Crystalloid FLUID Choices for Resuscitation of Hospitalized Patients (FLUID)

Crystalloid FLUID Choices for Resuscitation of Hospital Patients: A Pragmatic Cluster Cross Over Trial

The aim of the FLUID Trial is to conduct a pragmatic, multi-centre, open label randomized cluster cross-over trial (RCT) to determine whether fluid administration with 0.9% saline as compared to Ringer's lactate decreases death or re-admission to hospital with 90 days of the index admission.

Study Overview

• Status: Completed
• Conditions: Fluid Therapy
• Intervention / Treatment: Drug: Ringer's lactate; Drug: 0.9% saline

Detailed Description

Crystalloid fluids are used extensively for acutely ill patients who are admitted to hospital. Two fluids most commonly used are 0.9% saline and Ringer's Lactate. Both are used to rehydrate patients, restore fluid volume and help stabilize blood pressure and failing organ and both have been used for several decades. Until recently, it was thought the fluids are essentially equivalent other than some minor differences related to the concentration of salt components (sodium and chloride) and buffers (Ringer's Lactate has lactate as a buffer). The safety of 0.9% saline is now being questioned due to its high chloride content and its association with the development of hyperchloremic metabolic acidosis. Until recently, the evidence base supporting the superiority of Ringer's Lactate has been derived from observational studies. Two recent pilot studies in critically ill patients comparing 0.9% saline to balanced crystalloid fluids (Ringer's lactate and/or Plasma-Lyte, another balanced crystalloid) did not detect clinical outcome differences between the fluid groups, but the trials were not powered to do so. Furthermore, two multiple period cluster cross-over studies conducted at one institution comparing 0.9% saline to balanced crystalloids (Ringer's lactate and Plasma-Lyte) in the emergency department (ED) and intensive care unit (ICU) found small differences in a composite outcome which included death, requirement for dialysis or persistent renal dysfunction, in favor of balanced crystalloids. In contrast, two large multi-centre randomized trials (BaSICS, n=11 052 and PLUS, n=5037) examined the efficacy of NS as compared with a balanced crystalloid (RL and Plasma-Lyte 148, respectively) on the primary outcome 90-day mortality. Neither of these trials detected a difference in 90-day mortality; in BaSICS, the mortality rate was 22.0% versus 21.8%; in PLUS, mortality was 27.2% versus 26.4%. Renal function did not differ between the fluid groups in either trial, although the PLUS trial was stopped early due to recruitment challenges and insufficient funding during the pandemic. In a systematic review of 13 critical care trials to January 2022 and 35 884 participants, there were no detectable differences in renal function. In low risk of bias trials, there was no significant difference in mortality for the 0.9% saline as compared with balanced crystalloid group (28.2% and 27.9%, respectively; relative risk (RR) 0.96 (95% CI 0.91 to 1.01)), nor renal function. However, authors concluded that there is a high probability balanced crystalloids reduce death since the CIs ranged from a 9% relative reduction to a 1% relative increase in death. Authors and editorialists urge the conduct of large multi-centre randomized trials, with longer-term patient centred outcomes supported by health economic evaluations to provide confirmatory evidence to guide future clinical practice and resource allocation related to these usual care crystalloid fluids.

Small differences in clinical outcomes between crystalloid resuscitation fluids are highly relevant. Furthermore, small absolute differences in important clinical outcomes may translate into substantial savings to hospitals and the health care system. The FLUID trial will determine if there are differences in the clinically important outcomes of death and hospital re-admissions. FLUID is novel in its design because it is a hospital wide pragmatic cluster cross-over comparative effectiveness trial that will be conducted in both academic and community sites which will use provincial health administrative data available through the Institute of Clinical Evaluative Sciences (ICES) for all clinical data collection. Our trial will answer this fundamental fluid resuscitation question and determine if Ringer's Lactate is superior to 0.9% saline at much lower cost in comparison to an individual patient randomized controlled trial (RCT), or even a conventional cluster RCT.

• Study Type: Interventional
• Enrollment (Estimated): 140000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tracy McArdle, RN BScN; Phone Number: 73837 613 737 8899; Email: tmcardle@ohri.ca
• Study Contact Backup: Name: Lauralyn McIntyre, MD MHSc; Phone Number: 73231 613 737 8899; Email: lmcintyre@ohri.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital
    • London, Ontario, Canada, N6A 5A5
      • University Hospital
    • London, Ontario, Canada, N6A 5W9
      • Victoria Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital Civic Campus
    • Ottawa, Ontario, Canada, K1K 0T2
      • Montfort Hospital
    • Ottawa, Ontario, Canada, K2H 8P4
      • Queensway Carleton Hospital
    • Ottawa, Ontario, Canada, K1V7C6
      • The Ottawa Hospital General Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

● All adult and pediatric patients with an index admission to the participating hospitals during study periods

Exclusion Criteria:

• neonates
• physicians may opt out of the use of the allocated study fluid for a specific patient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ringer's lactate; administered as infusions or boluses as per the treating physician	Drug: Ringer's lactate; Half of the hospitals will be randomized to Ringer's Lactate for a 12 week study period; after a 2 week run-out, the study fluid will be switched to 0.9% saline for another 12 week study period, followed by a 2 week run-out.; Other Names: Lactated Ringer's
Active Comparator: 0.9% Saline; administered as infusions or boluses as per the treating physician	Drug: 0.9% saline; Half of the hospitals will be randomized to 0.9% saline for a 12 week study period; after a 2 week run-out, the study fluid will be switched to Ringer's Lactate for another 12 week study period, followed by a 2 week run-out.; Other Names: sodium chloride 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that died or were readmitted to hospital	the number of deaths or readmission to hospital	90 days from index hospital admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that died	The number of deaths	90 days from index hospital admission
Number of participants re-admitted to hospital	the number of participants re-admitted to any hospital in Ontario	90 days from index hospital admission
Number of participants that required dialysis or continuous renal replacement therapy	the number of participants who required the initiation of dialysis or continuous renal replacement therapy in the first 90 days from index hospital admission with no history of renal disease requiring dialysis in the previous 6 months	90 days from index hospital admission
Number of participants that required re-intubation in the post anesthetic care unit operative period	the number of post operative participants who failed their initial extubation and required re-intubation in the post anesthetic care unit	during index hospital admission
Duration of hospitalization	the number of days participants were hospitalized during index admission	Up to 90 Days from index hospital admission
ED visits	number of index ED visits	number of index ED visits within 90 days of index hospital admission
Discharged to a facility other than home	number of participants discharged from index hospitalization to a facility other than home	90 days from index hospital admission

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incremental cost, life-year saved, quality-adjusted life-year (QALY)	cost per life-year saved and cost per QALY gained	90 days from index hospitalization

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Investigators: Principal Investigator: Lauralyn McIntyre, MS MHSc, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2016
• Primary Completion (Actual): June 13, 2020
• Study Completion (Actual): June 13, 2020

Study Registration Dates

• First Submitted: June 3, 2019
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 14, 2020

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Resuscitation; Ringer's Lactate; Rehydration; Hypovolemia; 0.9% saline
• Other Study ID Numbers: 0778

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: all data will be obtained from the Institute of Clinical Evaluative Sciences - no individual patient data will be obtained

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No