Intravenous Methylene Blue for Treating Refractory Neonatal Septic Shock

March 5, 2024 updated by: Sourabh Dutta, Post Graduate Institute of Medical Education and Research, Chandigarh

Intravenous Methylene Blue for Treating Fluid-refractory, Catecholamine-resistant, Neonatal Septic Shock: a Randomized, Placebo-controlled, Superiority Trial

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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

Study Type

Interventional

Enrollment (Estimated)

130

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • India
      • Chandigarh, India, 160012
        • Post Graduate Institute of Medical Education and Research (PGIMER)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Methylene 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.
Drug: Methylene 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.
Other Names:
  • MB
Placebo Comparator: Placebo infusion
Subjects in the control arm will receive a placebo infusion (normal saline) at the same volumetric rate.
Other: Placebo
Subjects in the placebo arm will receive normal saline in the same volumetric dose as methylene blue in the intervention arm
Other Names:
  • Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause mortality within 7 days after randomization
Time Frame: 7 days
Mortality due to any cause over 7 days after randomization
7 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time taken to achieve therapeutic end-points within 7 days after randomization
Time Frame: 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.
7 days
Time taken to stop all inotrope/vasopressor treatment within 7 days after randomisation
Time Frame: 7 days
Time taken for all inotrope and vasopressor therapy to finally stop up to a maximum of 7 days after randomisation
7 days
Echocardiographic fractional shortening at 24 hour after randomization
Time Frame: 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.
24 hour
Left ventricular end-diastolic diameter (LVEDD) by echocardiography at 24 hour after randomization
Time Frame: 24 hour
Left ventricular end-diastolic diameter (LVEDD) will be measured in millimetres by echocardiography at 24 hour after randomization
24 hour
Left ventricular end-systolic diameter (LVESD) by echocardiography at 24 hour after randomization
Time Frame: 24 hour
Left ventricular end-systolic diameter (LVESD) will be measured in millimeters by echocardiography at 24 hour after randomization
24 hour
Aortic diameter by echocardiography at 24 hour after randomization
Time Frame: 24 hour
Aortic diameter will be measured in millimeters by echocardiography at 24 hour after randomization
24 hour
Velocity time integral (LVI) by echocardiography at 24 hours after randomization
Time Frame: 24 hour
Velocity time integral (LVI) will be measured in centimeters by echocardiography at 24 hours after randomization to calculate the cardiac output.
24 hour
Echocardiographic fractional shortening at 48 hour after randomization
Time Frame: 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.
48 hour
Left ventricular end-diastolic diameter (LVEDD) on echocardiography at 48 hour after randomization
Time Frame: 48 hour
Left ventricular end-diastolic diameter (LVEDD) will be measured in millimeters by echocardiography at 48 hour after randomization
48 hour
Left ventricular end-systolic diameter (LVESD) by echocardiography at 48 hour after randomization
Time Frame: 48 hour
Left ventricular end-systolic diameter (LVESD) will be measured in millimeters by echocardiography at 48 hour after randomization
48 hour
Aortic diameter by echocardiography at 48 hour after randomization
Time Frame: 48 hour
Aortic diameter will be measured in millimeters by echocardiography at 48 hour after randomization
48 hour
Velocity time integral (LVI) by echocardiography at 48 hours after randomization
Time Frame: 48 hour
Velocity time integral (LVI) be measured by echocardiography in centimeters at 48 hours after randomization to calculate the cardiac output.
48 hour
Time taken to stop vasopressor treatment
Time Frame: 100 days
Time taken to stop all vasopressors during hospital stay up to a maximum of 100 days
100 days
Mortality during hospital stay
Time Frame: 100 days
Mortality during the period of hospital stay up to a maximum of 100 days
100 days
Serious adverse effects
Time Frame: 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
100 days
Septic shock-related mortality
Time Frame: 7 days
Mortality attributed to septic shock up to 7 days post-randomisation
7 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Post Graduate Institute of Medical Education and Research, Chandigarh

Investigators

  • Principal Investigator: Sourabh Dutta, MD, PhD, Postgraduate Institute of Medical Education and Research

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 15, 2024

Primary Completion (Estimated)

March 14, 2026

Study Completion (Estimated)

February 1, 2027

Study Registration Dates

First Submitted

February 20, 2024

First Submitted That Met QC Criteria

March 5, 2024

First Posted (Actual)

March 12, 2024

Study Record Updates

Last Update Posted (Actual)

March 12, 2024

Last Update Submitted That Met QC Criteria

March 5, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IIRP-2023-1820/F1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymized, individual patient data pertaining to publications from the study which are in the public domain will be shared with other researchers planning to conduct a study, upon reasonable written request

IPD Sharing Time Frame

Data will be made available one year after the publication from the study for a period of 3 years

IPD Sharing Access Criteria

To be decided

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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