Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol

doi:10.1097/PCC.0000000000003674

. 2025 Mar 1;26(3):e374-e385.

doi: 10.1097/PCC.0000000000003674. Epub 2024 Dec 26.

Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol

Sainath Raman^{1

2}, Kristen S Gibbons¹, Muralidharan Jayashree³, A V Lalitha⁴, Rinaldo Bellomo^{5

6

7

8}, Robin Blythe⁹, David Buckley¹⁰, Warwick Butt¹¹, Hwa Jin Cho¹², Michele Cree^{13

14}, Daniela C de Souza¹⁵, Simon Erickson¹⁶, Marino Festa¹⁷, Subodh Ganu¹⁸, Shane George¹⁹, Ebor Jacob James²⁰, Kerry Johnson², Renate Le Marsney¹, Paula Lister^{1

21

22}, Trang M T Pham¹, Puneet Singh²³, Balasubramanian Venkatesh^{14

24}, Renee Wall²⁵, Debbie A Long^{2

9}, Luregn J Schlapbach^{1

26}; Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG)

Collaborators, Affiliations

Collaborators

Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG):
Ebor James Jacob²⁷, Shane George²⁸, Kieran Owen²⁸, Daniela Carla De Souza²⁹, Simon Erickson³⁰, Nick Williams³⁰, Arielle Jolly³⁰, Muralidharan Jayashree³¹, Sainath Raman³², Michele Cree³², Kerry Johnson³², Debbie Long³³, Puneet Singh³⁴, Claire Collins³⁴, Lalitha Av³⁵, David Buckley³⁶, John Beca³⁶, Claire Sherring³⁶, Paula Lister³⁷, Charlotte Moore³⁷, Marino Festa³⁸, Heidi Baillie³⁸, Bala Venkatesh³⁹, Vivekanand Jha³⁹, Abhinav Bassi³⁹, Nikita Bathla³⁹, Naomi Hammond³⁹, Kristen Gibbons⁴⁰, Renate Le Marsney⁴⁰, Trang Pham⁴⁰, Luregn J Schlapbach⁴¹, Tatjana Kerig⁴², Jennifer Darvas³⁸, Marino Festa³⁸, Shane George⁴³, Corrine Balit⁴⁴, Felix Oberender⁴⁵, Simon Erickson³⁰, Jenipher Chumbes Flores³⁰, Karina Charles³², Sainath Raman³², Michaela Waak³², Tara Williams³², Debbie Long³³, Warwick Butt⁴⁶, Ben Gelbart⁴⁷, Kate Masterson⁴⁷, Johnny Millar⁴⁷, Anusha Ganeshalingam³⁶, Claire Sherring³⁶, Puneet Singh⁴⁸, Vicky Smith⁴⁸, Kristen S Gibbons⁴⁰, Luregn J Schlapbach⁴⁰, Jessica Schults⁴⁰

Affiliations

¹ Children's Intensive Care Research Program, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, South Brisbane, QLD, Australia.
³ Pediatric Critical Care Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
⁴ Paediatric Intensive Care Unit, St. John's Medical College, Bangalore, India.
⁵ Austin Health, Melbourne, VIC, Australia.
⁶ Intensive Care Unit, The Royal Melbourne Hospital, Parkville, VIC, Australia.
⁷ Department of Critical Care, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.
⁸ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
⁹ Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁰ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
¹¹ Paediatric Intensive Care Unit, The Royal Children's Hospital, Melbourne, VIC, Australia.
¹² Paediatric Intensive Care Unit, Department of Pediatrics, Chonnam National University Children's Hospital and Medical school, Gwangju, Korea.
¹³ Department of Pharmacy, Queensland Children's Hospital, South Brisbane, QLD, Australia.
¹⁴ Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
¹⁵ Paediatric Intensive Care Unit, Hospital Universitário da Universidade de São Paulo, Sao Paolo, Brazil.
¹⁶ Paediatric Intensive Care Unit, Perth Children's Hospital, Perth, WA, Australia.
¹⁷ Kids Critical Care Research, Paediatric Intensive Care Unit, Westmead Children's Hospital, Sydney, NSW, Australia.
¹⁸ Paediatric Intensive Care Unit, Women's and Children's Hospital, Adelaide, SA, Australia.
¹⁹ Paediatric Critical Care Unit, Gold Coast University Hospital, Gold Coast, QLD, Australia.
²⁰ Paediatric Intensive Care Unit, Christian Medical College (CMC), Vellore, India.
²¹ Paediatric Critical Care Unit, Sunshine Coast University Hospital, Sunshine Coast, QLD, Australia.
²² School of Medicine and Dentistry, Griffith University, Southport, QLD, Australia.
²³ Paediatric Intensive Care Unit, Sydney Children's Hospital, Randwick, NSW, Australia.
²⁴ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
²⁵ Consumer Representative, Brisbane, QLD, Australia.
²⁶ Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁷ Christian Medical College, Vellore, India.
²⁸ Gold Coast University Hospital, Southport, QLD, Australia.
²⁹ Hospital Universitário da Universidade de São Paulo, Sao Paolo, Brazil.
³⁰ Perth Children's Hospital, Perth, WA, Australia.
³¹ Post Graduate Institute of Medical Education and Research, Chandigarh, India.
³² Queensland Children's Hospital, Brisbane, QLD, Australia.
³³ Queensland University of Technology, Brisbane, QLD, Australia.
³⁴ Sydney Children's Hospital, Sydney, NSW, Australia.
³⁵ St John's Hospital, Bangalore, India.
³⁶ Starship Children's Hospital, Auckland, New Zealand.
³⁷ Sunshine Coast University Hospital, Sunshine Coast, QLD, Australia.
³⁸ The Children's Hospital at Westmead, Sydney, NSW, Australia.
³⁹ The George Institute, New Delhi, India; Sydney, NSW, Australia.
⁴⁰ The University of Queensland, Brisbane, QLD, Australia.
⁴¹ University Children's Hospital Zurich, Zurich, Switzerland.
⁴² Australian and New Zealand Paediatric Intensive Care Registry.
⁴³ Gold Coast University Hospital, Gold Coast, QLD, Australia.
⁴⁴ John Hunter Hospital, Newcastle, NSW, Australia.
⁴⁵ Monash Children's Hospital, Melbourne, VIC, Australia.
⁴⁶ Chair.
⁴⁷ Royal Children's Hospital, Melbourne, VIC, Australia.
⁴⁸ Sydney Children's Hospital, Randwick, NSW, Australia.

PMID: 39724024
PMCID: PMC11878590
DOI: 10.1097/PCC.0000000000003674

Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol

Sainath Raman et al. Pediatr Crit Care Med. 2025.

. 2025 Mar 1;26(3):e374-e385.

doi: 10.1097/PCC.0000000000003674. Epub 2024 Dec 26.

Authors

Collaborators

Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG):
Ebor James Jacob²⁷, Shane George²⁸, Kieran Owen²⁸, Daniela Carla De Souza²⁹, Simon Erickson³⁰, Nick Williams³⁰, Arielle Jolly³⁰, Muralidharan Jayashree³¹, Sainath Raman³², Michele Cree³², Kerry Johnson³², Debbie Long³³, Puneet Singh³⁴, Claire Collins³⁴, Lalitha Av³⁵, David Buckley³⁶, John Beca³⁶, Claire Sherring³⁶, Paula Lister³⁷, Charlotte Moore³⁷, Marino Festa³⁸, Heidi Baillie³⁸, Bala Venkatesh³⁹, Vivekanand Jha³⁹, Abhinav Bassi³⁹, Nikita Bathla³⁹, Naomi Hammond³⁹, Kristen Gibbons⁴⁰, Renate Le Marsney⁴⁰, Trang Pham⁴⁰, Luregn J Schlapbach⁴¹, Tatjana Kerig⁴², Jennifer Darvas³⁸, Marino Festa³⁸, Shane George⁴³, Corrine Balit⁴⁴, Felix Oberender⁴⁵, Simon Erickson³⁰, Jenipher Chumbes Flores³⁰, Karina Charles³², Sainath Raman³², Michaela Waak³², Tara Williams³², Debbie Long³³, Warwick Butt⁴⁶, Ben Gelbart⁴⁷, Kate Masterson⁴⁷, Johnny Millar⁴⁷, Anusha Ganeshalingam³⁶, Claire Sherring³⁶, Puneet Singh⁴⁸, Vicky Smith⁴⁸, Kristen S Gibbons⁴⁰, Luregn J Schlapbach⁴⁰, Jessica Schults⁴⁰

Affiliations

¹ Children's Intensive Care Research Program, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, South Brisbane, QLD, Australia.
³ Pediatric Critical Care Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
⁴ Paediatric Intensive Care Unit, St. John's Medical College, Bangalore, India.
⁵ Austin Health, Melbourne, VIC, Australia.
⁶ Intensive Care Unit, The Royal Melbourne Hospital, Parkville, VIC, Australia.
⁷ Department of Critical Care, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.
⁸ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
⁹ Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁰ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
¹¹ Paediatric Intensive Care Unit, The Royal Children's Hospital, Melbourne, VIC, Australia.
¹² Paediatric Intensive Care Unit, Department of Pediatrics, Chonnam National University Children's Hospital and Medical school, Gwangju, Korea.
¹³ Department of Pharmacy, Queensland Children's Hospital, South Brisbane, QLD, Australia.
¹⁴ Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
¹⁵ Paediatric Intensive Care Unit, Hospital Universitário da Universidade de São Paulo, Sao Paolo, Brazil.
¹⁶ Paediatric Intensive Care Unit, Perth Children's Hospital, Perth, WA, Australia.
¹⁷ Kids Critical Care Research, Paediatric Intensive Care Unit, Westmead Children's Hospital, Sydney, NSW, Australia.
¹⁸ Paediatric Intensive Care Unit, Women's and Children's Hospital, Adelaide, SA, Australia.
¹⁹ Paediatric Critical Care Unit, Gold Coast University Hospital, Gold Coast, QLD, Australia.
²⁰ Paediatric Intensive Care Unit, Christian Medical College (CMC), Vellore, India.
²¹ Paediatric Critical Care Unit, Sunshine Coast University Hospital, Sunshine Coast, QLD, Australia.
²² School of Medicine and Dentistry, Griffith University, Southport, QLD, Australia.
²³ Paediatric Intensive Care Unit, Sydney Children's Hospital, Randwick, NSW, Australia.
²⁴ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
²⁵ Consumer Representative, Brisbane, QLD, Australia.
²⁶ Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁷ Christian Medical College, Vellore, India.
²⁸ Gold Coast University Hospital, Southport, QLD, Australia.
²⁹ Hospital Universitário da Universidade de São Paulo, Sao Paolo, Brazil.
³⁰ Perth Children's Hospital, Perth, WA, Australia.
³¹ Post Graduate Institute of Medical Education and Research, Chandigarh, India.
³² Queensland Children's Hospital, Brisbane, QLD, Australia.
³³ Queensland University of Technology, Brisbane, QLD, Australia.
³⁴ Sydney Children's Hospital, Sydney, NSW, Australia.
³⁵ St John's Hospital, Bangalore, India.
³⁶ Starship Children's Hospital, Auckland, New Zealand.
³⁷ Sunshine Coast University Hospital, Sunshine Coast, QLD, Australia.
³⁸ The Children's Hospital at Westmead, Sydney, NSW, Australia.
³⁹ The George Institute, New Delhi, India; Sydney, NSW, Australia.
⁴⁰ The University of Queensland, Brisbane, QLD, Australia.
⁴¹ University Children's Hospital Zurich, Zurich, Switzerland.
⁴² Australian and New Zealand Paediatric Intensive Care Registry.
⁴³ Gold Coast University Hospital, Gold Coast, QLD, Australia.
⁴⁴ John Hunter Hospital, Newcastle, NSW, Australia.
⁴⁵ Monash Children's Hospital, Melbourne, VIC, Australia.
⁴⁶ Chair.
⁴⁷ Royal Children's Hospital, Melbourne, VIC, Australia.
⁴⁸ Sydney Children's Hospital, Randwick, NSW, Australia.

PMID: 39724024
PMCID: PMC11878590
DOI: 10.1097/PCC.0000000000003674

Abstract

Objectives: Pediatric sepsis results in significant morbidity and mortality worldwide. There is an urgent need to investigate adjunctive therapies that can be administered early. We hypothesize that using vitamin C combined with hydrocortisone increases survival free of inotropes/vasopressors support until day 7 compared with standard care. Here we describe the Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) trial protocol, which aims to address this hypothesis.

Design: Randomized, open label, controlled, parallel-group, three-arm trial with integrated economic evaluation.

Setting: Nine Australia and New Zealand PICUs, with interest from additional international sites.

Patients: Children between 7 days and younger than 18 years old who are treated for suspected or confirmed sepsis and receiving inotropes/vasopressors for greater than 1 hour.

Interventions: IV vitamin C (100 mg/kg [maximum 5 g] every 6 hr) and hydrocortisone (1 mg/kg [maximum 50 mg] every 6 hr), or IV hydrocortisone alone (1 mg/kg [maximum 50 mg] every 6 hr) or standard care.

Measurements and main results: Three hundred eighty-four children will be randomly assigned to receive the interventions, or standard care in a 1:1:1 ratio with stratification by steroid administration pre-randomization and hospital site. The primary outcome is time alive and free of inotropes/vasopressors, censored at 7 days. Secondary outcomes include 28-day mortality, survival free of organ support, PICU length of stay, quality of life, functional status and neurodevelopmental vulnerability at 6 months post-enrollment, and hospitalization-related costs. Statistical analysis will be based on an intention-to-treat principle. The study has ethical approval (HREC/20/QCHQ/69922, dated December 21, 2020), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12621000247875), commenced recruitment on December 8, 2021, and is expected to finish recruitment by mid-2026.

Conclusions: Dissemination of the results will occur through publication in peer-reviewed journals, presentations at international conferences, and additional consumer-informed pathways.

PubMed Disclaimer

Conflict of interest statement

Drs. Gibbons and Venkatesh receive support from National Healthand Medical Research Council Investigator Grants. Dr. Venkatesh received institutional research support from Baxter. Dr. Schlapbach is supported by the Thomas & Doris Ammann Foundation and the NOMIS Foundation (Switzerland). The vitamin C used in Australian and New Zealand is provided free of cost by Biological Therapies, Australia. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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Cited by

The Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG): 20 Years of Collaborative Research.
Gibbons KS, Beca J, Delzoppo C, Erickson S, Festa M, Gelbart B, Long D, Masterson K, Millar J, Raman S, Schlapbach LJ, Butt W; Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG). Gibbons KS, et al. Pediatr Crit Care Med. 2025 Jan 1;26(1):e122-e130. doi: 10.1097/PCC.0000000000003653. Epub 2024 Dec 17. Pediatr Crit Care Med. 2025. PMID: 39688453 Free PMC article. No abstract available.

References

1. Schlapbach LJ, Kissoon N: Defining pediatric sepsis. JAMA Pediatr. 2018; 172:312–314 - PubMed
1. Weiss SL, Balamuth F, Hensley J, et al. : The epidemiology of hospital death following pediatric severe sepsis: When, why, and how children with sepsis die. Pediatr Crit Care Med. 2017; 18:823–830 - PMC - PubMed
1. Tan B, Wong JJ, Sultana R, et al. : Global case-fatality rates in pediatric severe sepsis and septic shock: A systematic review and meta-analysis. JAMA Pediatr. 2019; 173:352–362 - PMC - PubMed
1. Weiss SL, Peters MJ, Alhazzani W, et al. : Executive summary: Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020; 21:186–195 - PubMed
1. Schlapbach LJ, Oliveira CFD, Raman S, et al. : Metabolic resuscitation in pediatric sepsis: A narrative review. Transl Pediatr. 2021; 10:2678–2688 - PMC - PubMed

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[1] Schlapbach LJ, Kissoon N: Defining pediatric sepsis. JAMA Pediatr. 2018; 172:312–314 - PubMed

[2] Schlapbach LJ, Kissoon N: Defining pediatric sepsis. JAMA Pediatr. 2018; 172:312–314 - PubMed

[3] Weiss SL, Balamuth F, Hensley J, et al. : The epidemiology of hospital death following pediatric severe sepsis: When, why, and how children with sepsis die. Pediatr Crit Care Med. 2017; 18:823–830 - PMC - PubMed

[4] Weiss SL, Balamuth F, Hensley J, et al. : The epidemiology of hospital death following pediatric severe sepsis: When, why, and how children with sepsis die. Pediatr Crit Care Med. 2017; 18:823–830 - PMC - PubMed

[5] Tan B, Wong JJ, Sultana R, et al. : Global case-fatality rates in pediatric severe sepsis and septic shock: A systematic review and meta-analysis. JAMA Pediatr. 2019; 173:352–362 - PMC - PubMed

[6] Tan B, Wong JJ, Sultana R, et al. : Global case-fatality rates in pediatric severe sepsis and septic shock: A systematic review and meta-analysis. JAMA Pediatr. 2019; 173:352–362 - PMC - PubMed

[7] Weiss SL, Peters MJ, Alhazzani W, et al. : Executive summary: Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020; 21:186–195 - PubMed

[8] Weiss SL, Peters MJ, Alhazzani W, et al. : Executive summary: Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020; 21:186–195 - PubMed

[9] Schlapbach LJ, Oliveira CFD, Raman S, et al. : Metabolic resuscitation in pediatric sepsis: A narrative review. Transl Pediatr. 2021; 10:2678–2688 - PMC - PubMed

[10] Schlapbach LJ, Oliveira CFD, Raman S, et al. : Metabolic resuscitation in pediatric sepsis: A narrative review. Transl Pediatr. 2021; 10:2678–2688 - PMC - PubMed

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Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol

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Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol

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