Buffered salt solution versus 0.9% sodium chloride as fluid therapy for patients presenting with moderate to severe diabetic ketoacidosis: Study protocol for a Phase-3 cluster-crossover, blinded, randomised, controlled trial

Mahesh Ramanan^{1

2

3}, Dorrilyn Rajbhandari², Carolyn Koch², Yasmine Ali Abdelhamid^{4

5}, Antony Attokaran^{6

7}, Laurent Billot^{8

9}, Severine Bompoint¹⁰, Jeremy Cohen^{10

11

12}, Anthony Delaney^{2

13}, Anthony Devaux¹⁰, Elif Ekinci^{14

15}, Simon Finfer^{2

13

16}, Tessa Garside^{13

17}, Naomi Hammond^{2

18}, Alisa Higgins^{2

19}, Gerben Keijzers^{20

21

22}, Qiang Li¹⁰, Benjamin Moran^{2

23

24}, John Myburgh^{2

25}, Priya Nair²⁶, Sandra Peake^{27

28}, Anthony Russell²⁹, Alexis Tabah^{3

30}, Stacey Watts³¹, Balasubramanian Venkatesh^{2

32}

Affiliations

¹ Intensive Care Services, Caboolture and Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
² Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
³ Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
⁴ Intensive Care Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁵ University of Melbourne, Melbourne Medical School, Department of Critical Care, Parkville, Victoria, Australia.
⁶ Intensive Care Unit, Rockhampton Hospital, Rockhampton, Queensland, Australia.
⁷ Rural Clinical School, University of Queensland, Rockhampton, Queensland, Australia.
⁸ Statistics Division, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁹ Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
¹¹ School of Medicine, University of Queensland, St Lucia, Brisbane, Queensland, Australia.
¹² The Wesley and Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹³ Intensive Care Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁴ Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁵ Austin Health, Heidelberg, Victoria, Australia.
¹⁶ School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
¹⁷ University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁹ Australia New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia.
²⁰ Emergency Department, Gold Coast University Hospital, Gold Coast, Australia.
²¹ School of Medicine, Griffith University, Gold Coast, Australia.
²² Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, Australia.
²³ Department of Intensive Care and Department of Anaesthesia and Pain Medicine, Gosford Hospital, Gosford, New South Wales, Australia.
²⁴ School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
²⁵ Intensive Care Department, St George Hospital, Kogarah, New South Wales, Australia.
²⁶ Intensive Care Services, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.
²⁷ Intensive Care Unit, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
²⁸ School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
²⁹ School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria, Australia.
³⁰ Intensive Care Unit, Redcliffe Hospital, Redcliffe, Queensland, Australia.
³¹ Department of Emergency Medicine, Caboolture Hospital, Caboolture, Queensland, Australia.
³² Gold Coast University Hospital, Southport, Queensland, Australia.

PMID: 40160240
PMCID: PMC11952770
DOI: 10.1016/j.ccrj.2025.100104

Buffered salt solution versus 0.9% sodium chloride as fluid therapy for patients presenting with moderate to severe diabetic ketoacidosis: Study protocol for a Phase-3 cluster-crossover, blinded, randomised, controlled trial

Mahesh Ramanan et al. Crit Care Resusc. 2025.

. 2025 Mar 13;27(1):100104.

doi: 10.1016/j.ccrj.2025.100104. eCollection 2025 Mar.

Authors

Affiliations

¹ Intensive Care Services, Caboolture and Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
² Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
³ Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
⁴ Intensive Care Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁵ University of Melbourne, Melbourne Medical School, Department of Critical Care, Parkville, Victoria, Australia.
⁶ Intensive Care Unit, Rockhampton Hospital, Rockhampton, Queensland, Australia.
⁷ Rural Clinical School, University of Queensland, Rockhampton, Queensland, Australia.
⁸ Statistics Division, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁹ Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
¹¹ School of Medicine, University of Queensland, St Lucia, Brisbane, Queensland, Australia.
¹² The Wesley and Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹³ Intensive Care Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁴ Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁵ Austin Health, Heidelberg, Victoria, Australia.
¹⁶ School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
¹⁷ University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁹ Australia New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia.
²⁰ Emergency Department, Gold Coast University Hospital, Gold Coast, Australia.
²¹ School of Medicine, Griffith University, Gold Coast, Australia.
²² Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, Australia.
²³ Department of Intensive Care and Department of Anaesthesia and Pain Medicine, Gosford Hospital, Gosford, New South Wales, Australia.
²⁴ School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
²⁵ Intensive Care Department, St George Hospital, Kogarah, New South Wales, Australia.
²⁶ Intensive Care Services, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.
²⁷ Intensive Care Unit, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
²⁸ School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
²⁹ School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria, Australia.
³⁰ Intensive Care Unit, Redcliffe Hospital, Redcliffe, Queensland, Australia.
³¹ Department of Emergency Medicine, Caboolture Hospital, Caboolture, Queensland, Australia.
³² Gold Coast University Hospital, Southport, Queensland, Australia.

PMID: 40160240
PMCID: PMC11952770
DOI: 10.1016/j.ccrj.2025.100104

Abstract

Background: The optimal choice of fluid therapy for patients with diabetic ketoacidosis (DKA) is uncertain, though preliminary data suggest that buffered crystalloid solutions (Plasma-Lyte® 148) may offer some advantages over 0.9% saline.

Objective: To describe the study protocol for the 'Balanced Electrolyte Solution versus Saline Trial for Diabetic Ketoacidosis' (BEST-DKA) trial.

Design setting and participants: BEST-DKA is a Phase 3 cluster-crossover, blinded, pragmatic, randomised, controlled trial comparing the effects of saline or buffered crystalloid solution in patients with moderate to severe DKA treated in the emergency department and/or intensive care unit at twenty hospitals in Australia. Each hospital will be randomised to use either saline or buffered crystalloid solution for a period of 12 months before crossing over to the alternate fluid for the next 12 months. The blinded study fluid will be used for all resuscitation and maintenance purposes for included patients.

Main outcome measures: This cluster-randomised, crossover randomised controlled trial (RCT) has been designed with the aim of enrolling a minimum of 400 patients, which will provide >91.4% power to detect a 2-day increase in the primary outcome, days alive and out of hospital to day 28, chosen with consumer representation. Secondary outcomes include quality of life and fatigue scores at day 28, intensive care unit and hospital lengths of stay, acute kidney injury, and time to resolution of DKA. All analyses will be conducted on an intention-to-treat basis. A prespecified statistical analysis plan will be developed prior to interim analysis.

Results and conclusion: The BEST-DKA trial commenced enrolment in March 2024 and should generate results that will determine whether treatment with Plasma-Lyte® 148, compared with saline, results in increased days alive, and out of hospital to day 28 for patients with moderate or severe DKA.

Keywords: Critical care; Diabetes; Diabetic ketoacidosis; Emergency; Fluid.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mahesh Ramanan reports financial support for BEST-DKA was provided by Medical Research Futures Fund. Gerben Keijzers reports financial support for BEST-DKA was provided by Emergency Medicine Foundation. Anthony Russell reports financial support for BEST-DKA was provided by Diabetes Australia. Balasubramanian Venkatesh reports financial support and equipment, drugs, or supplies for BETS-DKA were provided by Baxter Healthcare Ltd. Elif Ekinci reports clinical trial funding from Eli Lilly, Novo Nordisk, Boehringer-Ingelheim, Versanic, Amgen, Novartis and Endogenex. Elif Ekinci sits on advisory boards and given presentations for Bayer, Eli Lilly, Astra Zeneca, Boehringer and these funds are donated to her institution for diabetes research. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 3**
Study assessments schedule. HR-heart rate; BP- blood pressure; RR-respiratory rate; GCS- Glasgow coma score; APACHE-acute physiology and chronic health evaluation; ICU- intensive care unit; EQ-5D-5L- EuroQOL five dimension five level scale.

See this image and copyright information in PMC

References

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1. Australian Institute of Health and Wefare . 2016. Diabetic ketoacidosis (DKA) among children and young people with type 1 diabetes; pp. 1–4.
1. Venkatesh B., Pilcher D., Prins J., Bellomo R., Morgan T.J., Bailey M. Incidence and outcome of adults with diabetic ketoacidosis admitted to ICUs in Australia and New Zealand. Crit Care Lond Engl. 2015;19:451. doi: 10.1186/s13054-015-1171-7. - DOI - PMC - PubMed
1. ANZICS Centre for Outcome and Resource Evaluation Centre for outcome and resource evaluation 2020 report. 2020. https://www.anzics.com.au/annual-reports/
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Buffered salt solution versus 0.9% sodium chloride as fluid therapy for patients presenting with moderate to severe diabetic ketoacidosis: Study protocol for a Phase-3 cluster-crossover, blinded, randomised, controlled trial

Affiliations

Buffered salt solution versus 0.9% sodium chloride as fluid therapy for patients presenting with moderate to severe diabetic ketoacidosis: Study protocol for a Phase-3 cluster-crossover, blinded, randomised, controlled trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources