Intravenous Methylene Blue for Treating Refractory Neonatal Septic Shock

Neonatal Sepsis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06306001
• Other study ID #: IIRP-2023-1820/F1
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: March 15, 2024
• Est. completion date: February 2027

Study information

• Verified date: March 2024
• Source: Post Graduate Institute of Medical Education and Research, Chandigarh
• Contact: Sourabh Dutta, MD, PhD
• Phone: +91-1722755313
• Email: sourabhdutta1[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 130
• Est. completion date: February 2027
• Est. primary completion date: March 14, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Days to 28 Days

Eligibility

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

Related Conditions & MeSH terms

• Neonatal Sepsis
• Shock
• Shock, Septic

Intervention

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

Locations

Country	Name	City	State
India	Post Graduate Institute of Medical Education and Research (PGIMER)	Chandigarh

Sponsors (1)

Lead Sponsor	Collaborator
Post Graduate Institute of Medical Education and Research, Chandigarh

Country where clinical trial is conducted

India, 

References & Publications (24)

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. — View Citation

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. — View Citation

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. — View Citation

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, Dug — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 wi — View Citation

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. — View Citation

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. — View Citation

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: 10.1097/0000 — View Citation

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. — View Citation

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. — View Citation

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 respo — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 durin — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

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

External Links

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