Crystalloid FLUID Choices for Resuscitation of Hospitalized Patients

NCT ID: NCT04512950

Last Updated: 2025-05-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 43626 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-15
• Study Completion Date: 2020-06-13

Brief Summary

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.

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.

Conditions

Fluid Therapy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ringer's lactate

administered as infusions or boluses as per the treating physician

Group Type: ACTIVE_COMPARATOR

Ringer's lactate

Intervention Type: DRUG

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.

0.9% Saline

administered as infusions or boluses as per the treating physician

Group Type: ACTIVE_COMPARATOR

0.9% saline

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Lactated Ringer's; sodium chloride 0.9%

Eligibility Criteria

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

• Minimum Eligible Age: 29 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ottawa Hospital Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lauralyn McIntyre, MS MHSc

Role: PRINCIPAL_INVESTIGATOR

Ottawa Hospital Research Institute

Locations

Hamilton General Hospital

Hamilton, Ontario, Canada

University Hospital

London, Ontario, Canada

Victoria Hospital

London, Ontario, Canada

Montfort Hospital

Ottawa, Ontario, Canada

The Ottawa Hospital General Campus

Ottawa, Ontario, Canada

The Ottawa Hospital Civic Campus

Ottawa, Ontario, Canada

Queensway Carleton Hospital

Ottawa, Ontario, Canada

Countries

Canada

References

McIntyre L, Fergusson D, McArdle T, English S, Cook DJ, Fox-Robichaud AE, Martin C, Marshall J, Pugliese M, Menon K, Thavorn K, Graham ID, Hawken S, Iyengar A, Kyeremanteng K, Saginur R, Seely AJE, Stiell IG, Bainbridge D, Weijer C, Taljaard M; Canadian Critical Care Trials Group. A Crossover Trial of Hospital-Wide Lactated Ringer's Solution versus Normal Saline. N Engl J Med. 2025 Aug 14;393(7):660-670. doi: 10.1056/NEJMoa2416761. Epub 2025 Jun 12.

Reference Type: DERIVED

PMID: 40503714 (View on PubMed)

Shaw JF, Ouyang Y, Fergusson DA, McArdle T, Martin C, Cook D, Graham ID, Hawken S, McCartney CJL, Menon K, Saginur R, Seely A, Stiell I, Fox-Robichaud A, English S, Marshall J, Thavorn K, Taljaard M, McIntyre LA; Canadian Critical Care Trials Group. A Hospital-Wide Open-Label Cluster Crossover Pragmatic Comparative Effectiveness Randomized Trial Comparing Normal Saline to Ringer's Lactate: Protocol and Statistical Analysis Plan of The FLUID Trial. JMIR Res Protoc. 2023 Oct 6;12:e51783. doi: 10.2196/51783.

Reference Type: DERIVED

PMID: 37801356 (View on PubMed)

Other Identifiers

0778

Identifier Type: -

Identifier Source: org_study_id