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NCT Number: NCT06568744

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

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

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Key information

Age range

18 year–100 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Hospital Biprovincial Quillota-Petorca, Quillota, Chile

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Intervention resuscitation

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 resuscitation

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.

Primary outcomes

  1. Delta of PaO2: fraction of inspired oxygen (FiO2) ratio between 0-6 hours

    Time frame: 6 hours

    evolution of lung function during the study period (6h)

Secondary outcomes

  1. Delta of proBNP between 0-6 hours

    Time frame: 6 hours

    evolution of cardiac function during the study period (6h)

  2. Delta of plasma neutrophil gelatinase-associated lipocalin (NGAL) between 0-6 hours

    Time frame: 6 hours

    evolution of renal function during the study period (6h)

  3. Delta of creatinine between 0-6 hours

    Time frame: 6 hours

    evolution of renal function during the study period (6h)

  4. Delta of capillary refill time between 0-6 hours

    Time frame: 6 hours

    evolution of peripheral perfusion during the study period (6h)

  5. Delta of arterial lactate between 0-6 hours

    Time frame: 6 hours

    evolution of lactate during the study period (6h)

Other outcomes

  1. Delta of PaO2:FiO2 ratio between 24 hours

    Time frame: 24 hours

    lung function at the first day since recruitment

  2. Delta of plasma NGAL between 0-24 hours

    Time frame: 24 hours

    evolution of kidney function during the first day since recruitment

  3. Delta of creatinine between 0-24 hours

    Time frame: 24 hours

    evolution of kidney function during the first day since recruitment

  4. Delta of proBNP between 0-24 hours

    Time frame: 24 hours

    evolution of cardiac function during the first day since recruitment

  5. Delta of arterial lactate between 0-24 hours

    Time frame: 24 hours

    evolution of lactate during the first day since recruitment

  6. Delta of capillary refill time between 0-24h

    Time frame: 24 hours

    evolution of peripheral perfusion during the first day since recruitment

  7. Fluid balance at 24 hours

    Time frame: 24 hours

    fluids administered during the first day of protocol

  8. Mortality

    Time frame: 28 days

    mortality rate during the first 28 days

  9. ICU length of stay

    Time frame: 28 days

    length of stay in the intensive care unit

  10. Organ dysfunction free days

    Time frame: 28 days

    days alive without vasopressor, renal replacement or mechanical ventilation support

Study contacts

Contact information is provided by the study sponsor or research team.

Eduardo Kattan, MD, PhD

CONTACT

[email protected]

+56223543292

Ricardo Castro, MD

CONTACT

[email protected]

+56223543292

Sponsors and collaborators

Lead sponsor

Pontificia Universidad Catolica de Chile

Other

Registry information

Important dates

Study start
2024
Primary completion
2026
Study completion
2026
First posted
Aug 23, 2024
Registry last updated
Oct 2, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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