Preemptive Resuscitation for Eradication of Septic Shock

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the ability of an empiric resuscitation strategy compared to standard care to decrease the incidence of organ failure in normotensive sepsis patients.

Detailed Description
-----------------
Sepsis is a challenging and elusive entity with a high mortality rate. As a syndrome, clinicians are challenged to distinguish individuals with systemic infection warranting further interventions from lower severity patients. Sepsis is now recognized as a time-sensitive emergency, as patients stand the best chance for survival when effective therapeutic interventions are delivered as early as possible. Recent data has shown that in-hospital disease progression from sepsis to septic shock is associated with a higher risk of morbidity and mortality than those with shock on initial presentation. Yet, even when identified and treated with early aggressive interventions, the development of septic shock is still associated with a mortality rate of 25-40%. Although the presence of sustained arterial hypotension or serum lactate elevation (>4.0 mmol/L) are the currently recommended threshold to define the presence of overt shock and the need for aggressive resuscitation, the investigators have shown that, in patients with systemic infection, a moderate lactate elevation (2.0-3.9 mmol/L) is a common occurrence and an important warning sign for the increased risk of disease progression and death. Sepsis with an elevated lactate between 2.0-3.9, referred to as the PRE-SHOCK state, identifies this population of patients at-risk for poor outcome. Current guidelines for sepsis management do not recommend any specific resuscitation measures or therapies for this at-risk population. This study marks the first in a series of investigations addressing the PRE-SHOCK population to further define the adverse events within this cohort and to investigate novel interventions to improve outcomes. The investigators hypothesize that an early quantitative resuscitation strategy using a protocol-directed IV fluid resuscitation will result in a significant reduction in the development of worsening organ failure (including shock) and mortality compared to standard care.

Official Title
-----------------
Preemptive Empiric Resuscitation Protocol for the Prevention of Disease Progression in the Treatment of Sepsis

Conditions
-----------------
Sepsis, Severe Sepsis

Intervention / Treatment
-----------------
* Drug: Intravenous fluid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Emergency department patient with suspected or confirmed infection as primary reason for admission Serum venous lactate 2.0 - 3.9 mmol/L Hospital admission planned Exclusion Criteria: Age < 18 years Pregnancy Serum lactate ≥ 4.0 mmol/L Any vasopressor or inotrope requirement Mechanical ventilation or non-invasive positive pressure ventilation Chronic end-stage renal disease requiring hemodialysis Pulmonary edema as diagnosed by the primary care team Requirement for surgery within the treatment protocol timeframe Inability to obtain informed consent from subject or surrogate Patient to receive comfort measures only

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 |
| --- | --- |
| No Intervention: Control<br>Standard medical care by the primary treatment team. | |
| Experimental: Interventional arm<br>Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization | Drug: Intravenous fluid<br>* 0.9% Sodium chloride intravenous fluid<br>* Other names: Normal saline;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Worsening Organ System Dysfunction Defined by SOFA Score Increase ≥ 1 | Development of worsening organ failure defined by the Sequential Organ Failure Assessment (SOFA) score. The SOFA score defines the presence and severity of dysfunction within 6 organ systems (cardiovascular, respiratory, coagulation, liver, renal, and nervous system) with a value of 0 for assigned to normal function to a maximum value of 4 for severe dysfunction in each of the organ systems. Each component of the SOFA score is added together, ranging from 0 indicating no organ dysfunction in any of the 6 organ systems, to 24 indicating maximal organ dysfunction across all 6 organ systems. Within this trial, the occurrence of organ failure was defined by any increase in the total SOFA score by ≥ 1 point over the first 72 hours after randomization. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital Mortality | Any occurrence of mortality while the participant is in-hospital is counted as an outcome. | In-hospital discharge or up to maximum 30 days | 
| Number of Participants With Experiencing Complications Related to Intravascular Volume Overload | Composite safety endpoint: Premature termination of the protocol-directed intravenous fluid administration by the investigator or primary physician due to presumed volume overload Administration of intravenous diuretic for acute pulmonary edema Respiratory failure requiring ventilatory assistance (BiPAP, CPAP, or mechanical ventilation) secondary to pulmonary edema per primary care team | 12 hours following treatment initiation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sepsis, Multiple organ failure, Resuscitation