Sepsis, Severe Sepsis
Conditions
Keywords
Sepsis, Multiple organ failure, Resuscitation
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.
Interventions
0.9% Sodium chloride intravenous fluid
Sponsors
Christiana Care Health Services
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Worsening Organ System Dysfunction Defined by SOFA Score Increase ≥ 1 | 72 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| In-hospital Mortality | In-hospital discharge or up to maximum 30 days | Any occurrence of mortality while the participant is in-hospital is counted as an outcome. |
| Number of Participants With Experiencing Complications Related to Intravascular Volume Overload | 12 hours following treatment initiation | 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 |
Countries
United States
Participant flow
Pre-assignment details
Prior to interventional arm of the trial, a 5-month observational period was performed identifying 94 patients in the control arm. At the initiation of the interventional study, subjects were randomized in a 2:1 ratio to intervention:control, enrolling an additional 18 patients to the control arm, and 30 patients to the intervention.
Participants by arm
| Arm | Count |
|---|---|
| Control Standard medical care by the primary treatment team. | 112 |
| Interventional Arm Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization
Intravenous fluid: 0.9% Sodium chloride intravenous fluid | 30 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Control | Interventional Arm | Total |
|---|---|---|---|
| Age, Continuous | 58.3 years STANDARD_DEVIATION 15 | 56.8 years STANDARD_DEVIATION 16 | 58 years STANDARD_DEVIATION 15 |
| Sex: Female, Male Female | 51 Participants | 12 Participants | 63 Participants |
| Sex: Female, Male Male | 61 Participants | 18 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 112 | 0 / 30 |
| other Total, other adverse events | 0 / 112 | 0 / 30 |
| serious Total, serious adverse events | 4 / 112 | 3 / 30 |
Outcome results
Primary
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.
Time frame: 72 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants With Worsening Organ System Dysfunction Defined by SOFA Score Increase ≥ 1 | 34 Participants |
| Interventional Arm | Number of Participants With Worsening Organ System Dysfunction Defined by SOFA Score Increase ≥ 1 | 20 Participants |
Comparison: Null hypothesis: In patients with moderate severity sepsis, there is no change in the incidence of organ dysfunction within 72 hours associated with the use of an empiric fluid resuscitation algorithm.p-value: 0.0642-sample z-test
Secondary
In-hospital Mortality
Any occurrence of mortality while the participant is in-hospital is counted as an outcome.
Time frame: In-hospital discharge or up to maximum 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | In-hospital Mortality | 4 Participants |
| Interventional Arm | In-hospital Mortality | 0 Participants |
Secondary
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
Time frame: 12 hours following treatment initiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants With Experiencing Complications Related to Intravascular Volume Overload | 4 Participants |
| Interventional Arm | Number of Participants With Experiencing Complications Related to Intravascular Volume Overload | 3 Participants |