Fluid Intolerance Signals as Safety Limits to Prevent Fluid-induced Harm During Septic Shock Resuscitation

NCT ID: NCT06568744

Last Updated: 2024-10-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-08-22
• Study Completion Date: 2026-07-31

Brief Summary

The goal of this multicentric randomized controlled trial is to compare, in septic shock patients who require further fluid resuscitation, two strategies of administering fluids. The intervention group will integrate fluid intolerance signals to the decision making process, while the control group will follow standard of care, for a 6 hour study protocol. The main question it aims to answer is

1. To compare the effect of both resuscitation strategies on fluid-induced harm, assessed by the change in pulmonary, cardiac, and renal function biomarkers during the study period.

2. To assess the safety of both resuscitation strategies on hypoperfusion resolution, measured by the improvement of capillary refill time (CRT) and lactate during the study period.

3. To determine the dynamics of the different fluid intolerance signals

Detailed Description

Fluids are the first-line hemodynamic therapy during septic shock resuscitation, restoring tissue perfusion by effectively increasing cardiac output and oxygen delivery. Nevertheless, resuscitation fluids can be seen as a double-edged sword since they have a narrow therapeutic index. In the one hand, insufficient fluid administration can perpetuate hypoperfusion, leading to irreversible tissue hypoxia, while excessive fluid administration can lead to fluid-induced harm. The extreme scenario of this condition, fluid overload, has been consistently associated with worse clinical outcomes, including increased risks of prolonged mechanical ventilation, acute kidney injury and mortality. As an eminently retrospective diagnosis, it may underestimate the importance of timely recognition of fluid-induced harm during the resuscitation period and could shift clinicians' efforts to treatment rather than prevention. Thus, identifying organ-specific venous congestion signals early on during the resuscitation process is desirable and could avoid these adverse outcomes. Recent studies have shown that venous congestion signals are present even during the first day of ICU admission.

The investigators hypothesized that in critically ill patients with septic shock, a fluid resuscitation strategy that integrates fluid intolerance signals as safety limits will prevent fluid-induced harm, without compromising hypoperfusion resolution, compared to a standard resuscitation strategy.

To confirm this hypothesis, the investigators propose a multicenter prospective randomized controlled study in 62 critically ill patients with septic shock, comparing two strategies for conducting fluid resuscitation, aiming to decrease fluid-induced harm. One strategy will follow the standard of care, while the other will rest on real-time ultrasound-based monitoring of fluid intolerance signals. The latter approach will allow clinicians to limit fluid administration when potentially deleterious signals appear. The impact of both strategies on fluid-induced harm will be assessed by the evolution of key organ function biomarkers, namely lungs, heart, and kidneys during the 6-hour study period. Perfusion dynamics will be assessed by capillary refill time and arterial lactate kinetics during the study period. Patients will receive general monitoring and management according to ICU standards. Patients will be followed-up for 28 days for other relevant outcomes.

Conditions

Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Intervention

This group will follow a resuscitation algorithm aimed at macrohemodynamic stabilization and improvement of tissue hypoperfusion. Fluid administration will be tailored according to fluid responsiveness status, fluid intolerance signals, and hypoperfusion signals such as capillary refill time. Mechanical ventilation and sedation will follow standard management as per current recommendations.

Group Type: EXPERIMENTAL

Intervention resuscitation

Intervention Type: OTHER

In fluid responsive patients, fluid intolerance will be checked.

Lung Ultrasound (LUS): Anterior LUS with 4-point assessment at each hemithorax. Min:0 and a max:24. Low risk: < 10; intermediate risk: 10-14 or delta of 2 points. High risk: >14, or an increase >4 from baseline.

VExUS: Low risk: Grade 0-1. Intermediate risk: 2. High risk: 3 E/e' ratio: Low risk: <8. Intermediate risk: 8-13. High risk >14. Central venous pressure (CVP): Low risk <12 mmHg. Intermediate risk: 12-15 mmHg or a delta of 3 mmHg. High risk > 15 mmHg or >5 mmHg increase after a fluid challenge.

In low-risk, a fluid challenge of 500 ml of balanced crystalloid will be performed in 30 minutes. If intermediate risk, a fluid challenge of 250 ml of balanced crystalloid in 30 minutes. If high-risk signals, alternative strategies (vasopressor and inodilator tests) will be deployed. After each challenge, peripheral perfusion, fluid responsiveness and intolerance will be re-assessed.

Standard of Care

This group will follow a resuscitation algorithm aimed at macrohemodynamic stabilization and improvement of tissue hypoperfusion. Fluid administration will be tailored according to fluid responsiveness status, and hypoperfusion signals such as capillary refill time. Mechanical ventilation and sedation will follow standard management as per current recommendations.

Group Type: ACTIVE_COMPARATOR

Standard of Care resuscitation

Intervention Type: OTHER

In fluid responsive patients, fluid challenges of 500 ml of balanced crystalloid will be performed in 30 minutes. After a fluid challenge, peripheral perfusion status and fluid responsiveness will be re-measured. If the patient persists with hypoperfusion, successive fluid challenges will be performed until hypoperfusion resolves or the patient becomes fluid unresponsive. If hypoperfusion signals persists and the patient becomes fluid unresponsive, alternative resuscitation interventions will be deployed, which include: 1) vasopressor titration to higher mean arterial pressure (MAP) targets in a MAP-test, and 2) addition of an inotrope to increase cardiac output in an inodilator test. If hypoperfusion fails to resolve, rescue therapies such as high-volume hemofiltration will be initiated.

Interventions

Intervention resuscitation

In fluid responsive patients, fluid intolerance will be checked.

Lung Ultrasound (LUS): Anterior LUS with 4-point assessment at each hemithorax. Min:0 and a max:24. Low risk: < 10; intermediate risk: 10-14 or delta of 2 points. High risk: >14, or an increase >4 from baseline.

VExUS: Low risk: Grade 0-1. Intermediate risk: 2. High risk: 3 E/e' ratio: Low risk: <8. Intermediate risk: 8-13. High risk >14. Central venous pressure (CVP): Low risk <12 mmHg. Intermediate risk: 12-15 mmHg or a delta of 3 mmHg. High risk > 15 mmHg or >5 mmHg increase after a fluid challenge.

In low-risk, a fluid challenge of 500 ml of balanced crystalloid will be performed in 30 minutes. If intermediate risk, a fluid challenge of 250 ml of balanced crystalloid in 30 minutes. If high-risk signals, alternative strategies (vasopressor and inodilator tests) will be deployed. After each challenge, peripheral perfusion, fluid responsiveness and intolerance will be re-assessed.

Intervention Type: OTHER

Standard of Care resuscitation

In fluid responsive patients, fluid challenges of 500 ml of balanced crystalloid will be performed in 30 minutes. After a fluid challenge, peripheral perfusion status and fluid responsiveness will be re-measured. If the patient persists with hypoperfusion, successive fluid challenges will be performed until hypoperfusion resolves or the patient becomes fluid unresponsive. If hypoperfusion signals persists and the patient becomes fluid unresponsive, alternative resuscitation interventions will be deployed, which include: 1) vasopressor titration to higher mean arterial pressure (MAP) targets in a MAP-test, and 2) addition of an inotrope to increase cardiac output in an inodilator test. If hypoperfusion fails to resolve, rescue therapies such as high-volume hemofiltration will be initiated.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Diagnosed or suspected septic shock
• < 24 hours since diagnosis
• Hypoperfusion signal (altered arterial lactate or CRT) that requires further resuscitation
• Mechanical ventilation
• Positive fluid responsiveness status

Exclusion Criteria

• Pregnancy
• Do-not-resuscitate status
• Acute coronary syndrome
• Active bleeding
• Severe concomitant acute respiratory distress syndrome (ARDS) (PaO2:FiO2 ratio < 100)
• Anticipated surgery, prone positioning, or renal replacement therapy in the next 6 hours
• Refractory shock according to attending physician
• BMI > 40.
• Inadequate echocardiographic window

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pontificia Universidad Catolica de Chile

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eduardo Kattan, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Pontifiia Universidad Catolica de Chile

Locations

Hospital Biprovincial Quillota-Petorca

Quillota, , Chile

Site Status: RECRUITING

Hospital Barros Luco

Santiago, , Chile

Site Status: RECRUITING

Hospital Clinico UC Christus

Santiago, , Chile

Site Status: RECRUITING

Countries

Chile

Central Contacts

Eduardo Kattan, MD, PhD

Role: CONTACT

e.kattan@gmail.com

+56223543292

Ricardo Castro, MD

Role: CONTACT

rcastro.med@gmail.com

+56223543292

Facility Contacts

Roberto Contreras, MD

Role: primary

Cesar Santis, MD

Role: primary

csantis05@gmail.com

Eduardo Kattan, MD, PhD

Role: primary

e.kattan@gmail.com

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Other Identifiers

1230475

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

220607015

Identifier Type: -

Identifier Source: org_study_id