Neonatal Sepsis, Shock, Septic
Conditions
Keywords
Methylene blue, Neonate, Septic shock, Clinical trial
Brief summary
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.
Detailed description
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
Interventions
DRUGMethylene Blue
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.
OTHERPlacebo
Subjects in the placebo arm will receive normal saline in the same volumetric dose as methylene blue in the intervention arm
Sponsors
Post Graduate Institute of Medical Education and Research, Chandigarh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Masking description
The random allocation will be concealed using serially numbered opaque sealed envelopes. After opening the envelope, a research nurse will administer a bolus of the study drug or placebo behind a screen, shielded from other staff. The infusion will be drawn up in an opaque syringe by the research nurse and infused through an intravenous tubing covered completely with aluminum foil. The research nurses will not be masked to the study drug. The parents of the subject, the regular staff nurses and doctors working in the unit and the project coordinator will be masked.
Intervention model description
Subjects will be randomly allocated to an intervention arm and a placebo arm. The 2 arms of the trial will run concurrently.
Eligibility
Sex/Gender
ALL
Age
0 Days to 28 Days
Healthy volunteers
No
Inclusion criteria
Screening Criteria: preterm infants (\<37 weeks, \<28 days) clinically diagnosed to have septic shock will be screened for inclusion Inclusion criteria: Subjects must fulfill all the following 1. 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. 2. Shock: adapted from the definition given by Davis et al 2017 1. Either SBP \< age and gestation appropriate cut-off OR 2. 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 3. Fluid and catecholamine-resistant shock: received fluid boluses up to a maximum of 40 ml/kg followed by catecholamine infusion titrated up to the maximum dose. The catecholamine infusion could be either dopamine (maximum dose 20 µg/kg/min) or epinephrine (maximum dose 0.4 µg/kg/min) or norepinephrine (maximum dose 0.4 µg/kg/min).
Exclusion criteria
excluded if ≥1 criterion positive: 1. G6PD deficient or family history of G6PD deficiency 2. Potentially lethal malformation 3. Congenital heart disease 4. Severe acute kidney injury 5. Family history of allergy to methylene blue or food dyes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality within 7 days after randomization | 7 days | Mortality due to any cause over 7 days after randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time taken to stop all inotrope/vasopressor treatment within 7 days after randomisation | 7 days | 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 | 24 hour | 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 | 24 hour | Left ventricular end-diastolic diameter (LVEDD) will be measured in millimetres by echocardiography at 24 hour after randomization |
| Left ventricular end-systolic diameter (LVESD) by echocardiography at 24 hour after randomization | 24 hour | Left ventricular end-systolic diameter (LVESD) will be measured in millimeters by echocardiography at 24 hour after randomization |
| Aortic diameter by echocardiography at 24 hour after randomization | 24 hour | Aortic diameter will be measured in millimeters by echocardiography at 24 hour after randomization |
| Velocity time integral (LVI) by echocardiography at 24 hours after randomization | 24 hour | Velocity time integral (LVI) will be measured in centimeters by echocardiography at 24 hours after randomization to calculate the cardiac output. |
| Echocardiographic fractional shortening at 48 hour after randomization | 48 hour | 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 taken to achieve therapeutic end-points within 7 days after randomization | 7 days | 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. |
| Left ventricular end-systolic diameter (LVESD) by echocardiography at 48 hour after randomization | 48 hour | Left ventricular end-systolic diameter (LVESD) will be measured in millimeters by echocardiography at 48 hour after randomization |
| Aortic diameter by echocardiography at 48 hour after randomization | 48 hour | Aortic diameter will be measured in millimeters by echocardiography at 48 hour after randomization |
| Velocity time integral (LVI) by echocardiography at 48 hours after randomization | 48 hour | Velocity time integral (LVI) be measured by echocardiography in centimeters at 48 hours after randomization to calculate the cardiac output. |
| Time taken to stop vasopressor treatment | 100 days | Time taken to stop all vasopressors during hospital stay up to a maximum of 100 days |
| Mortality during hospital stay | 100 days | Mortality during the period of hospital stay up to a maximum of 100 days |
| Serious adverse effects | 100 days | 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 |
| Septic shock-related mortality | 7 days | Mortality attributed to septic shock up to 7 days post-randomisation |
| Left ventricular end-diastolic diameter (LVEDD) on echocardiography at 48 hour after randomization | 48 hour | Left ventricular end-diastolic diameter (LVEDD) will be measured in millimeters by echocardiography at 48 hour after randomization |
Countries
India
Contacts
Primary ContactSourabh Dutta, MD, PhD
Backup ContactSajan Saini, MD, DM
Outcome results
None listed