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.
Preterm infants with definite or probable sepsis and fluid-refractory, catecholamine-resistant septic shock will be eligible for enrolment if they have no contraindication to receive MB. After obtaining parental consent, they will be stratified as per the first-line catecholamine used and randomly allocated to receive MB (bolus followed by infusion) or no MB for 24 hours. They will be observed for all-cause mortality (primary outcome), cause-specific mortality, time to achieve hemodynamic stability and adverse effects (secondary outcomes) over a 7-day period, all-cause mortality and cause-specific mortality hospital stay and duration of hospital stay. The main questions it aims to answer are 1. To determine whether treatment with intravenous MB therapy reduces all-cause mortality when compared to no MB treatment, among preterm neonates with catecholamine-resistant septic shock 2. To compare the time to achieve therapeutic endpoints among preterm neonates with catecholamine-resistant septic shock treated with intravenous MB versus no MB 3. To compare time to stoppage of all inotrope/vasopressor treatment among preterm neonates with catecholamine-resistant septic shock treated with intravenous MB versus no MB 4. To compare echocardiographic parameters (at 24 hours after randomization) among preterm neonates with catecholamine-resistant septic shock treated with intravenous MB versus no MB
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
130
Subjects 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.
Subjects in the placebo arm will receive normal saline in the same volumetric dose as methylene blue in the intervention arm
Post Graduate Institute of Medical Education and Research (PGIMER)
Chandigarh, India
All-cause mortality within 7 days after randomization
Mortality due to any cause over 7 days after randomization
Time frame: 7 days
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 frame: 7 days
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
Time frame: 7 days
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.
Time frame: 24 hour
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
Time frame: 24 hour
Left ventricular end-systolic diameter (LVESD) by echocardiography at 24 hour after randomization
Left ventricular end-systolic diameter (LVESD) will be measured in millimeters by echocardiography at 24 hour after randomization
Time frame: 24 hour
Aortic diameter by echocardiography at 24 hour after randomization
Aortic diameter will be measured in millimeters by echocardiography at 24 hour after randomization
Time frame: 24 hour
Velocity time integral (LVI) by echocardiography at 24 hours after randomization
Velocity time integral (LVI) will be measured in centimeters by echocardiography at 24 hours after randomization to calculate the cardiac output.
Time frame: 24 hour
Echocardiographic fractional shortening at 48 hour after randomization
Fractional shortening will be calculated on echocardiography by measuring the percentage change in the left ventricular diameter during systole at 48 hours after randomization.
Time frame: 48 hour
Left ventricular end-diastolic diameter (LVEDD) on echocardiography at 48 hour after randomization
Left ventricular end-diastolic diameter (LVEDD) will be measured in millimeters by echocardiography at 48 hour after randomization
Time frame: 48 hour
Left ventricular end-systolic diameter (LVESD) by echocardiography at 48 hour after randomization
Left ventricular end-systolic diameter (LVESD) will be measured in millimeters by echocardiography at 48 hour after randomization
Time frame: 48 hour
Aortic diameter by echocardiography at 48 hour after randomization
Aortic diameter will be measured in millimeters by echocardiography at 48 hour after randomization
Time frame: 48 hour
Velocity time integral (LVI) by echocardiography at 48 hours after randomization
Velocity time integral (LVI) be measured by echocardiography in centimeters at 48 hours after randomization to calculate the cardiac output.
Time frame: 48 hour
Time taken to stop vasopressor treatment
Time taken to stop all vasopressors during hospital stay up to a maximum of 100 days
Time frame: 100 days
Mortality during hospital stay
Mortality during the period of hospital stay up to a maximum of 100 days
Time frame: 100 days
Serious adverse effects
Serious adverse effect with special reference to oliguria, gastrointestinal bleeds, abdominal distension, and bluish discoloration of skin and urine during hospital stay up to a maximum of 100 days
Time frame: 100 days
Septic shock-related mortality
Mortality attributed to septic shock up to 7 days post-randomisation
Time frame: 7 days
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