Resuscitation With Plasma in Surgical and Trauma Patients With Septic Shock

Study Overview
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Brief Summary
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There is a knowledge gap regarding the optimal initial fluid to achieve effective resuscitation and improved outcomes in septic shock. The purpose of this study is to compare initial resuscitation with plasma to initial resuscitation with balanced crystalloids.

Official Title
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Resuscitation With Plasma in Surgical and Trauma Patients With Septic Shock

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Plasma
* Drug: Balanced crystalloids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients meeting the following criteria will be enrolled: Have a Sepsis Screening Score (SSS) ≥ 4 with a suspected source of infection (Table 1); and Written informed consent obtained Patients meeting any of the following criteria will be randomized: Hypotension with MAP < 65 mmHg; Lactic acid > 4 mmol/L; Altered mental status; and Decreased urine output of < 0.5 mL/kg in the past hour. Exclusion Criteria: Pregnancy Prisoners Traumatic brain injury Evidence of ongoing hemorrhage, history of congenital bleeding disorders, therapeutic anticoagulation History of myocardial infarction or congestive heart failure History of acute cerebral vascular event Major burns (>20% total body surface area) History of adverse reactions to blood product transfusion Contraindications to blood transfusions (eg. Jehovah's Witness) Contraindications to central venous line and arterial line placement On intermittent hemodialysis Do-Not-Resuscitate or Comfort Care status Participation in another interventional study Pending transfer to another unit within the hospital that is not STICU or SIMU

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: initial resuscitation with plasma<br>Initial resuscitation with plasma will be 10 mL/kg (700 mL in a typical 70 kg adult). Traditional doses of plasma, when used to correct coagulopathy range from 10-15 mL/kg.23 The plasma will be administered at a rate of 2-3 mL/kg/hr (140-210 mL/hr in a typical 70 kg adult). A research physician will be at bedside to follow patient resuscitation. Plasma administration may be terminated before the entire dose is administered if patients show clinical improvement. After the initial dose of plasma has been given, subsequent resuscitation will follow usual care using balanced crystalloids. | Drug: Plasma<br>* Initial resuscitation with plasma will be 10 mL/kg (700 mL in a typical 70 kg adult). Traditional doses of plasma, when used to correct coagulopathy range from 10-15 mL/kg.23 The plasma will be administered at a rate of 2-3 mL/kg/hr (140-210 mL/hr in a typical 70 kg adult). A research physician will be at bedside to follow patient resuscitation. Plasma administration may be terminated before the entire dose is administered if patients show clinical improvement. After the initial dose of plasma has been given, subsequent resuscitation will follow usual care using balanced crystalloids.<br>|
| Active Comparator: initial resuscitation with balanced crystalloids<br>Usual care using balanced crystalloids (Iso-Lyte or Plasma-Lyte) only will follow Surviving Sepsis Campaign guidelines. Controls will receive 30 mL/kg (2100 mL in a typical 70 kg adult) of crystalloids within the first 3 hours. Subsequent resuscitation with balanced crystalloids will be titrated to the endpoints of resuscitation. | Drug: Balanced crystalloids<br>* Usual care using balanced crystalloids (Iso-Lyte or Plasma-Lyte) only will follow Surviving Sepsis Campaign guidelines. Controls will receive 30 mL/kg (2100 mL in a typical 70 kg adult) of crystalloids within the first 3 hours. Subsequent resuscitation with balanced crystalloids will be titrated to the endpoints of resuscitation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycocalyx Breakdown as Assessed by Syndecan-1 Levels |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and at 24 hours | 
| Glycocalyx Breakdown and Endothelial Leakage as Assessed by Soluble Thrombomodulin (sTM) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Endothelial Leakage as Assessed by Soluble FMS-like Tyrosine Kinase-1 (sFLT-1) |  | 0, 2, end of initial bolus of fluid administration(about 3 hours), 12, and 24 hours | 
| Endothelial Leakage and Inflammation as Assessed by Vascular Endothelial Growth Factor (VEGF) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Sympatho-adrenal Activation as Assessed by Norepinephrine (NE) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Sympatho-adrenal Activation as Assessed by Epinephrine (Epi) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Inflammation as Assessed by Soluble Receptor for Advanced Glycation Endproduct (sRAGE) |  | 0, 2, end of initial bolus of fluid administration, 12, and 24 hours | 
| Inflammation as Assessed by High Mobility Group Protein-1 (HMGB-1) |  | 0, 2, end of initial bolus of fluid administration, 12, and 24 hours | 
| Inflammation as Assessed by Interleukin-6 (IL-6) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Inflammation as Assessed by Interleukin-8 (IL-8) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours) , 12, and 24 hours | 
| Inflammation as Assessed by Interleukin-10 (IL-10) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Inflammation as Assessed by Interleukin-1α (IL-1α) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 
| Inflammation as Assessed by Interleukin-1β (IL-1β) |  | 0, 2, end of initial bolus of fluid administration (about 3 hours), 12, and 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Volume of Fluid Required for Resuscitation After the Initial Bolus of Either Plasma or Crystalloids | Data were not collected for 1 participant in the initial resuscitation with plasma arm. | First 24 hours after initiation of fluid resuscitation | 
| Time Until Lactate Normalization |  | First 24 hours after initiation of fluid resuscitation | 
| Time on Vasopressors |  | First 30 days after initiation of fluid resuscitation | 
| Number of Days on Ventilator Support |  | First 30 days after initiation of fluid resuscitation | 
| Number of Intensive Care Unit (ICU)-Free Days |  | First 30 days after initiation of fluid resuscitation | 
| Number of Hospital Days |  | From the time of initiation of fluid resuscitation to the time of hospital discharge (up to about 170 days) | 
| Mortality |  | First 30 days after initiation of fluid resuscitation | 
| Number of Participants With Acute Lung Injury |  | First 30 days after initiation of fluid resuscitation | 
| Number of Participants With Acute Kidney Injury |  | First 30 days after initiation of fluid resuscitation |