Randomized Controlled Trial

. 2024 Feb 1;25(2):159-170.

doi: 10.1097/PCC.0000000000003346. Epub 2024 Jan 19.

Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study

Luregn J Schlapbach^{1

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16}, Sainath Raman^{1

2}, David Buckley⁴, Shane George^{1

5

6}, Megan King⁵, Roberta Ridolfi^{1

2}, Amanda Harley^{1

5

7}, Michele Cree^{1

2}, Debbie Long^{1

8}, Simon Erickson⁹, Puneet Singh¹⁰, Marino Festa^{11

12}, Kristen Gibbons¹, Rinaldo Bellomo^{1

2

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14

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16}; Resuscitation in Paediatric Sepsis Randomized Controlled Pilot Platform in the Paediatric Intensive Care Unit (RESPOND PICU) Study Investigators and the Australian and New Zealand Intensive Care Society Paediatric Study Group

Collaborators, Affiliations

Collaborators

Resuscitation in Paediatric Sepsis Randomized Controlled Pilot Platform in the Paediatric Intensive Care Unit (RESPOND PICU) Study Investigators and the Australian and New Zealand Intensive Care Society Paediatric Study Group:
Anusha Ganeshalingam, Claire Sherring¹⁷, Simon Erickson, Samantha Barr¹⁸, Sainath Raman, Debbie Long, Luregn Schlapbach, Kristen Gibbons¹⁹, Shane George²⁰, Puneet Singh, Vicky Smith²¹, Warwick Butt, Carmel Delzoppo, Johnny Millar²², Breanna Pellegrini, Felix Oberender²³, Subodh Ganu, Georgia Letton²⁴, Jennifer Darvas, Marino Festa²⁵

Affiliations

¹ Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, QLD, Australia.
³ Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁴ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
⁵ Departments of Emergency Medicine and Children's Critical Care, Gold Coast University Hospital, Southport, QLD, Australia.
⁶ School of Medicine and Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia.
⁷ School of Nursing, Midwifery and Social Work, University of Queensland, QLD, Australia.
⁸ School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, QLD, Australia.
⁹ Paediatric Critical Care Unit, Perth Children`s Hospital, Perth, WA, Australia.
¹⁰ Paediatric Intensive Care Unit, Sydney Children's Hospital, Sydney, NSW, Australia.
¹¹ Paediatric Intensive Care Unit, Children's Hospital Westmead, Sydney, NSW, Australia.
¹² Kids Critical Care Research Group, Kids Research, Sydney Children's Hospitals Network, Sydney, NSW, Australia.
¹³ Intensive Care Research, Austin Hospital and Monash University, Melbourne, VIC, Australia.
¹⁴ Department of Critical Care, University of Melbourne., Melbourne, VIC, Australia.
¹⁵ Australian and New Zealand Research Centre, Monash University, Melbourne, VIC, Australia.
¹⁶ Department of Intensive Care, Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁷ Starship Children's Hospital.
¹⁸ Perth Children`s Hospital.
¹⁹ Queensland Children's Hospital and The University of Queensland.
²⁰ Gold Coast University Hospital.
²¹ Sydney Children's Hospital.
²² Royal Children's Hospital.
²³ Monash Children`s Hospital.
²⁴ Women's and Children's Hospital.
²⁵ Children's Hospital Westmead, Sydney, Australia.

PMID: 38240537
PMCID: PMC10793796
DOI: 10.1097/PCC.0000000000003346

Randomized Controlled Trial

Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study

Luregn J Schlapbach et al. Pediatr Crit Care Med. 2024.

. 2024 Feb 1;25(2):159-170.

doi: 10.1097/PCC.0000000000003346. Epub 2024 Jan 19.

Authors

Collaborators

Resuscitation in Paediatric Sepsis Randomized Controlled Pilot Platform in the Paediatric Intensive Care Unit (RESPOND PICU) Study Investigators and the Australian and New Zealand Intensive Care Society Paediatric Study Group:
Anusha Ganeshalingam, Claire Sherring¹⁷, Simon Erickson, Samantha Barr¹⁸, Sainath Raman, Debbie Long, Luregn Schlapbach, Kristen Gibbons¹⁹, Shane George²⁰, Puneet Singh, Vicky Smith²¹, Warwick Butt, Carmel Delzoppo, Johnny Millar²², Breanna Pellegrini, Felix Oberender²³, Subodh Ganu, Georgia Letton²⁴, Jennifer Darvas, Marino Festa²⁵

Affiliations

¹ Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, QLD, Australia.
³ Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁴ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
⁵ Departments of Emergency Medicine and Children's Critical Care, Gold Coast University Hospital, Southport, QLD, Australia.
⁶ School of Medicine and Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia.
⁷ School of Nursing, Midwifery and Social Work, University of Queensland, QLD, Australia.
⁸ School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, QLD, Australia.
⁹ Paediatric Critical Care Unit, Perth Children`s Hospital, Perth, WA, Australia.
¹⁰ Paediatric Intensive Care Unit, Sydney Children's Hospital, Sydney, NSW, Australia.
¹¹ Paediatric Intensive Care Unit, Children's Hospital Westmead, Sydney, NSW, Australia.
¹² Kids Critical Care Research Group, Kids Research, Sydney Children's Hospitals Network, Sydney, NSW, Australia.
¹³ Intensive Care Research, Austin Hospital and Monash University, Melbourne, VIC, Australia.
¹⁴ Department of Critical Care, University of Melbourne., Melbourne, VIC, Australia.
¹⁵ Australian and New Zealand Research Centre, Monash University, Melbourne, VIC, Australia.
¹⁶ Department of Intensive Care, Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁷ Starship Children's Hospital.
¹⁸ Perth Children`s Hospital.
¹⁹ Queensland Children's Hospital and The University of Queensland.
²⁰ Gold Coast University Hospital.
²¹ Sydney Children's Hospital.
²² Royal Children's Hospital.
²³ Monash Children`s Hospital.
²⁴ Women's and Children's Hospital.
²⁵ Children's Hospital Westmead, Sydney, Australia.

PMID: 38240537
PMCID: PMC10793796
DOI: 10.1097/PCC.0000000000003346

Abstract

Objectives: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction.

Design: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy.

Setting: Six PICUs in Australia and New Zealand.

Patients: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021.

Interventions: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33).

Measurements and main results: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr).

Conclusions: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.

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Conflict of interest statement

Drs. Schlapbach and Long received funding from the National Health and Medical Research Council Practitioner Fellowship, the Children`s Hospital Foundation, the Emergency Medicine Foundation Queensland, Financial Markets for Children Australia, the Gold Coast Hospital Foundation, and Children’s Health Queensland Study, Education and Research Trust Account grant. Dr. George’s institution received funding from Gold Coast Hospital Foundation and Emergency Medicine Foundation. Drs. Singh and Festa’s institution received funding from the University of Queensland. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

**Figure 1.**
Consolidated Standards of Reporting Trials participant flow diagram for the Resuscitation in Paediatric Sepsis using Metabolic Resuscitation—a Randomized Controlled Pilot Study in the PICU trial.

**Figure 2.**
Cumulative incidence functions for survival free of organ dysfunction (accounting for mortality) for the study cohort. Hydrocort = hydrocortisone, Vit C = vitamin C.

See this image and copyright information in PMC

References

1. Rudd KE, Johnson SC, Agesa KM, et al. : Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study. Lancet. 2020; 395:200–211 - PMC - PubMed
1. Agyeman PKA, Schlapbach LJ, Giannoni E, et al. ; Swiss Pediatric Sepsis Study: Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: A population-based cohort study. Lancet Child Adolesc Health. 2017; 1:124–133 - PubMed
1. Moynihan KM, Alexander PMA, Schlapbach LJ, et al. ; Australian and New Zealand Intensive Care Society Pediatric Study Group (ANZICS PSG) and the ANZICS Centre for Outcome and Resource Evaluation (ANZICS CORE): Epidemiology of childhood death in Australian and New Zealand intensive care units. Intensive Care Med. 2019; 45:1262–1271 - PubMed
1. Maddux AB, Zimmerman JJ, Banks RK, et al. ; Life After Lapse Sepsis Evaluation (LAPSE) Investigators: Health resource use in survivors of pediatric septic shock in the United States. Pediatr Crit Care Med. 2022; 23:e277–e288 - PMC - PubMed
1. Schlapbach LJ, MacLaren G, Festa M, et al. ; Australian & New Zealand Intensive Care Society (ANZICS) Centre for Outcomes & Resource Evaluation (CORE) and Australian & New Zealand Intensive Care Society (ANZICS) Paediatric Study Group: Prediction of pediatric sepsis mortality within 1 h of intensive care admission. Intensive Care Med. 2017; 43:1085–1096 - PubMed

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Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study

Collaborators

Affiliations

Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study

Authors

Collaborators

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Abstract

Conflict of interest statement

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