclusion criteria-

The following patients will be excluded from the study:

Patients whose relatives refuse to give consent for the study.

Unstable coronary artery syndrome (acute myocardial infarction during this episode of shock based on the combination of history, electrocardiogram and enzyme changes) or underlying cardiac dysfunction [cardiac index (CI) <2.2 l/min/m2]

Stroke or head injury.

Chronic renal failure on maintenance dialysis.

Malignancy or other irreversible disease or condition for which mortality was estimated to be very high (defined by investigator),

Acute mesenteric ischemia either proven or suspected

Raynaud’s phenomenon

Pregnancy

Organ transplantation.

Known hypersensitivity to norepinephrine or methylene blue -G 6PD deficiency.

Parameters to be observed

Dose of Norepinephrine infusion required to maintain a MAP of above 65 mm of Hg.

Mean Arterial Pressure and Heart rate

Serum Lactate levels

Serum Procalcitonin levels

Dose of vasopressor required during the ICU stay

SOFA  score

Serum creatinine levels

Urine output (ml/hr).

.STATISTICAL ANALYSIS AND SAMPLE SIZE

 ElAdawy and Omran have reported a lower dose of norepinephrine in methylene blue group (0.1± 0.1 mg/kg/min ) as compared to that in vasopressin group (0.26±0.15). To detect a 40% decrease in the dose of norepinephrine from the level of 0.26±0.15, we estimate a sample size of 37 subjects in each group at alpha of 0.05, power of 80% and 10% contingency.

 7. ETHICAL CONSIDERATIONS

Informed written consent will be taken from patient’s attendant in English/Hindi language.

They will be given full information about the study & the intervention they are undergoing.

Strict confidentiality about the patient information will be maintained.

 Purpose of trial is to find the effect of early use of methylene blue on the dosage of noradrenaline.

Literature:

Review of literature:

A retrospective analysis by Porizka, M et al 2020,16  assessed 20 critically-ill patients who developed refractory shock. Study subjects  were grouped  into two study groups as responders with positive hemodynamic response to MB administration (defined as 10% decrease of norepinephrine dose) and non-responders. There were 9 (45%) responders and 11 (55%) non-responders to single bolus of MB administration. This study results inferred, MB to have limited effectiveness in subjects with refractory shock.

A retrospective  study by  Bitterman, Y et al,2020, 17 aimed to assess the MB for vasoplegic shock in paediatric  patients admitted to   intensive care unit. This study found favourable hemodynamic response with an increase in blood pressure and a reduction in vasopressor and inotropic support needed following MB administration in six patients. This study shows a small evidence of use of MB in paediatric subjects with distributive shock state.

A systematic review by Warrick, B et al 2016, aimed to evaluate MB in pharmacologically induced shock. The review of few studies showed improved improved hemodynamic status following MB, there are also several cases without observed change.  Hence recommended further research of MB in refractory pharmacologically induced shock.

A single blinded randomised controlled trial  by ElAdawy, 2016,18  aimed to compare the effect of methylene blue (MB) in the vasoplegic situation associated with sepsis with that of vasopressin. A total of  40 patients were randomised  into two groups (20 patients each); patients in the first group received MB, whereas patients in the second group received vasopressin as a hemodynamic support. This study found the mean arterial blood pressure to be significantly higher in the MB group compared with the vasopressin group, whereas within the MB group, it was significantly higher after 6 h compared with the baseline level. The systemic vascular resistance showed no difference between the two groups at the start but a marked difference only after 2 h, being higher for the MB group â€” that is, there was a significant decrease in the vasopressors and inotropes needed in the MB group. The use of MB in sepsis-induced refractory vasoplegic situations remains one of the rescue management strategies.

A systematic review by Paciullo, C et al 2010,19 aimed to evaluate the safety and efficacy of methylene blue for the treatment of septic shock. Observational studies with methylene blue have found beneficial effects on hemodynamic parameters and oxygen delivery, but use of methylene blue may be limited by adverse pulmonary effects. Methylene blue found to increase the mean arterial pressure while dropping catecholamine requirements in subjects suffering septic shock; however, its effects on morbidity and mortality remain unknown.