Hyperhydration for E. coli Infections

(HIKO-STEC Trial)

Recruiting at 25 trial locations

Overseen By Study Manager

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Calgary

Disqualifiers: Advanced HUS, Chronic disease, Anuria, others

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

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

1040 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications. Please consult with the study team for guidance.

What data supports the effectiveness of the treatment Hyperhydration for E. coli Infections?

Research shows that using balanced crystalloids (a type of fluid with essential salts) instead of saline can lower the risk of death and kidney problems in critically ill patients. This suggests that balanced crystalloids might be beneficial in treating E. coli infections by improving hydration and reducing complications. ^{1 2 3 4 5}

Is hyperhydration with balanced crystalloid solutions safe for humans?

Balanced crystalloid solutions, when used for hyperhydration, are generally considered safe and may have fewer side effects compared to saline, such as lower risks of kidney injury and metabolic acidosis (a condition where the body produces too much acid or the kidneys are not removing enough acid from the body). Studies suggest they are preferable to saline in critically ill patients. ^{1 4 6 7 8}

How does the hyperhydration treatment for E. coli infections differ from other treatments?

This treatment uses a high volume of balanced crystalloid fluids, which are designed to maintain water and electrolyte balance, unlike traditional saline solutions that can cause imbalances. The use of balanced crystalloids may lead to better outcomes, such as lower mortality and reduced kidney injury, compared to saline in critically ill patients. ^{1 2 9 10 11}

What is the purpose of this trial?

The objective of this study is to determine if early high volume intravenous fluid administration (hyperhydration) may be effective in mitigating or preventing complications of shiga toxin-producing E. coli (STEC) infection in children and adolescents when compared with traditional approaches (conservative fluid management).

Research Team

Stephen Freedman, MDCM

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for children and adolescents aged 9 months to under 21 years with a high-risk strain of E. coli infection that may lead to Hemolytic Uremic Syndrome (HUS). They must have symptoms like diarrhea or anemia, low platelet count, and kidney issues. It's not for those who are pregnant, have chronic diseases affecting fluid intake, started showing symptoms over 10 days ago, need oxygen therapy due to low blood oxygen levels, haven't urinated in over 24 hours, had HUS before or have severe HUS.

Inclusion Criteria

I have a severe E. coli infection confirmed by tests.

I am between 9 months and 21 years old.

I tested positive for a dangerous E. coli strain.

Exclusion Criteria

I need oxygen therapy due to low blood oxygen levels.

You are pregnant.

I have had HUS or been diagnosed with atypical HUS before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either conservative fluid management or hyperhydration to manage STEC infection

4 weeks

Weekly monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on kidney outcomes and adverse events

4 weeks

2 visits (in-person)

Long-term Follow-up

Participants are monitored for long-term sequelae such as chronic kidney disease, hypertension, and diabetes

6 months

Treatment Details

Interventions

• Infusion of 200% maintenance fluids as balanced crystalloid IV solution
• Infusion of up to 110% maintenance fluids as balanced crystalloid IV solution
• Oral fluids

Trial Overview The study tests if giving lots of IV fluids early on (hyperhydration) can help kids with serious E. coli infections better than the usual amount of fluids. One group gets double the normal fluid rate through an IV; another gets up to just a bit more than normal plus oral fluids.

Participant Groups

Group I: Hyperhydration Experimental Treatment 1 Intervention

In this study arm, all eligible children are admitted for the administration of intravenous fluids. The following specifics will form the basis of the fluid management protocol: 1. Reversal of dehydration: Initial ED rehydration strategies should focus on rapidly reversing dehydration. 2. Infusion of 200% of maintenance fluids x 24 hours 3. If hematocrit reduction \< 20% from initial value, repeat step #2 \[infusion of 200% maintenance fluids x 24 hours\]. 4. Oral fluids permitted ad lib. 5. Once the target hematocrit reduction is achieved (20% decrement in initial HCT) AND a 10% weight gain, adjust total IV fluid volume to maintain targeted weight gain: insensible plus output (i.e., urine plus stool).

Group II: Conservative Fluid Management Active Control 1 Intervention

The conservative fluid management arm has been designed to align and integrate into existing local practice patterns. Implementation of this approach will allow institutions and their practitioners to choose their management of protocol eligible children. All children will undergo a protocolized baseline evaluation that includes reversal of dehydration (if present) and follow-up plan (see Pre-Pathway care). The fluid management decision in the ED (i.e., to treat dehydration) will be at the discretion of the clinical care team. In the absence of evidence of microangiopathy (i.e., normal urinalysis, LDH, hemoglobin and platelet counts, and creatinine concentrations), the decision to admit the child to hospital or discharge the child to home will be at the discretion of the clinical care team. If microangiopathy is present (i.e., abnormal urinalysis, LDH, hemoglobin or platelet counts, or creatinine concentrations) admission for monitoring will be required.

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Indiana University School of Medicine

Collaborator

Trials

194

Recruited

181,000+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Case Western Reserve University

Collaborator

Trials

314

Recruited

236,000+

Children's National Research Institute

Collaborator

Trials

227

Recruited

258,000+

Seattle Children's Hospital

Collaborator

Trials

319

Recruited

5,232,000+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

University of Kentucky

Collaborator

Trials

198

Recruited

224,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

University of California, San Diego

Collaborator

Trials

1,215

Recruited

1,593,000+

Findings from Research

In a review of 13 studies involving nearly 31,000 critically ill adults, balanced crystalloids were associated with lower hospital and 28-/30-day mortality rates compared to 0.9% sodium chloride (saline), suggesting they may be a safer option for fluid resuscitation.

Balanced crystalloids also resulted in a lower incidence of new acute kidney injury compared to saline, indicating they may be more effective in protecting kidney function during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Balanced Crystalloids Versus Saline in Critically Ill Adults: A Systematic Review and Meta-analysis. Hammond, DA., Lam, SW., Rech, MA., et al.[2020]

Infusing 0.9% saline, which has equal concentrations of sodium (Na+) and chloride (Cl-), can lead to hyperchloremic acidosis, potentially affecting critically ill patients, but the clinical significance of this effect is still unclear.

Observational data suggest that using fluids with lower chloride concentrations may reduce risks of renal dysfunction, infections, and possibly mortality, highlighting the need for large randomized trials to confirm these associations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Balanced versus unbalanced salt solutions: what difference does it make? Magder, S.[2018]

In a meta-analysis of six trials involving 34,685 ICU patients, balanced crystalloids showed a high probability of reducing in-hospital mortality compared to saline, although the absolute risk reduction was small (0.4 percentage points).

However, in patients with traumatic brain injury, balanced solutions were associated with increased in-hospital mortality, indicating that their use may not be beneficial in this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Balanced crystalloids versus saline for critically ill patients (BEST-Living): a systematic review and individual patient data meta-analysis. Zampieri, FG., Cavalcanti, AB., Di Tanna, GL., et al.[2023]

The BaSICS trial will involve 11,000 critically ill patients across over 100 Brazilian intensive care units to compare the effects of balanced crystalloid solutions (Plasma-Lyte 148) versus saline on 90-day all-cause mortality.

The study will also investigate whether the rate of fluid infusion (rapid vs. slow) impacts patient outcomes, including renal failure and organ dysfunction, providing valuable insights into fluid management in critical care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol for the Balanced Solution versus Saline in Intensive Care Study (BaSICS): a factorial randomised trial. Zampieri, FG., Azevedo, LCP., Corrêa, TD., et al.[2022]

In a study of 10,520 ICU patients, the use of a balanced crystalloid solution (Plasma-Lyte 148) showed a high probability of reducing 90-day mortality for patients who received only balanced solutions before enrollment, particularly benefiting those with unplanned admissions due to sepsis.

Overall, while the balanced solution did not show a significant mortality benefit for the entire trial population, it was associated with improved outcomes for specific groups, indicating that prior fluid use and admission type can influence clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between Type of Fluid Received Prior to Enrollment, Type of Admission, and Effect of Balanced Crystalloid in Critically Ill Adults: A Secondary Exploratory Analysis of the BaSICS Clinical Trial. Zampieri, FG., Machado, FR., Biondi, RS., et al.[2023]

Balanced intravenous solutions, which have an electrolyte composition similar to plasma, are thought to minimize disruptions in acid-base balance compared to standard saline solutions, which can cause hyperchloremic metabolic acidosis.

Recent large-scale studies, including the SPLIT trial, indicate that balanced solutions do not show significant advantages over unbalanced solutions in terms of renal function in critically ill patients, suggesting that the search for an ideal balanced solution is ongoing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous balanced solutions: from physiology to clinical evidence. Langer, T., Santini, A., Scotti, E., et al.[2022]

Balanced crystalloid solutions, like lactated Ringer's and Plasma-Lyte, are increasingly preferred over saline (0.9% sodium chloride) for intravenous fluid therapy in acutely ill patients due to their closer resemblance to extracellular fluid and fewer adverse effects on acid-base balance.

Research indicates that using balanced crystalloids can prevent hyperchloremic metabolic acidosis and may lower the risk of complications such as acute kidney injury and death compared to saline, suggesting a need to reconsider saline as the primary intravenous fluid in critical care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Balanced Crystalloid Solutions. Semler, MW., Kellum, JA.[2022]

Semisynthetic colloids, while having greater intravascular persistence, are associated with a higher risk of renal failure and increased mortality, suggesting their use should be limited in clinical practice.

Balanced crystalloids are preferred over normal saline due to their lower association with metabolic acidosis and renal complications, making them a better first-choice option for fluid resuscitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A critical appraisal of intravenous fluids: from the physiological basis to clinical evidence. Severs, D., Hoorn, EJ., Rookmaaker, MB.[2022]

In a study involving 15,802 critically ill adults, the use of balanced crystalloids (like lactated Ringer's solution) resulted in a lower rate of major adverse kidney events compared to saline, with 14.3% of patients in the balanced group experiencing such events versus 15.4% in the saline group.

The findings suggest that balanced crystalloids may be a safer option for intravenous fluid administration in critically ill patients, as they were associated with a marginally lower risk of death, new renal-replacement therapy, or persistent renal dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Balanced Crystalloids versus Saline in Critically Ill Adults. Semler, MW., Self, WH., Wanderer, JP., et al.[2022]

In critically ill patients, aiming for 'normal' plasma volume and electrolyte levels may not be the best approach, as a hyperosmolar state can help reduce tissue swelling in conditions like brain injury and major surgery.

Crystalloid solutions are more effective than vasopressors for treating shock from blunt trauma and are at least as effective as colloids in septic shock, suggesting that traditional resuscitation guidelines may need to be reevaluated to avoid excessive fluid administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isotonic and hypertonic crystalloid solutions in the critically ill. Bauer, M., Kortgen, A., Hartog, C., et al.[2019]

In a study of 79 pediatric patients with severe sepsis or septic shock, higher administration of crystalloid fluids (over 193 mL/kg) was associated with increased mortality and longer stays in the pediatric intensive care unit (PICU).

Patients receiving high volumes of crystalloids also experienced more days on mechanical ventilation, indicating that excessive fluid administration may negatively impact postoperative outcomes in children with sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crystalloid fluid administration was associated with outcomes in pediatric patients with severe sepsis or septic shock. Zhang, S., Dai, X., Guo, C.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Balanced Crystalloids Versus Saline in Critically Ill Adults: A Systematic Review and Meta-analysis. [2020]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Balanced versus unbalanced salt solutions: what difference does it make? [2018]

3. England pubmed.ncbi.nlm.nih.gov

Balanced crystalloids versus saline for critically ill patients (BEST-Living): a systematic review and individual patient data meta-analysis. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Study protocol for the Balanced Solution versus Saline in Intensive Care Study (BaSICS): a factorial randomised trial. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Association between Type of Fluid Received Prior to Enrollment, Type of Admission, and Effect of Balanced Crystalloid in Critically Ill Adults: A Secondary Exploratory Analysis of the BaSICS Clinical Trial. [2023]

6. Poland pubmed.ncbi.nlm.nih.gov

Intravenous balanced solutions: from physiology to clinical evidence. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Balanced Crystalloid Solutions. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A critical appraisal of intravenous fluids: from the physiological basis to clinical evidence. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Balanced Crystalloids versus Saline in Critically Ill Adults. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Isotonic and hypertonic crystalloid solutions in the critically ill. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Crystalloid fluid administration was associated with outcomes in pediatric patients with severe sepsis or septic shock. [2022]