Crystalloid Solutions for Septic Shock

(FISSH Trial)

Recruiting at 37 trial locations

Overseen By Bram Rochwerg, MSc,MD,FRCPC

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: McMaster University

Disqualifiers: Intracranial bleed, Acute burn, ESRD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: up to 30 days

1096 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if fluids with lower chloride levels benefit people with septic shock more than normal saline, which contains higher chloride. Researchers seek to assess whether low-chloride fluids can improve key outcomes like survival and prevent kidney issues. The trial will compare two groups: one receiving fluids with lower chloride (such as Balanced Crystalloids, Lactated Ringer's Solution, or Plasma-Lyte A) and the other receiving normal saline (0.9% Sodium Chloride Solution). This study is ideal for individuals with severe infections causing low blood pressure who require fluid support shortly after hospital arrival. As a Phase 2, Phase 3 trial, this research evaluates the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially life-saving advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that fluids with lower chloride levels, such as Ringer's lactate, might be safer than normal saline for treating septic shock. Studies have found that these balanced fluids can help prevent hyperchloremic acidosis, a condition where the blood becomes too acidic. High chloride levels in fluids like normal saline can disrupt the body's acid balance.

Normal saline is the most common fluid with higher chloride levels. However, some studies suggest that balanced fluids with lower chloride can lead to better outcomes, such as lower mortality rates, compared to normal saline.

In summary, research suggests that both types of fluids are generally safe, but those with lower chloride might offer additional benefits in critical care situations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for septic shock because they explore the effects of different chloride levels in crystalloid solutions. While normal saline, with a higher chloride concentration, is commonly used, this trial also tests Ringer's lactate, which has a lower chloride level. The goal is to determine if the lower chloride option can improve patient outcomes by reducing the potential for kidney damage and acid-base imbalance often associated with higher chloride solutions. Understanding the impact of these chloride levels could lead to safer and more effective fluid management in septic shock patients.

What evidence suggests that this trial's treatments could be effective for septic shock?

Research has shown that using fluids with less chloride, like Ringer's lactate, can lead to better outcomes for patients with septic shock. In this trial, participants will receive either lower chloride crystalloid solutions, such as Ringer's lactate, or higher chloride crystalloid solutions, such as normal saline. These lower chloride fluids reduce the risk of hyperchloremic acidosis, a condition where acid builds up in the body, often occurring with normal saline. A large study found that patients with sepsis who received these balanced fluids had a lower chance of dying in the hospital within 30 days compared to those who received saline. Additionally, a review of multiple studies found that using balanced fluids reduced the risk of dying within 28 days by 11% compared to normal saline. This suggests that fluids with less chloride might improve survival rates for patients with septic shock. ^{1 2 3 5 6}

Who Is on the Research Team?

Bram Rochwerg, MSc,MD,FRCPC

Principal Investigator

McMaster University

Are You a Good Fit for This Trial?

The FISSH trial is for patients aged 16 or older who are suspected of having an infection, within 6 hours of hospital admission, and need ICU care due to low blood pressure or organ issues after initial fluid treatment. Excluded are those with major burns, bleeding as the main issue, no commitment to life support, prior enrollment in FISSH or similar trials, end-stage kidney disease on dialysis, brain bleeds/hypertension during current stay.

Inclusion Criteria

I was admitted to the hospital or seen by a critical care team less than 6 hours ago.

I am 16 or older and need fluids for low blood pressure or poor organ blood flow.

are anticipated to require ICU admission

Exclusion Criteria

I have burns covering 10% of my body.

You are not willing to receive life support if needed.

My low blood pressure is likely due to bleeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous fluids with either high or low chloride concentration for resuscitation in septic shock

up to 30 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including mortality, kidney failure, and length of ICU stay

up to 30 days

What Are the Treatments Tested in This Trial?

Interventions

• Higher Chloride Crystalloid
• Lower Chloride Crystalloid

Trial Overview This study compares two types of IV fluids used in septic shock: one with higher chloride levels (normal saline) and another with lower chloride levels. It's a randomized controlled trial focusing on how these fluids affect mortality rates and acute kidney injury.

How Is the Trial Designed?

Group I: lower chloride solutions Active Control 1 Intervention

lower chloride crystalloid (Ringer's lactate - chloride concentration 110 mmol/L)

Group II: higher chloride solutions Active Control 1 Intervention

higher chloride crystalloid (Normal saline - chloride concentration 154 mmol/L)

Higher Chloride Crystalloid is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Normal Saline for:

• Resuscitation in septic shock
• General fluid replacement

Approved in United States as Normal Saline for:

• Resuscitation in septic shock
• General fluid replacement

Approved in Canada as Normal Saline for:

• Resuscitation in septic shock
• General fluid replacement

Approved in Japan as Normal Saline for:

• Resuscitation in septic shock
• General fluid replacement

Approved in China as Normal Saline for:

• Resuscitation in septic shock
• General fluid replacement

Approved in Switzerland as Normal Saline for:

• Resuscitation in septic shock
• General fluid replacement

Who Is Running the Clinical Trial?

McMaster University

Lead Sponsor

Trials

936

Recruited

2,630,000+

The Physicians' Services Incorporated Foundation

Collaborator

Trials

165

Recruited

31,700+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

In a study of 2022 sepsis patients, there was no significant difference in 30-day mortality, hospital length of stay, or need for mechanical ventilation between those receiving Lactated Ringer's (LR) and those receiving Normal Saline (NS) as their primary resuscitation fluid.

Although patients receiving LR had a longer hospital stay and higher ICU admission rates initially, these differences were not statistically significant after adjusting for multiple factors, indicating that both fluids may be similarly effective in managing sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of normal saline and lactated ringers as resuscitation fluid in sepsis. Isha, S., Satashia, PH., Yarrarapu, SNS., et al.[2023]

In a study of 120 septic patients in the emergency department, there was no significant difference in lactate clearance between those treated with lactated Ringer's solution (LRS) and normal saline solution (NSS) after 2 hours of resuscitation.

Both LRS and NSS resulted in similar changes in serum creatinine levels and 48-hour survival rates, indicating that neither solution was superior in these outcomes for septic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normal Saline Solution or Lactated Ringer's Solution to Enhance Lactate Clearance in Septic Patients After Initial Resuscitation in the ED: A Retrospective Cohort Trial. Limapichat, T., Pattanapong, K.[2022]

In a study involving 70 critically ill patients, Plasma-Lyte 148 (PL-148) was found to significantly lower serum chloride levels compared to normal saline (NS), which is known to cause hyperchloraemia.

However, there was no significant difference in metabolic acidosis (measured by base excess) or the incidence of acute kidney injury and mortality between the two groups, suggesting that while PL-148 may be safer in terms of chloride levels, it does not provide a clear advantage in other clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients. Verma, B., Luethi, N., Cioccari, L., et al.[2022]

In a study of 198 patients with septic shock, lactated Ringer's (LR) solution was associated with lower blood transfusion requirements and total fluid volumes compared to normal saline (NS) during the first three days of treatment.

Patients receiving NS experienced significantly higher rates of hyperlactacidemia and hyperchloremia, but there was no significant difference in 28-day mortality rates between the LR and NS groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of Lactated Ringer's versus Normal Saline in Treating Patients with Septic Shock]. Mao, XQ., Lou, BH., Wu, DJ.[2019]

The FLUID trial is a large-scale study involving 144,000 hospitalized patients across 16 hospitals in Ontario, Canada, comparing the effects of normal saline (NS) and Ringer's lactate (RL) on critical health outcomes, including death and hospital readmission within 90 days.

This trial aims to provide clarity on the safety and efficacy of these common intravenous fluids, addressing concerns about potential harms associated with NS, such as metabolic acidosis and kidney impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Shaw, JF., Ouyang, Y., Fergusson, DA., et al.[2023]

In a study involving 40 male Wistar rats with induced severe sepsis, the use of 0.9% sodium chloride (NaCl) for fluid resuscitation led to hyperchloremia and metabolic acidosis, while PlasmaLyte® (PL) did not cause these adverse effects.

Despite the differences in biochemical responses, both 0.9% NaCl and PL resulted in similar systemic and renal hemodynamics and renal function, suggesting that while 0.9% NaCl has negative side effects, it does not compromise hemodynamic stability in this model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of renal hemodynamic toxicity of fluid challenge with 0.9% NaCl compared to balanced crystalloid (PlasmaLyte®) in a rat model with severe sepsis. Olivier, PY., Beloncle, F., Seegers, V., et al.[2020]

Fluid resuscitation with crystalloids, particularly 0.9% normal saline (NS) and Ringer's lactate, has been a common practice for over a century, but recent studies raise concerns about the safety and efficacy of these solutions, especially regarding fluid overload and their chemical composition.

0.9% NS has been linked to complications such as acute kidney injury and negative effects on microcirculation and immune response due to its high chloride concentration and unbalanced composition, suggesting that alternative solutions like Ringer's lactate may be more beneficial in certain clinical situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A brief history of crystalloids: the origin of the controversy. Fernández-Sarmiento, J., Casas-Certain, C., Ferro-Jackaman, S., et al.[2023]

Normal saline, commonly used for volume replacement and resuscitation, may be more toxic than balanced, buffered crystalloids like Plasma-Lyte A and Lactated Ringer's, potentially causing metabolic acidosis and renal function changes.

Recent evidence indicates that normal saline leads to significantly more hemolysis of red blood cells compared to Plasma-Lyte A, raising concerns about its safety in blood-related applications, suggesting a shift towards safer alternatives in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

0.9% NaCl (Normal Saline) - Perhaps not so normal after all? Blumberg, N., Cholette, JM., Pietropaoli, AP., et al.[2019]

In a study involving healthy volunteers, the rapid infusion of 2 liters of isotonic sodium chloride and Ringer lactate solution resulted in minimal and statistically insignificant changes in serum electrolyte concentrations and acid-base status.

The infusion affected central venous pressure, which was linked to a delayed secretion of atrial natriuretic peptide, suggesting a physiological response to volume expansion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in serum electrolyte and atrial natriuretic peptide concentrations, acid-base and haemodynamic status after rapid infusion of isotonic saline and Ringer lactate solution in healthy volunteers. Kamp-Jensen, M., Olesen, KL., Bach, V., et al.[2019]

In a study of 1,641 ICU patients with sepsis, using balanced crystalloids (like lactated Ringer's solution) instead of saline showed a significant reduction in 30-day in-hospital mortality when fluid choice was managed from the emergency department (ED) through to the ICU.

Specifically, during the ED and ICU period, the mortality rate was 24.9% for patients receiving balanced crystalloids compared to 30.6% for those receiving saline, indicating that early intervention with balanced crystalloids may improve outcomes for sepsis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Early Balanced Crystalloids Before ICU Admission on Sepsis Outcomes. Jackson, KE., Wang, L., Casey, JD., et al.[2022]

The study successfully enrolled 85% of eligible pediatric patients with suspected septic shock, demonstrating the feasibility of conducting a pragmatic randomized trial comparing lactated Ringer's (LR) and normal saline (NS) for fluid resuscitation.

Patients receiving LR had a significantly lower proportion of their total fluid volume as NS (20%) compared to those in the NS group (99%), indicating effective adherence to the randomized fluid administration protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis: The PRoMPT BOLUS Randomized Controlled Trial Pilot Feasibility Study. Balamuth, F., Kittick, M., McBride, P., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6909845/

Balanced Crystalloids versus Saline in Sepsis. A ... Conclusions: Among patients with sepsis in a large randomized trial, use of balanced crystalloids was associated with a lower 30-day in-hospital mortality ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1711584

Balanced Crystalloids versus Saline in Critically Ill Adults Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4905777/

Choice of fluid therapy in the initial management of sepsis ... The authors concluded that resuscitation using balanced crystalloid or albumin compared to normal saline or HES solutions was associated with reduced mortality ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0735675725003766

Fluid resuscitation management in patients with sepsis and ... Conclusion. BC holds significant clinical potential for fluid resuscitation in patients with sepsis and septic shock. It outperforms both L-HES and saline in ...

5. journals.lww.com journals.lww.com/ccmjournal/fulltext/2025/05000/lactated_ringer_s_or_normal_saline_for_initial.10.aspx

Lactated Ringer's or Normal Saline for Initial Fluid... Initial fluid resuscitation with lactated Ringer's solution, compared with 0.9% saline, might be associated with improved survival in patients with sepsis- ...

6. chestcc.org chestcc.org/article/S2949-7884(25)00057-7/fulltext

Fluids in Septic Shock The most common crystalloid resuscitation fluids include 0.9% normal saline (NS), which contains a supraphysiologic concentration of chloride ( ...