Intravenous Methylene Blue for Treating Refractory Neonatal Septic Shock

Official title

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

Overview

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

• 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 Placebo
  Subjects in the placebo arm will receive normal saline in the same volumetric dose as methylene blue in the intervention arm

Primary outcome measures

• All-cause mortality within 7 days after randomization [Time frame: 7 days]

Secondary outcome measures (12)

• Time taken to achieve therapeutic end-points within 7 days after randomization [Time frame: 7 days]
• Time taken to stop all inotrope/vasopressor treatment within 7 days after randomisation [Time frame: 7 days]
• Echocardiographic fractional shortening at 24 hour after randomization [Time frame: 24 hour]
• Left ventricular end-diastolic diameter (LVEDD) by echocardiography at 24 hour after randomization [Time frame: 24 hour]
• Left ventricular end-systolic diameter (LVESD) by echocardiography at 24 hour after randomization [Time frame: 24 hour]
• Aortic diameter by echocardiography at 24 hour after randomization [Time frame: 24 hour]
• Velocity time integral (LVI) by echocardiography at 24 hours after randomization [Time frame: 24 hour]
• Echocardiographic fractional shortening at 48 hour after randomization [Time frame: 48 hour]
• Left ventricular end-diastolic diameter (LVEDD) on echocardiography at 48 hour after randomization [Time frame: 48 hour]
• Left ventricular end-systolic diameter (LVESD) by echocardiography at 48 hour after randomization [Time frame: 48 hour]
• Aortic diameter by echocardiography at 48 hour after randomization [Time frame: 48 hour]
• Velocity time integral (LVI) by echocardiography at 48 hours after randomization [Time frame: 48 hour]

Eligibility 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

• 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
• 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:

• G6PD deficient or family history of G6PD deficiency
• Potentially lethal malformation
• Congenital heart disease
• Severe acute kidney injury
• Family history of allergy to methylene blue or food dyes

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

India · 1 center

• Post Graduate Institute of Medical Education and Research (PGIMER) — Chandigarh

Publications

• Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. doi: 10.1056/NEJMra021333. No abstract available. PMID 12519925
• Stolk RF, Kox M, Pickkers P. Noradrenaline drives immunosuppression in sepsis: clinical consequences. Intensive Care Med. 2020 Jun;46(6):1246-1248. doi: 10.1007/s00134-020-06025-2. Epub 2020 Apr 8. No abstract available. PMID 32270211
• Stolk RF, van der Pasch E, Naumann F, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth MM, van der Hoeven JG, van Leeuwen H, Pickkers P, Kox M. Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis. Am J Respir Crit Care Med. 2020 Sep 15;202(6):830-842. doi: 10.1164/rccm.202002-0339OC. PMID 32520577
• Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004 Feb;77(2):496-9. doi: 10.1016/S0003-4975(03)01510-8. PMID 14759425
• Ismail R, Awad H, Allam R, Youssef O, Ibrahim M, Shehata B. Methylene blue versus vasopressin analog for refractory septic shock in the preterm neonate: A randomized controlled trial. J Neonatal Perinatal Med. 2022;15(2):265-273. doi: 10.3233/NPM-210824. PMID 34719443
• Otero Luna AV, Johnson R, Funaro M, Canarie MF, Pierce RW. Methylene Blue for Refractory Shock in Children: A Systematic Review and Survey Practice Analysis. Pediatr Crit Care Med. 2020 Jun;21(6):e378-e386. doi: 10.1097/PCC.0000000000002295. PMID 32453920
• Luis-Silva F, Menegueti MG, Sato L, Peres LM, Dos Reis Sepeda C, Petroski-Moraes BC, Donadel MD, Gallo GB, Jordani MC, Mestriner F, Becari C, Basile-Filho A, Evora PRB, Martins-Filho OA, Auxiliadora-Martins M. Effect of methylene blue on hemodynamic response in the early phase of septic shock: A case series. Medicine (Baltimore). 2023 Jan 27;102(4):e32743. doi: 10.1097/MD.0000000000032743. PMID 36705345
• Ibarra-Estrada M, Kattan E, Aguilera-Gonzalez P, Sandoval-Plascencia L, Rico-Jauregui U, Gomez-Partida CA, Ortiz-Macias IX, Lopez-Pulgarin JA, Chavez-Pena Q, Mijangos-Mendez JC, Aguirre-Avalos G, Hernandez G. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023 Mar 13;27(1):110. doi: 10.1186/s13054-023-04397-7. PMID 36915146

Identifiers

NCT: NCT06306001 · IIRP-2023-1820/F1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗