Intravenous Methylene Blue for Treating Refractory Neonatal Septic Shock

Post Graduate Institute of Medical Education and Research, Chandigarh

Status and phase: Not yet enrolling; Phase 3; Phase 2

Conditions: Shock, Septic; Neonatal Sepsis

Treatments: Drug: Methylene Blue; Other: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT06306001

IIRP-2023-1820/F1

Details and patient eligibility

About

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.

Full 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

Enrollment: 130 estimated patients

Sex: All

Ages: Under 28 days old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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130 participants in 2 patient groups, including a placebo group

Methylene blue

Experimental group

Description:

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.

Treatment:

Drug: Methylene Blue

Placebo infusion

Placebo Comparator group

Description:

Subjects in the control arm will receive a placebo infusion (normal saline) at the same volumetric rate.

Treatment:

Other: Placebo