Emergency Echocardiography in Sepsis

Study Overview
=================
Brief Summary
-----------------
Acute circulatory failure that combines hypovolemia, vasoplegia and cardiac dysfunction plays a major role in the development of sepsis-related organ dysfunction. Pathophysiological mechanisms are multiple and complex. The objective of the GENESIS study is to determine the impact of early haemodynamic assessment using echocardiography in association with a therapeutic algorithm (intervention arm), when compared with standard of care based on the current Surviving Sepsis Campaign (SSC) recommendations (control arm), on the development of organ dysfunctions in patients admitted to the Emergency Department for sepsis or septic shock.

Detailed Description
-----------------
Sepsis is currently defined as life-threatening organ dysfunction secondary to a dysregulated host response to infection (Sepsis-3). Septic shock is a subgroup of patients who also have sustained arterial hypotension requiring vasopressors and tissue dysoxia. The mortality varies from 10 to 40% depending on the severity. The latest bundles of the SSC request to perform within the first hour of sepsis identification a fluid loading of 30 mL/kg of crystalloids in the presence of hypotension, and to initiate a vasopressor support in case of persistent hypotension to maintain a mean arterial pressure ≥ 65 mmHg. However, early fluid resuscitation is not necessarily associated with an improvement of sepsis prognosis and may even be deleterious when leading to excessive positive fluid balance. Accordingly, the SSC recommends investigating a personalized approach to define for each patient the appropriate volume of fluids to be administered according to the initial mechanism of sepsis-induced cardiovascular failure. Echocardiography is currently recommended as a first-line modality to identify the origin of acute circulatory failure, sepsis remaining the leading cause. It has been shown to alter ongoing treatment based on the sole SSC recommendations in the intensive care unit. In contrast, the impact of hemodynamic assessment using echocardiography at the early stage of sepsis in patients admitted to the Emergency Department (ED) is unknown. In this randomized trial, patients will be either assessed hemodynamically using transthoracic echocardiography to guide early therapeutic management (intervention arm) or managed according to standards of care based on current SSC recommendations (control arm). Early echocardiography will be performed after 500 mL of fluid loading initiated upon identification of septic patients based on the qSOFA score (hemodynamic criterion required: systolic blood pressure ≤ 100 mmHg). This will allow identifying the hemodynamic profile at the origin of sepsis-induced circulatory failure and to monitor both the efficacy and tolerance of fluid resuscitation, or of any other therapeutic intervention (e.g., inotropic support) according to a predefined therapeutic algorithm. Patients allocated to the control arm will be managed conventionally according to current SSC recommendations, including a standardized fluid loading of 30 mL/kg. Organ dysfunctions will be assessed in the two study arms by the SOFA score 24 hours after randomization and patient will be followed up until hospital discharge to determine outcome.

Official Title
-----------------
Impact of Early Haemodynamic Assessment by Echocardiography on Organ Dysfunction of Patients Admitted in the Emergency Department for Sepsis or Septic Shock

Conditions
-----------------
Sepsis, Echocardiography, Organ Dysfunction Syndrome Sepsis, Emergencies

Intervention / Treatment
-----------------
* Procedure: early transthoracic echocardiography
* Procedure: standards of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients admitted to the ED Age ≥ 18 years and affiliation to Social Security With sepsis (Sepsis-3 definition): Clinically suspected or documented acute infection AND a quick score Sequential Organ Failure Assessment (qSOFA) ≥ 2 points with: Systolic blood pressure ≤ 100 mmHg (1 point) requiring fluid loading AND encephalopathy (1 point) OR respiratory rate ≥ 22 cpm (1 point) AND a systolic blood pressure ≤ 100 mmHg after 500 mL of crystalloid vascular filling - Informed consent Exclusion Criteria: Decision to limit care or moribund status Pregnancy or breast feeding Subject under juridical protection.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention arm<br>Assessment using an early transthoracic echocardiography (after 500 mL of fluids) to identify the hemodynamic profile responsible for the acute circulatory failure associated with sepsis / septic shock and to guide ongoing treatment (therapeutic algorithm) and monitor its efficacy and tolerance. | Procedure: early transthoracic echocardiography<br>* In the intervention arm, echocardiography will be performed immediately and potentially repeated to confirm the need for additional fluid resuscitation up to 30 mL/kg in the presence of persisting hypovolemia, or not (e.g., severe ventricular dysfunction). A therapeutic algorithm will allow standardized impact on ongoing management according to the hemodynamic profile identified by early echocardiography. After the completion of initial fluid resuscitation up to 30 mL/kg if required, a new echocardiographic assessment will be systematically performed by the same operator to stop or not fluid resuscitation, and to potentially initiate another treatment according to both the hemodynamic profile and clinical context.<br>|
| Other: Control arm<br>Conventional management according to current standards of care based on SSC recommendations, including a standardized fluid resuscitation of 30 mL/kg. | Procedure: standards of care<br>* In the control arm, patients will be treated according to standards of care based on current SSC recommendations, including a fluid resuscitation of 30 mL/kg.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sequential Organ Failure Assessment (SOFA) score | Crude variation of the SOFA score between inclusion and 24h following randomization. | change from Hour 0 at Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interruption of fluid resuscitation | Number and proportion of patients in whom echocardiography performed in the ED (intervention arm) modified ongoing therapy based on SSC recommendations (standard of care) according to the hemodynamic profile. Interruption of fluid resuscitation before having administrated 30 mL/kg | Hour 3 | 
| Maintains of fluid resuscitation | Number and proportion of patients in whom echocardiography performed in the ED (intervention arm) modified ongoing therapy based on SSC recommendations (standard of care) according to the hemodynamic profile. Fluid resuscitation maintained beyond 30 mL/kg | Hour 3 | 
| Initiation of inotropes | Number and proportion of patients in whom echocardiography performed in the ED (intervention arm) modified ongoing therapy based on SSC recommendations (standard of care) according to the hemodynamic profile. Initiation of inotropes | Hour 3 | 
| Initiation of vasopressor support | Number and proportion of patients in whom echocardiography performed in the ED (intervention arm) modified ongoing therapy based on SSC recommendations (standard of care) according to the hemodynamic profile. Initiation of vasopressor support | Hour 3 | 
| Therapeutic modification | Number and proportion of patients in whom echocardiography performed in the ED (intervention arm) modified ongoing therapy based on SSC recommendations (standard of care) according to the hemodynamic profile. Therapeutic modification directly related to the echocardiographic examination | Hour 3 | 
| Persisting hypovolemia | Number and proportion of patients presenting at the time of early hemodynamic assessment using echocardiography (intervention arm) | Hour 0 | 
| Left ventricular failure | Number and proportion of patients presenting at the time of early hemodynamic assessment using echocardiography (intervention arm) | Hour 0 | 
| Vasoplegia with left ventricular hyperkinesia | Number and proportion of patients presenting at the time of early hemodynamic assessment using echocardiography (intervention arm) | Hour 0 | 
| Right ventricular failure | Number and proportion of patients presenting at the time of early hemodynamic assessment using echocardiography (intervention arm) | Hour 0 | 
| Stabilized hemodynamic status | Number and proportion of patients presenting at the time of early hemodynamic assessment using echocardiography (intervention arm). Stabilized hemodynamic status (none of above-mentioned abnormalities) due to adequate management of acute circulatory failure (avoid any deleterious therapeutic change). | Hour 0 | 
| Hydrostatic pulmonary edema | Number of Hydrostatic pulmonary edema (cardiogenic or volume overload) since potentially related to excessive fluid loading | through study completion, an average of 1 month | 
| Supraventricular arrhythmias | Number of Supraventricular arrhythmias since potentially related to the initiation of positive inotropes | through study completion, an average of 1 month | 
| ventricular arrhythmias | Number of ventricular arrhythmias since potentially related to the initiation of positive inotropes | through study completion, an average of 1 month | 
| acute coronary syndrome, | Number of acute coronary syndrome since potentially related to the initiation of positive inotropes | through study completion, an average of 1 month | 
| ischemic stroke | Number of ischemic stroke since potentially related to the initiation of positive inotropes | through study completion, an average of 1 month | 
| hemorrhagic stroke | Number of hemorrhagic stroke since potentially related to the initiation of positive inotropes | through study completion, an average of 1 month | 
| Lactate clearance | Lactate clearance (lactate 6h after randomization compared to lactate at baseline) | Hour 0 to Hour 6 | 
| septic shock | Number and proportion of patients who developed septic shock 24 h after inclusion | Hour 24 | 
| Patient course | Patient course after emergency department discharge: hospitalization in regular ward (medicine / surgery), stepdown unit or intensive care unit. | through study completion, an average of 1 month | 
| Mortality | Mortality (all-cause and sepsis-related) at Day 7 and at hospital discharge | Day 7 and through study completion, an average of 1 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sepsis, Echocardiography, Haemodynamic, Emergency Medicine