Preterm infants (born at less than 37 weeks of pregnancy) sometimes develop a serious blood infection leading to low blood pressure, which does not respond to saline or to the standard medicines for increasing blood pressure, such as dopamine and epinephrine. The goal of this research study is to compare the effect of giving an injectable medicine called Methylene blue (MB) versus not giving MB to such preterm infants who are unresponsive to standard treatment. The main questions that this study aims to answer is:
1. Whether MB treatment reduces death to any cause as compared to no MB treatment. 2. Whether treatment with MB reduces the time to achieve normal blood pressure 3. Whether treatment with MB reduces the time to stoppage of all blood pressure medications, steroids and normal saline. 4. Whether treatment with MB improves heart function as measured by echocardiography at 24 and 48 hours.
Definite/probable sepsis :Clinical syndrome of sepsis for which bedside neonatologist starts intravenous antibiotics AND either a positive culture of otherwise sterile body fluid OR presence of any 2 or more of the following five markers of sepsis: (a) C-reactive protein >10 mg/dL; (b) procalcitonin as per age-appropriate cut-off (c) total leukocyte count and absolute neutrophilic count beyond acceptable range (d) chest X-ray adjudged as pneumonia by two independent Neonatologists.
Shock: adapted from the definition given by Davis et al 2017
Either SBP < age and gestation appropriate cut-off OR
Presence of any 2 of the following 6 parameters i. HR >205/min ii. Central pulses either week OR bounding iii. CRT >3 sec OR flash refill (<1 sec) iv. skin mottled/cool OR flushed v. urine output <0.5 ml/kg/h in the preceding 6 hours vi. DBP < age and gestation appropriate cut-off
G6PD deficient or family history of G6PD deficiency
Potentially lethal malformation
Congenital heart disease
Severe acute kidney injury
Parallel
Methylene Blue
DrugSubjects in the intervention arm will receive a 1 mg/kg bolus of methylene blue over 30 minutes, followed by an infusion of 0.15 mg/kg/h. The infusion rate may be increased in steps of 0.15 mg/kg/h every 30 minutes until a maximum of 0.5 mg/kg/h.
Placebo
Other interventionSubjects in the placebo arm will receive normal saline in the same volumetric dose as methylene blue in the intervention arm
All-cause mortality within 7 days after randomization
Mortality due to any cause over 7 days after randomization
Time taken to achieve therapeutic end-points within 7 days after randomization
Time taken to achieve therapeutic end points of shock (which include capillary refill time less than 3 seconds, normal volume pulses, warm extremities, urine output greater than 1 ml/kg/h, normal sensorium, normal mean blood pressure, normal systolic blood pressure and normal diastolic blood pressure) up to 7 days after randomization.
Time taken to stop all inotrope/vasopressor treatment within 7 days after randomisation
Time taken for all inotrope and vasopressor therapy to finally stop up to a maximum of 7 days after randomisation
Echocardiographic fractional shortening at 24 hour after randomization
Fractional shortening will be calculated on echocardiography by measuring the percentage change in the left ventricular diameter during systole at 24 hours after randomization.
Left ventricular end-diastolic diameter (LVEDD) by echocardiography at 24 hour after randomization
Left ventricular end-diastolic diameter (LVEDD) will be measured in millimetres by echocardiography at 24 hour after randomization
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