Hemodynamic Phenotype-Based,Capillary Refill Time-Targeted Resuscitation In Early Septic Shock:ANDROMEDA-SHOCK-2 (ANDROMEDA-FR)

Hemodynamic Phenotype-Based, Capillary Refill Time-Targeted Resuscitation In Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial (A2)

Over-resuscitation including fluid overload has been associated with increased morbidity (prolonged duration of organ failure) and mortality in septic shock. "One-size-fits-all" resuscitation strategies may increase septic shock mortality. However, clinical studies on individualized resuscitation are lacking. Hemodynamic phenotyping may allow to individualize septic shock resuscitation. The ANDROMEDA-SHOCK trial found that a simple clinical and bedside CRT-targeted resuscitation reduces organ dysfunction and 28-day mortality in septic shock. The current study will examine the hypothesis that a CRT-targeted resuscitation based on hemodynamic phenotyping considering within an decision tree usual bedside clinical parameters such as pulse pressure, diastolic blood pressure, fluid responsiveness and cardiac performance can further decrease mortality in septic shock as compared to usual care.

Study Overview

• Status: Recruiting
• Conditions: Shock, Septic; Intensive Care Unit Acquired Weakness
• Intervention / Treatment: Other: Usual care (UC)

Detailed Description

Septic shock is associated with a high mortality risk related to progressive tissue hypoperfusion.However, despite extensive research on the best monitoring and resuscitation strategies, many uncertainties remain. Over-resuscitation, particularly when inducing fluid overload, might contribute to a worse outcome. Fluid overload more likely occurs when fluids are administered to fluid unresponsive patients, but also when inappropriate resuscitation goals are pursued, or a "one-size-fit all" strategy is followed. From a hemodynamic point of view, several pathogenic mechanisms determine a progressive circulatory dysfunction While loss of vascular tone and relative hypovolemia predominate in early phases, more complex mechanisms such as endothelial and microcirculatory dysfunction, progressive vasoplegia, and myocardial dysfunction may be involved later. In effect, from a clinical point of view, many patients despite been fluid loaded in pre-intensive care unit settings, are still evidently hypovolemic and benefit from further administration of fluid boluses. Others, however, present very low diastolic arterial pressures reflecting profound vasoplegia, and recent data suggest that these patients may benefit from early norepinephrine instead of fluids[; on the contrary, administering fluids may fail to correct vascular tone and increase the risk of fluid overload[2]. In addition, a recent echocardiography-based study confirms that a relevant myocardial dysfunction is present in a significant number of patients, and that several cardiovascular phenotypes with a potentially different therapeutic approach may be recognized[8]. Unfortunately, despite the availability of most of the parameters at the bedside and research efforts, no universally applicable clinical phenotyping method for septic shock patients has been translated to usual practice. This is particularly problematic since chocardiography is not immediately available in the majority of centers worldwide, and therefore initial decisions on fluid resuscitation are usually based on clinical grounds and tend to follow the one-size-fits-all principle, leading to the risk of fluid overload.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Olfa MD Hamzaoui, PhD; Phone Number: 0033310736973; Email: ohamzaoui@chu-reims.fr

Study Locations

• France
  • Reims, France, 51092
    • Recruiting
    • Hôpital Robert Debré, Université de Reims
    • Contact: Hamzaoui MD Olfa, PhD; Phone Number: 0033310736973; Email: ohamzaoui@chu-reims.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Consecutive adult patients (≥ 18 years)
• Patients with septic shock according to Sepsis-3 consensus conference. In short, septic shock is defined as suspected or confirmed infection, plus hyperlactatemia and NE requirements due to persistent hypotension, after a fluid load of at least 1000mL in 1h
• Patient and/or relative informed and having signed the information and consent form for participation in the study

Exclusion Criteria:

• More than 4 hours since septic shock diagnosis,
• Anticipated surgery or acute hemodialysis procedure to start during the 6h intervention period
• Active bleeding,
• Do not resuscitate status,
• Child B-C Cirrhosis
• Underlying disease process with a life expectancy < 90 days and/or the attending clinician deems aggressive resuscitation unsuitable
• Refractory shock (high risk of death within 24h)
• Pregnancy
• Concomitant severe acute respiratory distress syndrome
• Patients in whom CRT cannot be accurately assessed
• Non-affiliation to a social security scheme or to another social protection scheme
• Patient on AME (state medical aid) (unless exemption from affiliation
• Patient under legal protection (guardianship, curatorship)
• Participation in another interventional study involving human participants or being in the exclusion period at the end of a previous study involving human participants, if applicable
• Inability, according to the investigator, to understand the study (non-French-speaking patient, cognitive disorders)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Compartor arm; - Patients allocated to the usual care group will be managed by the clinical staff according to usual practice at their sites including decisions about hemodynamic and perfusion monitoring, and all treatments, but should follow general recommendations of the Surviving Sepsis Campaign to avoid extremes of clinical practice. This includes basic hemodynamic targets such as a MAP >65 mmHg, HR (heart rate) <120 beats per minute (BPM), arterial oxygen saturation (SaO2) >94%, Hb > 7 gr/dl, and the use of NE as the first vasopressor and crystalloids as the fluid of choice.
Active Comparator: Capillary-refill time and phenotyping group; Patients w/normal baseline CRT will be periodically monitored. Patients with abnormal CRT and septic shock will be categorized according to pulse pressure (PP). If <40 mmHg, will go to fluid responsiveness (FR) assessment. FR (-) patients will undergo cardiac echo to rule out significant dysfunction. Fluid boluses will be administered in 30 min intervals and repeated as needed if CRT is still abnormal. Patients with PP ≥40 mmHg will proceed according to diastolic pressure (DAP). If ≥50 mmHg will move to FR assessment. If <50 mmHg NE will be increased for MAP >65 mmHg and DAP ≥50 mmHg w/CRT assessed 1 h after. NE will be increased in 0.1 mcg/k/m increments up to 0.5 mcg/k/m. If CRT is normal, patients will proceed to periodic monitoring. Patients with persistent abnormal CRT or that reached NE safety limit will proceed directly to echo. Patients that correct CRT with first tier interventions will not be subjected to obligatory echo but will just proceed to periodic monitoring.	Other: Usual care (UC); - Patients allocated to the UC group will be managed by the clinical staff according to usual practice at their sites including decisions about hemodynamic and perfusion monitoring, and all treatments, but should follow general recommendations of the Surviving Sepsis Campaign to avoid extremes of clinical practice. This includes basic hemodynamic targets such as a MAP >65 mmHg, heart rate (HR) <120 beats per minute (BPM), arterial oxygen saturation (SaO2) >94%, Hb > 7 gr/dl, and the use of NE as the first vasopressor and crystalloids as the fluid of choice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A composite of all cause 28-days mortality plus time to cessation of vital support and length of hospital stay	A hierarchical composite of all cause mortality within 28 days, time to cessation of vital support (truncated at 28 days) and length of hospital stay (truncated at 28 days).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality within 28 days	All-cause mortality within 28 days	28 days
Vital support free days	The number of calendar days between randomization and 28 days that the patient is alive and with no requirement of cardiovascular, respiratory and renal support. Patients who die within 28 days will have zero days counted for this variable, irrespective of vital support status. Resolution of cardiovascular failure implies complete stopping of vasopressor support for at least 24 consecutive hours. Resolution of respiratory failure implies extubation / liberation from mechanical ventilation for at least 48 hours. Resolution of renal failure implies liberation of renal replacement therapy for at least 72 hours in those receiving continuous replacement modalities and at least 5 days for those receiving intermittent ones.	28 days
Length of hospital stay	Number of days remaining hospitalized (from randomization up to hospital discharge), truncated at day 28.	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of ICU stay	Number of days remaining in ICU (from randomization up to ICU discharge). Re-admission to ICU during follow-up period will be accounted for the original ICU length of stay only if occurred within the next week of ICU discharge and by a cause related with the original admission.	28 days
Time to cessation of mechanical ventilation	The number of calendar days between intubation / start of mechanical ventilation and extubation / liberation from mechanical ventilation (maintained for at least 48 hours) within 28 days from randomization.	28 days
Time to cessation of renal replacement therapy	The number of calendar days between start of renal replacement therapy and complete liberation from renal replacement therapy (at least 48 hours for continuous replacement modalities and 5 days for intermittent ones) within 28 days from randomization.	28 days
Vasopressor support-free days	The number of calendar days without vasopressor support from randomization up to day 28. Cessation of vasopressor support implies its complete interruption for at least 24 consecutive hours.	28 days
Mechanical ventilation-free days	The number of calendar days without mechanical ventilation support from randomization up to day 28. Cessation of mechanical ventilation support implies its complete interruption for at least 48 consecutive hours. Re-start of mechanical ventilation during follow-up period will be accounted for the original mechanical ventilation-free days only if this occurs within the next week of ICU discharge and by a cause related with the original admission.	28 days
Renal replacement therapy-free days	The number of calendar days without renal replacement therapy from randomization up to day 28. Cessation of renal replacement therapy implies its complete interruption for at least 72 hours in those receiving continuous replacement modalities and at least 5 days for those receiving intermittent ones. Re-start of renal replacement therapy during follow-up period will be accounted for the original renal replacement-free days only if this occurs within the next week of ICU discharge and by a cause related with the original admission.	28 days
Variation in Sequential Organ Failure Assessment (SOFA) score	The Sequential Organ Failure Assessment (SOFA) is used to track a patient's status during the stay in the ICU to determine the extent of organ dysfunction. Its values ranges from 0 to 24. Higher SOFA scores associate with a worse outcome. The SOFA score will be calculated upon the maximum values observed on the day of enrollment and then, at days 2, 3, 4, 5 and 7 (or until patient discharge or death, if this happened before day-7), using clinically available data. If an individual organ dysfunction value is not available (i.e., cardiovascular, respiratory, renal, etc.), it will be assumed to be zero unless previous value was abnormal (in which case it would be considered the same organ score). Neurological score under sedation/invasive mechanical ventilation will be computed as that observed just before sedation/intubation.	7 days
Variation of creatinine-based KDIGO stage	Renal function assessed according to "Kidney Disease: Improving Global Outcomes (KDIGO) staging system from randomization through day 7 to assess for "de novo" or "worsening" acute kidney injury. Patients under chronic renal replacement therapy will not meet this end-point	7 days
Volume of resuscitation fluids	The volume of fluids administered with resuscitative intention up to 72 hours from randomization.	72 hours
Net fluid balance	The volume of cumulated fluids during the first 72 hours from randomization.	72 hours
Evolvement of capillary refill time (CRT)	Evolvement of CRT within the first 72 hours after randomization.	72 hours
Evolvement of lactate levels	Evolvement of arterial lactate levels within the first 72 hours after randomization.	72 hours
Evolvement of central venous pressure	Evolvement of Central venous pressure within the first 72 hours after randomization.	72 hours
Evolvement of central venous to arterial carbon dioxide difference	Evolvement of central venous to arterial carbon dioxide difference within the first 72 hours after randomization.	72 hours
All-cause mortality within 90 days	All-cause mortality within 90 days	90 days
Length of hospital stay	Number of days remaining hospitalized (from randomization up to hospital discharge), truncated at day 90.	90 days
Time to cessation of vasopressor support	The number of hours between randomization and complete stopping of vasopressor support (defined as its complete interruption for at least 24 consecutive hours), within 28 days from randomization	28 days
Evolvement of central venous oxygen saturation	Evolvement of central venous oxygen saturation within the first 72 hours after randomization	72 hours

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2024
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): May 30, 2025

Study Registration Dates

• First Submitted: September 25, 2023
• First Submitted That Met QC Criteria: September 25, 2023
• First Posted (Actual): October 2, 2023

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: APHP220794

Drug and device information, study documents

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