Fluids in Septic Shock (FISSH) (FISSH)

Fluids in Septic Shock (FISSH): a Randomized Controlled Trial

Despite evidence of the physiologic benefits and possible lower mortality associated with low chloride solutions, normal saline remains the most wildly used fluid in the world. Given uncertainty about the impact of lower chloride versus higher chloride solutions on mortality, it is unlikely that clinical practice will change without new and direct randomized controlled trial (RCT) evidence. Editorials published in leading critical care journals have called for RCT's to address this important clinical question. This trial will directly compare low chloride versus normal chloride for resuscitation in septic shock on patient-important outcomes such as mortality and AKI.

Study Overview

• Status: Completed
• Conditions: Sepsis, Septic Shock
• Intervention / Treatment: Other: higher chloride crystalloid; Other: lower chloride crystalloid

Detailed Description

Severe infection can lead to many complications within the human body including low blood pressure, which is called septic shock. The main treatments for septic shock are intravenous antibiotics and intravenous fluid.

There are many different intravenous fluids available for doctors to use. Each one of these fluids has potential advantages as well as potential disadvantages. Doctors will often look at many things when deciding which fluid to give including the results of bloodwork and the clinical characteristics of the patients themselves. There is limited direction from research studies that using one fluid type is better than another. Some preliminary research in the field has suggested that one specific electrolyte, call chloride, may be harmful when given to patients in high concentrations. Animal research has shown that the administration of high chloride fluids may be harmful to the lungs, kidneys, gastrointestinal and muscle cells. Some intravenous fluids have higher concentrations of chloride than others.

The investigators plan to study the impact of giving patients with severe infection intravenous fluids with either a high chloride concentration (normal saline or high chloride albumin) or a low chloride concentration (Ringers Lactate or low chloride albumin). This trial will build on the earlier pilot, phase 1 study and will look at patient-important outcomes such as rate of death, kidney failure and length of stay in the ICU. This larger study has the potential to guide the care of critically ill patients with infection worldwide.

• Study Type: Interventional
• Enrollment (Actual): 1113
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • University of Calgary - Foothills Medical Centre
    • Calgary, Alberta, Canada
      • University of Calgary - Rockyview General Hospital
    • Edmonton, Alberta, Canada
      • Grey Nuns Community Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Victoria General
    • Halifax, Nova Scotia, Canada
      • Halifax Infirmary
    • Sydney, Nova Scotia, Canada
      • Cape Breton Regional Hospital
  • Ontario
    • Ajax, Ontario, Canada
      • Lakeridge Health - Ajax Pickering
    • Brantford, Ontario, Canada, N3R 1G9
      • Brantford General Hospital
    • Hamilton, Ontario, Canada
      • Hamilton General Hospital
    • Hamilton, Ontario, Canada, L8N 4A6
      • St Joseph's Healthcare
    • Hamilton, Ontario, Canada, L8V 1C1
      • Juravinski Hospital-Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre - Victoria Hospital
    • London, Ontario, Canada
      • London Health Sciences - University Hospital
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health
    • St. Catharines, Ontario, Canada, L2S 0A9
      • Niagara Health, St Catharines Site
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • Unity Health (St. Michael's Hospital)
    • Windsor, Ontario, Canada
      • Windsor Regional Hospital - Ouellette Campus
    • Windsor, Ontario, Canada
      • Windsor Regional Hospital -Metropolitan Campus
  • Quebec
    • Montreal, Quebec, Canada
      • Centre Hospitalier de l'Universite de Montreal (CHUM)
    • Montreal, Quebec, Canada, H4J 1C5
      • Centre intégré Universitaire de santé et de services sociaux du Nord de l'île de Montréal
    • Québec, Quebec, Canada, G1J 1Z4
      • CHU de Quebec Universite Laval
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre de recherche du CIUSSS de l'Estrie - CHUS de Sherbrooke
    • Trois-Rivières, Quebec, Canada
      • Centre intégré universitaire de santé et de services sociaux de la Mauricie-et-du-Centre-du-Québec (CIUSSS MCQ)
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Royal University Hospital
    • Saskatoon, Saskatchewan, Canada
      • St Paul's Hospital
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • King Faisal Specialist Hospital & Research Centre
  • Riyadh, Saudi Arabia
    • King Abdulaziz Medical City- Riyadh (KAMC-R)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• patients 16 years or greater who meet all of the following:
• require fluid resuscitation for refractory hypotension (systolic blood pressure <90 mmHg or mean arterial blood pressure<65 mmHg after 1 Litre bolus over 1 hour or less or organ hypo-perfusion (serum lactate >4 mmol/L)
• have a clinical suspicion of infection
• are within 6 hours of hospital admission or critical care response team consultation
• are anticipated to require ICU admission

Exclusion Criteria:

• intracranial bleed or intracranial hypertension during the index hospital admission
• 10% of body surface area acute burn injury
• bleeding/hemorrhage as likely cause of hypotension
• a lack of commitment to life support
• have previously enrolled in FISSH, or a confounding trial (e.g. a trial examining the effect of other intravenous fluids in septic shock patients)
• been transferred from another hospital or facility >6 hours since presentation to first hospital
• pre-established end stage renal disease (ESRD) or are receiving hemodialysis (intermittent or continuous) at time of enrolment, or
• been admitted to ICU directly from the operating room or post anaesthetic care unit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: higher chloride solutions; higher chloride crystalloid (Normal saline - chloride concentration 154 mmol/L)	Other: higher chloride crystalloid; Normal saline (chloride concentration 154 mmol/L)
Active Comparator: lower chloride solutions; lower chloride crystalloid (Ringer's lactate - chloride concentration 110 mmol/L)	Other: lower chloride crystalloid; Ringer's Lactate (chloride concentration 110 mmol/L)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30 day mortality	Investigators expect that if a difference in survival is demonstrated that this will be evident within 30 days.	up to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital length of stay	length of hospital stay up to 30 days	up to 30 days
ICU length of stay	length of ICU stay up to 30 days	up to 30 days
Acute Kidney Injury	Acute kidney injury - development of stage 2 or worse acute kidney injury (AKI) according to KDIGO guidelines17 based strictly on serum creatinine criteria. Stage 2 AKI is defined as serum creatinine 2.0-2.9 times baseline. For the purposes of analysis, baseline creatinine will be an outpatient reading within 365 days of the current admission date. If multiple pre-hospitalization values are available, the value closest to the date of hospital admission will be used. If an outpatient pre-hospitalization value is not available, the lowest creatinine value obtained during the current hospitalization will be considered baseline 18.	up to 30 days
Ventilator free days	defined as cumulative number of days alive without receiving greater than or equal to 2 hours of mechanical ventilation, censored at 30 days; patients who die prior to 30 days will be assigned -1	up to 30 days
Vasopressor-free days	defined as the cumulative number of days alive without requiring greater than or equal to 2 hours of intravenous vasopressor support, censored at 30 days; patients who die prior to 30 days will be assigned -1	up to 30 days
Hospital mortality	Investigators expect that if a difference in survival is demonstrated, that this will be evident within 30 days.	up to 30 days
ICU mortality	Investigators expect that if a difference in survival is demonstrated, that this will be evident within 30 days.	up to 30 days
Change in organ failure score	calculated using the SOFA score (sequential organ failure assessments score) , defined as the net change in SOFA from day 1 until ICU discharge or death minimum 0, maximum 24 higher score is worse	up to 30 days
Serious adverse events related to study fluid	critically ill patients are admitted to the ICU for life-sustaining therapies and medical complications are likely to occur in this population consistent with severity of illness. Due to these unique morbidity and mortality expectations, we don't collect generic adverse events but instead focus on study-related SAEs that the attending physician believes related to the study fluid with plausible time sequence and biological plausibility	up to 30 days
hyperchloremia	the number of patients with hyperchloremia	up to 30 days
Hyperkalemia	the number of patients with hyperkalemia	up to 30 days
Hypernatremia	the number of patients with hypernatremia	up to 30 days
Acidosis	the number of patients with acidosis	up to 30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital/ICU length of stay	length of hospital/ICU stay up to 30 days	up to 30 days
Ventilator free days	Number of ventilator free days	censored at 30 days
Number of days requiring vasoactive agents	defined as the number of days requiring great than or equal to 2 hours of intravenous vasopressor support	up to 30 days
Incidence of biochemical abnormalities during study period	any serum blood test results showing hyperchloremia, hyperkalemia, hypernatremia, or acidosis	up to 30 days

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Canadian Institutes of Health Research (CIHR); The Physicians' Services Incorporated Foundation
• Investigators: Principal Investigator: Bram Rochwerg, MSc,MD,FRCPC, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2018
• Primary Completion (Actual): February 2, 2026
• Study Completion (Actual): February 10, 2026

Study Registration Dates

• First Submitted: August 27, 2018
• First Submitted That Met QC Criteria: September 17, 2018
• First Posted (Actual): September 19, 2018

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Sepsis; Shock, Septic
• Other Study ID Numbers: 1515

Drug and device information, study documents

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