Intravenous Methylene Blue for Treating Refractory Neonatal Septic Shock

NCT06306001 | Not Yet Recruiting Phase 2

• 1 other identifier: IIRP-2023-1820/F1
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 1

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. 1.Whether MB treatment reduces death to any cause as compared to no MB treatment.
2. 2.Whether treatment with MB reduces the time to achieve normal blood pressure
3. 3.Whether treatment with MB reduces the time to stoppage of all blood pressure medications, steroids and normal saline.
4. 4.Whether treatment with MB improves heart function as measured by echocardiography at 24 and 48 hours.

Conditions

Neonatal Sepsis; Shock, Septic

Keywords

Methylene blue; Neonate; Septic shock; Clinical trial

Outcome Measures

Primary Outcomes (1)

• All-cause mortality within 7 days after randomization

  Mortality due to any cause over 7 days after randomization

  7 days

Secondary Outcomes (16)

• Time taken to achieve therapeutic end-points within 7 days after randomization

  7 days

• Time taken to stop all inotrope/vasopressor treatment within 7 days after randomisation

  7 days

• Echocardiographic fractional shortening at 24 hour after randomization

  24 hour

• Left ventricular end-diastolic diameter (LVEDD) by echocardiography at 24 hour after randomization

  24 hour

• Left ventricular end-systolic diameter (LVESD) by echocardiography at 24 hour after randomization

  24 hour

Study Arms (2)

Methylene blue

EXPERIMENTAL

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

Placebo infusion

PLACEBO COMPARATOR

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

Other: Placebo

Interventions

Methylene Blue DRUG

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.

Also known as: MB

Methylene blue

Placebo OTHER

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

Also known as: Normal saline

Placebo infusion

Eligibility Criteria

• Age: 0 Days - 28 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

Post Graduate Institute of Medical Education and Research (PGIMER)

Chandigarh, 160012, India

Location

Related Publications (24)

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care. 2002 Dec;30(6):755-62. doi: 10.1177/0310057X0203000606.

  PMID: 12500513 RESULT

• Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, Nedashkovsky EV, Bjertnaes LJ. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001 Oct;29(10):1860-7. doi: 10.1097/00003246-200110000-00002.

  PMID: 11588440 RESULT

• Zhang X, Gao Y, Pan P, Wang Y, Li W, Yu X. [Methylene blue in the treatment of vasodilatory shock: a Meta-analysis]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2017 Nov;29(11):982-987. doi: 10.3760/cma.j.issn.2095-4352.2017.11.005. Chinese.

  PMID: 29151412 RESULT

• Dumbarton TC, Minor S, Yeung CK, Green R. Prolonged methylene blue infusion in refractory septic shock: a case report. Can J Anaesth. 2011 Apr;58(4):401-5. doi: 10.1007/s12630-011-9458-x. Epub 2011 Jan 19.

  PMID: 21246318 RESULT

• Zhao CC, Zhai YJ, Hu ZJ, Huo Y, Li ZQ, Zhu GJ. Efficacy and safety of methylene blue in patients with vasodilatory shock: A systematic review and meta-analysis. Front Med (Lausanne). 2022 Sep 26;9:950596. doi: 10.3389/fmed.2022.950596. eCollection 2022.

  PMID: 36237547 RESULT

• Fleischmann-Struzek C, Goldfarb DM, Schlattmann P, Schlapbach LJ, Reinhart K, Kissoon N. The global burden of paediatric and neonatal sepsis: a systematic review. Lancet Respir Med. 2018 Mar;6(3):223-230. doi: 10.1016/S2213-2600(18)30063-8.

  PMID: 29508706 RESULT

• Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will This Hemodynamically Unstable Patient Respond to a Bolus of Intravenous Fluids? JAMA. 2016 Sep 27;316(12):1298-309. doi: 10.1001/jama.2016.12310.

  PMID: 27673307 RESULT

• Aya HD, Ster IC, Fletcher N, Grounds RM, Rhodes A, Cecconi M. Pharmacodynamic Analysis of a Fluid Challenge. Crit Care Med. 2016 May;44(5):880-91. doi: 10.1097/CCM.0000000000001517.

  PMID: 26683506 RESULT

• Nandhabalan P, Ioannou N, Meadows C, Wyncoll D. Refractory septic shock: our pragmatic approach. Crit Care. 2018 Sep 19;22(1):215. doi: 10.1186/s13054-018-2144-4.

  PMID: 30231909 RESULT

• Park BK, Shim TS, Lim CM, Lee SD, Kim WS, Kim DS, Kim WD, Koh Y. The effects of methylene blue on hemodynamic parameters and cytokine levels in refractory septic shock. Korean J Intern Med. 2005 Jun;20(2):123-8. doi: 10.3904/kjim.2005.20.2.123.

  PMID: 16134766 RESULT

• Evora PR, Roselino CH, Schiaveto PM. Methylene blue in anaphylactic shock. Ann Emerg Med. 1997 Aug;30(2):240. doi: 10.1016/s0196-0644(97)70152-5. No abstract available.

  PMID: 9250657 RESULT

• Kudawla M, Dutta S, Narang A. Validation of a clinical score for the diagnosis of late onset neonatal septicemia in babies weighing 1000-2500 g. J Trop Pediatr. 2008 Feb;54(1):66-9. doi: 10.1093/tropej/fmm065. Epub 2007 Aug 14.

  PMID: 17698886 RESULT

• Davis AL, Carcillo JA, Aneja RK, Deymann AJ, Lin JC, Nguyen TC, Okhuysen-Cawley RS, Relvas MS, Rozenfeld RA, Skippen PW, Stojadinovic BJ, Williams EA, Yeh TS, Balamuth F, Brierley J, de Caen AR, Cheifetz IM, Choong K, Conway E Jr, Cornell T, Doctor A, Dugas MA, Feldman JD, Fitzgerald JC, Flori HR, Fortenberry JD, Graciano AL, Greenwald BM, Hall MW, Han YY, Hernan LJ, Irazuzta JE, Iselin E, van der Jagt EW, Jeffries HE, Kache S, Katyal C, Kissoon N, Kon AA, Kutko MC, MacLaren G, Maul T, Mehta R, Odetola F, Parbuoni K, Paul R, Peters MJ, Ranjit S, Reuter-Rice KE, Schnitzler EJ, Scott HF, Torres A Jr, Weingarten-Abrams J, Weiss SL, Zimmerman JJ, Zuckerberg AL. The American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock: Executive Summary. Pediatr Crit Care Med. 2017 Sep;18(9):884-890. doi: 10.1097/PCC.0000000000001259. No abstract available.

  PMID: 28723883 RESULT

• Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol. 1995 Nov-Dec;15(6):470-9.

  PMID: 8648456 RESULT

• Kermorvant-Duchemin E, Laborie S, Rabilloud M, Lapillonne A, Claris O. Outcome and prognostic factors in neonates with septic shock. Pediatr Crit Care Med. 2008 Mar;9(2):186-91. doi: 10.1097/PCC.0b013e31816689a8.

  PMID: 18477932 RESULT

• Baske K, Saini SS, Dutta S, Sundaram V. Epinephrine versus dopamine in neonatal septic shock: a double-blind randomized controlled trial. Eur J Pediatr. 2018 Sep;177(9):1335-1342. doi: 10.1007/s00431-018-3195-x. Epub 2018 Jun 23.

  PMID: 29936590 RESULT

Related Links

• Global report on the epidemiology and burden of sepsis \[Internet\]. 2020

MeSH Terms

Conditions

Neonatal Sepsis; Shock, Septic

Interventions

Methylene Blue; Saline Solution

Condition Hierarchy (Ancestors)

Sepsis; Infections; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Sourabh Dutta, MD, PhD

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sourabh Dutta, MD, PhD

CONTACT

+91-1722755313; sourabhdutta1@gmail.com

Sajan Saini, MD, DM

CONTACT

+91-1722756264; sajansaini1@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Subjects will be randomly allocated to an intervention arm and a placebo arm. The 2 arms of the trial will run concurrently.

Study Record Dates

• First Submitted: February 20, 2024
• First Posted: March 12, 2024
• Study Start: March 15, 2024
• Primary Completion: March 14, 2026
• Study Completion (Estimated): February 1, 2027
• Last Updated: March 12, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available one year after the publication from the study for a period of 3 years
• Access Criteria: To be decided

Locations

IN (1)