FLUID trial: a protocol for a hospital-wide open-label cluster crossover pragmatic comparative effectiveness randomised pilot trial

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Abstract

Introduction

0.9% saline and Ringer’s lactate are the two most common resuscitation crystalloid fluids. 0.9% saline may lead to hyperchloraemic metabolic acidosis and may be associated with impaired kidney function and death. Few large multicentre randomised trials have been conducted to evaluate the effect of these two fluids on clinically important outcomes.

Methods

FLUID is a pragmatic pilot cluster randomised crossover trial in which four hospitals will be randomised to normal saline or Ringer’s lactate for 14 weeks, then crossover to the alternative fluid for the subsequent 14 weeks after 1 to 3 week transition. With waiver of informed consent, all adult and paediatric patients admitted to participating sites will be included in the FLUID trial except for neonates. Primary feasibility outcome is study fluid protocol adherence (target:≥80%). Secondary feasibility outcomes include time to research ethics board (REB) approval and readiness to trial initiation (≤3 months from REB submission and approval). Primary (composite of death or re-admission to hospital in first 90 days of index hospitalisation) and secondary clinical outcomes for the future large FLUID trial will be described. Protocol adherence will be collected by site at specified time points. All clinical data will be obtained at patient level through provincial health administrative data held at the Institute for Clinical Evaluative Sciences (ICES). Event rates for the primary and secondary outcomes will be described using frequencies and proportions with 95% CIs. Intracluster and interperiod correlation coefficients will be calculated from population-level data available at ICES.

Ethics and dissemination

The study protocol has been approved by the Ottawa Health Science Research Ethics Board. The FLUID pilot will determine feasibility, and ICES data across all potential sites in Ontario will allow calculation of sample size parameter estimates to inform the design and implementation of the large trial.

Trial registration number

NCT02721485; Pre-results.

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Most cited references 29

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A tutorial on pilot studies: the what, why and how

Lehana Thabane, Jinhui Ma, Rong Chu … (2010)

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.

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Design and analysis of pilot studies: recommendations for good practice.

Susanna Dodd, G Lancaster, Paula Williamson … (2004)

Pilot studies play an important role in health research, but they can be misused, mistreated and misrepresented. In this paper we focus on pilot studies that are used specifically to plan a randomized controlled trial (RCT). Citing examples from the literature, we provide a methodological framework in which to work, and discuss reasons why a pilot study might be undertaken. A well-conducted pilot study, giving a clear list of aims and objectives within a formal framework will encourage methodological rigour, ensure that the work is scientifically valid and publishable, and will lead to higher quality RCTs. It will also safeguard against pilot studies being conducted simply because of small numbers of available patients.

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Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults.

Nor'azim Mohd Yunos, Rinaldo Bellomo, Colin Hegarty … (2012)

Administration of traditional chloride-liberal intravenous fluids may precipitate acute kidney injury (AKI). To assess the association of a chloride-restrictive (vs chloride-liberal) intravenous fluid strategy with AKI in critically ill patients. Prospective, open-label, sequential period pilot study of 760 patients admitted consecutively to the intensive care unit (ICU) during the control period (February 18 to August 17, 2008) compared with 773 patients admitted consecutively during the intervention period (February 18 to August 17, 2009) at a university-affiliated hospital in Melbourne, Australia. During the control period, patients received standard intravenous fluids. After a 6-month phase-out period (August 18, 2008, to February 17, 2009), any use of chloride-rich intravenous fluids (0.9% saline, 4% succinylated gelatin solution, or 4% albumin solution) was restricted to attending specialist approval only during the intervention period; patients instead received a lactated solution (Hartmann solution), a balanced solution (Plasma-Lyte 148), and chloride-poor 20% albumin. The primary outcomes included increase from baseline to peak creatinine level in the ICU and incidence of AKI according to the risk, injury, failure, loss, end-stage (RIFLE) classification. Secondary post hoc analysis outcomes included the need for renal replacement therapy (RRT), length of stay in ICU and hospital, and survival. RESULTS Chloride administration decreased by 144 504 mmol (from 694 to 496 mmol/patient) from the control period to the intervention period. Comparing the control period with the intervention period, the mean serum creatinine level increase while in the ICU was 22.6 μmol/L (95% CI, 17.5-27.7 μmol/L) vs 14.8 μmol/L (95% CI, 9.8-19.9 μmol/L) (P = .03), the incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%-16%; n = 105) vs 8.4% (95% CI, 6.4%-10%; n = 65) (P <.001), and the use of RRT was 10% (95% CI, 8.1%-12%; n = 78) vs 6.3% (95% CI, 4.6%-8.1%; n = 49) (P = .005). After adjustment for covariates, this association remained for incidence of injury and failure class of RIFLE-defined AKI (odds ratio, 0.52 [95% CI, 0.37-0.75]; P <.001) and use of RRT (odds ratio, 0.52 [95% CI, 0.33-0.81]; P = .004). There were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge. CONCLUSION The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT. Clinicaltrials.gov Identifier: NCT00885404.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2018

Publication date (Electronic): 23 August 2018

Volume: 8

Issue: 8

Electronic Location Identifier: e022780

Affiliations

[1 ] departmentDepartment of Epidemiology , The Ottawa Hospital Research Institute , Ottawa, Ontario, Canada

[2 ] departmentDepartment of Medicine, Division of Critical Care , University of Ottawa , Ottawa, Ontario, Canada

[3 ] School of Epidemiology and Public Health, University of Ottawa , Ottawa, Ontario, Canada

[4 ] departmentDepartment of Medicine, Hamilton Health Sciences , McMaster University , Hamilton, Ontario, Canada

[5 ] departmentDivision of Critical Care Medicine , London Health Sciences Centre, Western University , London, Ontario, Canada

[6 ] departmentDepartment of Surgery , St Michael’s Hospital, University of Toronto , Toronto, Ontario, Canada

[7 ] Children’s Hospital of Eastern Ontario, University of Ottawa , Ottawa, Ontario, Canada

[8 ] departmentDepartment of Critical Care Medicine , Kingston General Hospital, Queen’s University , Kingston, Ontario, Canada

[9 ] departmentDepartments of Medicine, Clinical Epidemiology and Biostatistics , St Joseph’s Healthcare Hamilton, McMaster University , Hamilton, Ontario, Canada

[10 ] Rotman Institute of Philosophy, Western University , London, Ontario, Canada

[11 ] departmentDepartment of Medicine , The Ottawa Hospital (Infectious Diseases), University of Ottawa , Ottawa, Ontario, Canada

[12 ] Patient Engagement Advisory Board, Bruyère Research Institute , Ottawa, Ontario, Canada

[13 ] The Queensway Carleton Hospital , Ottawa, Ontario, Canada

[14 ] departmentDepartment of Anesthesiology , The Ottawa Hospital , Ottawa, Ontario, Canada

[15 ] departmentDepartment of Surgery , The Ottawa Hospital , Ottawa, Ontario, Canada

Author notes

[Correspondence to ] Dr Lauralyn McIntyre; lmcintyre@ 123456ohri.ca

Author information

Alison Fox-Robichaud http://orcid.org/0000-0001-9912-3606

Shane W English http://orcid.org/0000-0002-9477-6146

Article

Publisher ID: bmjopen-2018-022780

DOI: 10.1136/bmjopen-2018-022780

PMC ID: 6112401

PubMed ID: 30139908

SO-VID: d75e204c-c06f-4457-a651-a94dcced28e4

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 05 March 2018

Date revision received : 22 May 2018

Date accepted : 03 July 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000037, Institute of Health Services and Policy Research;

Funded by: The Ottawa Hospital Academic Medical Organization;

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ScienceOpen disciplines: Medicine

Keywords: crystalloid fluid,ringer’s lactate,cluster cross over rct,fluid therapy,0.9% saline

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ScienceOpen disciplines: Medicine

Keywords: crystalloid fluid, ringer’s lactate, cluster cross over rct, fluid therapy, 0.9% saline

FLUID trial: a protocol for a hospital-wide open-label cluster crossover pragmatic comparative effectiveness randomised pilot trial

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Abstract

Introduction

Methods

Ethics and dissemination

Trial registration number

Related collections

Herbal Medicines Journal (Herb Med J)

Most cited references 29

A tutorial on pilot studies: the what, why and how

Design and analysis of pilot studies: recommendations for good practice.

Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults.

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Affiliations

Author notes

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Funding

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