Clinical trial NCT03366220
Conditions: Septic Shock
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2018-03-26; Completion date: 2019-10-16
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Plasma intervention 2: Balanced crystalloids
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-17-0714 
IRB APPROVAL DATE: 06/26/2019 
1 
 
 
 
 
 
 
 
 
 
Resuscitation With Plasma in Surgical and Trauma Patients With Septic Shock  
 
NCT03366220   
 
Version Date: 06/26/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB NUMBER: HSC-MS-17-0714 
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Resuscitation with Plasma in Patients with Septic Shock 
 
 
Background: 
Sepsis and septic shock are a major worldwide public health problem. Although implementation 
of the evidence-based Surviving Sepsis Guidelines has resulted in improvement in sepsis-related 
deaths, in-hospital mortality continues to range from 12-40%. The guidelines provide strong 
recommendations for initial resuscitation with crystalloids – 30 mL/kg within the first 3 hours.1 
However, the guidelines state that there is “little available evidence from RCTs to support its 
practice; this is an area in which research is urgently needed”.1 Randomized trials have primarily 
compared crystalloids to colloids and have not evaluated the recommended fluid volume. 
Furthermore, there is observational data from large administrative databases that increased fluid 
administration in the first 24 hours increases mortality.2 
Figure 1: Conceptual 
model of how septic 
shock leads to 
sympathoadrenal 
activation, 
inflammation, and 
ischemia, which 
affects the endothelial 
glycocalyx, endothelial 
permeability, and 
hemostatic balance, 
resulting in edema 
and microcirculatory 
disturbances that 
cause organ 
dysfunction 
Recently, shock-induced endotheliopathy (SHINE) has been proposed as a shared 
pathophysiologic mechanism associated with worsened outcomes in patients with critical illness 
including trauma and sepsis.3 Activation of the sympathoadrenal system and release of 
catecholamines due to acute injury (i.e., sepsis or trauma) leads to breakdown of the glycocalyx, 
or the network of membrane-bound proteoglycans and glycoproteins that covers the endothelium 
(Figure 1).4-7 This has been associated with capillary leakage and microvascular thrombosis, 
ultimately  resulting  in  organ  dysfunction  and  increased  mortality.  Research  suggests   that 
Summary: There is a knowledge gap regarding the optimal initial fluid to achieve 
effective resuscitation and improved outcomes in septic shock. Shock-induced 
endotheliopathy (SHINE) may be an underlying pathologic mechanism for worsened 
outcomes in septic shock and a potential therapeutic target that can be modulated by 
resuscitation fluids. This project proposes a pilot randomized controlled trial to 
address this knowledge gap by evaluating plasma as a potential novel strategy to 
mitigate SHINE and improve clinical outcomes. 


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endotheliopathy is both a marker and a driver of worsened outcome.3 Thus, interventions to 
prevent, mitigate, or treat SHINE may improve outcomes in patients with shock. SHINE 
biomarkers, such as syndecan-1,8 interleukin-6 (IL-6),9 and soluble fms-like tyrosine kinase 
(sFLT-1),7  have been shown to correlate with clinical outcomes in septic patients. 
Resuscitation of shock patients with plasma shows promise as a novel resuscitative strategy. 
Specifically, plasma may improve outcomes by modulating SHINE as measured by biomarkers 
of glycocalyx damage (i.e., syndecan-1),10,11 and endothelial injury (i.e., sFLT-1, VEGF, sTM).7,8 
Resuscitation with plasma as the primary volume expander in trauma patients have been 
associated with a reduction in serum biomarkers of endotheliopathy,12 improved survival, and 
decreased morbidity associated with inflammatory and edema-related complications such as 
acute lung injury13 and abdominal compartment syndrome.14 Animal models of sepsis and a 
prospective sub-study of a randomized, controlled trial (RCT), have shown that resuscitation with 
plasma is associated with decreased levels of syndecan-1, which may reflect restoration of 
endothelial integrity, although the underlying mechanism is unknown.15-17 Plasma resuscitation in 
a rat model of sepsis demonstrated attenuation of inflammatory markers, endothelial injury, and 
catecholamines; significantly reduced pulmonary edema as measured by wet-to-dry weight ratios; 
and improved 48-hour survival as compared to normal saline.18 However, although these studies 
suggest that plasma may be a promising therapy in septic shock, there have been no human 
RCTs. Furthermore, there have been no studies establishing causation between SHINE and 
outcome. 
Hypothesis and Specific Aims: 
Hypothesis: We hypothesize that among patients with septic shock, initial resuscitation with 
plasma versus balanced crystalloids will decrease biomarkers of endotheliopathy, improve patient 
outcomes (such as decrease number of ICU-free days, decreased morbidity associated with end- 
organ damage), and reduce in-hospital all-cause mortality. We propose to perform a pilot RCT to 
test this hypothesis using the following specific aims: 
Specific Aim 1: To evaluate the effects of plasma versus balanced crystalloids on serum markers 
of glycocalyx breakdown, endothelial leakage, inflammation, hemostasis, sympathy-adrenal 
activation, and degree of coagulopathy (using rapid thromboelastography parameters) [Figure 1]. 
Specific Aim 2: To evaluate differences in total volume of fluids needed to resuscitate patients 
in the plasma group versus crystalloids group during the initial 24 hours of resuscitation. 
Specific Aim 3: To determine the effect of plasma resuscitation on organ dysfunction, ventilator- 
free days, intensive care unit (ICU) free days, hospital length of stay, mortality, and adverse 
events. 
Significance: 
This will be the first randomized trial comparing plasma, which has been demonstrated to have 
beneficial effects in animal models and in other types of shock, to usual care or balanced 
crystalloids. Furthermore, this study will provide insights regarding the mechanism by which fluids 
can influence outcomes in septic shock. 
Preliminary Data: 
Plasma Resuscitation in Rat Model of Septic Shock - We randomized rats who underwent cecal 
ligation and puncture to resuscitation with plasma (n = 14), normal saline (n = 11), and sham (n = 
5). Resuscitation with plasma as determined by lactic acid clearance attenuated inflammatory 
markers   (interleukin-6)   [Figure   2],   glycocalyx   shedding   (syndecan-1)   [Figure   3],   and 


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catecholamines (norepinephrine). Plasma significantly reduced pulmonary wet-to-dry weight 
ratios, increased mean arterial pressures (MAPs), reduced volume of total fluids administered, 
and improved 48-hour survival. 
 
Study Design & Methods: 
The proposed trial is a pilot, efficacy, single-center RCT comparing initial plasma to balanced 
crystalloid resuscitation in surgical patients with septic shock. The trial will investigate modulation 
of SHINE as a strategy by which outcomes in shock patients may be improved. The trial will follow 
the Consolidated Standards in Reporting of Trials (CONSORT) guidelines19 and has been 
registered on ClinicalTrials.gov (NCT03366220). 
Setting: The study will take place at Memorial Hermann Hospital – Texas Medical Center (MHH- 
TMC), a Level I trauma and tertiary care center located in Houston, Texas. 
Study population: The target population includes critically ill (including medical patients), 
traumatically-injured or surgical patients who have sepsis, hypotension with MAP < 65 mmHg, 
and signs of hypoperfusion such as lactic acid > 2.2 mmol/L, altered mental status or decreased 
urine output (< 0.5 mL/kg in the past hour).20 
 
Inclusion Criteria: 
Patients meeting the following criteria will be enrolled: 
• 
≥ 18 years old and 
• 
Have a Sepsis Screening Score (SSS) ≥ 4 with a suspected source of infection (Table 1) 
• 
Written informed consent obtained 
 
Patients meeting any of the following criteria will be randomized: 
• 
Hypotension with MAP < 65 mmHg 
• 
Lactic acid > 2.2 mmol/L, 
• 
Altered mental status 
• 
Decreased urine output of < 0.5 mL/kg in the past hour. 
Figure 2 – Significant decrease in serum IL-6 in 
septic rats resuscitation with plasma as 
compared to normal saline.18 
Figure 3 – Significant decrease in serum syndecan-1 
in septic rats resuscitation with plasma as compared 
to normal saline.18 


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Table 1 – The Sepsis Screening Score22 
This cutoff has a negative predictive value of 96%,22 which would rule out the majority patients 
without sepsis. Enrolled patients will be randomized only if they meet criteria for septic shock: 1) 
hypotension with MAP < 65 mmHg, and 2) evidence of hypoperfusion including lactic acid > 2.2 
mmol/L, altered mental status, or decreased urine output of < 0.5 mL/kg in the past hour. 
 
Exclusion Criteria: 
-Pregnancy 
-Prisoners 
-Non-survivable traumatic brain injury 
-Evidence of ongoing hemorrhage (eg. active gastrointestinal bleed), history of congenital 
bleeding disorders, therapeutic anticoagulation 
-History of congestive heart failure 
-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 
-Do-Not-Resuscitate or Comfort Care status 
-Participation in another interventional study that specifically focuses on sepsis, involves 
the use of a non-approved product (medication or equipment), or interventions that affect blood 
coagulation. 
-Pending transfer to another unit within the hospital that is not Shock Trauma Intensive 
Care Unit (STICU) or Medical Intensive Care Unit (MICU). 
 
Screening and Enrollment: Patient screening and enrollment will take place at Memorial 
Hermann Hospital. The research team will screen patients by communicating with the on-call 
STICU and emergency department (ED) physicians daily to identify patients eligible for 
enrollment. Hospitalized medical patients on the floor who develop severe sepsis will be identified 
using the rapid response page, which is already in place to alert the rapid response team of 
medical floor patients with potential severe sepsis. 


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Enrolled patients will be monitored for up to 72 hours (in time for cultures to result) by the research 
team for development of septic shock (MAP ≤ 65 mmHg and evidence of poor perfusion, such as 
urine output < 0.5 mL/kg/hr, venous lactic acid ≥ 2.2 mmol/L, altered mental status from baseline). 
Upon meeting these criteria for septic shock, patients will be randomized and immediately started 
on therapy fluid (either plasma or balanced crystalloids). 
Crystalloid administration may already be underway prior to patient randomization. Receiving 
crystalloids prior to randomization will not be an exclusion criterion in this study as long as the 
total volume received has not met or exceeded 30 mL/kg. The research team will work 
expeditiously to obtain informed written consent, and once consent has been obtained and patient 
is randomized, prior fluids will be exchanged for therapy fluid (either plasma or balanced 
crystalloids). 
 
Informed Consent: 
Exception from Informed Consent will not be used in this trial. Written informed consent will be 
obtained from potential subjects or a legally authorized representative prior to randomization. 
Randomization: Randomization will occur once the informed consent has been obtained. A 1:1 
allocation will be used for the randomization. Subjects will be randomized to either the intervention 
arm (use of plasma) or the control arm (standard of care). Randomization will be performed using 
a computer-generated random sequence placed in opaque, consecutively-numbered, sealed 
envelopes kept in the locked Center for Translational Injury Research (CeTIR) office. A CeTIR 
research coordinator is available 24 hours a day, 7 days a week. Allocation will be 1:1. Patients 
will be stratified by enrollment location (STICU, ED, and Medical) in 5 blocks of 4 and 1 block of 
6 for a total of 26 patients.  [Figure 4]. 
 
Figure 4 – Flow diagram depicting patient screening, enrollment, and randomization. 
Intervention: 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, or if 
the treating clinician has concerns about circulatory overload. After the initial dose of plasma has 


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been given, subsequent fluid resuscitation (crystalloid or colloid) will be given at the discretion of 
the treating clinician. 
The blood bank will have thawed plasma available on call as soon as an eligible patient has been 
identified. Type and screen will be performed concurrently to provide donor-matched plasma for 
subjects randomized to intervention group. For patients who proceed to the operating room during 
fluid resuscitation, the anesthesiology team will continue fluid administration per study protocol. 
Control: 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.1 Crystalloid administration may be terminated 
before the entire dose has been administered if patients show clinical improvement, or if the 
treating clinician has concerns about circulatory overload. After the initial dose of crystalloids has 
been given, subsequent fluid resuscitation (crystalloid or colloid) will be given at the discretion of 
the treating clinician. 
 
 
Observational Arm: Patients with suspected sepsis who do not meet the criteria for 
randomization or unable to obtain informed consent in a timely fashion (within 3 hours of research 
team being notified) will be enrolled in a prospective observational arm of the study. Baseline 
demographic and hospitalization data including the fluid therapy per the attending physician’s 
discretion will be collected. Blood samples will also be collected at 0, 2, 3, 6, 12, and 24 hours 
upon determination of patients’ eligibility for the observational study arm. A waiver of informed 
consent with be requested given that no intervention will be performed on the patient and that the 
study will be at minimal risk to the patient. The research team will attempt to obtain written 
informed consent from the patient or his/her legal authorized representative for 24 hours after 
patient enrollment into the observational study arm. If informed consent is denied by the patient 
or his/her legal authorized representative, no further data or blood samples will be collected and 
any data or blood samples collected prior to decline of participation will not be used in this study. 
 
Endpoints of Resuscitation: Fluid resuscitation in both the intervention and the control arms will 
be titrated to serial reassessments of the patient’s volume status via blood pressure monitoring 
(MAP > 65 mmHg), urine output measurements (goal of ≥ 0.5 cc/kg/hr), CVP measurements (>8 
mmHg), stroke-volume variation on hemodynamic monitors (such as the Vigileo), inferior vena 
cava (IVC) collapsibility index via bedside ultrasound,24 and lactate clearance (goal of ≥ 50% 
clearance after 6 hours of resuscitation). Serial laboratory examinations including lactate levels 
will be performed per standard of care in the ICU, until the lactate has normalized. Additional fluid 
support after the initial plasma or crystalloid bolus will be given at the discretion of the treating 
clinician, keeping in mind that septic shock patients in several randomized trials required 6-8L 
crystalloid per day.25-27 
Co-interventions: Both groups will receive standard care following Surviving Sepsis Guidelines, 
including procurement of blood cultures, administration of broad-spectrum antibiotics, transfusion 
of packed red blood cells for hemoglobin < 7 mg/dL, and use of vasopressors to maintain MAP > 
65 mmHg. 
 
Data Collection: 
Data  collected will include: demographics,  past medical history,  hospital information  including 


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initial resuscitation information and post-operative care, complications (Appendix A), and 
discharge information. A list of the data elements to be collected can be found in Appendix A. 
Data will be collected from the subject’s medical record and the trauma registry. Risk/Safety 
evaluation will be performed at half enrollment (at 13 enrolled and randomized patients). 
 
All subjects enrolled in this study will be assigned a study specific number. The de-identified data 
will be entered into a secure, password protected database accessible to only those involved in 
the study. A study linking log which will link subject identifiers to the study number will be kept by 
the study PI. 
 
To ensure patient confidentiality is maintained at all times, all data will be maintained in 
accordance with HIPAA rules and regulations. Hard copy source documentation will be kept in a 
secure area in a locked office and electronic data will be stored on secure, password-protected 
computers accessible to only those study specific personnel. 
 
Outcomes - Biomarkers of Endothelial and Glycocalyx Injury: The primary outcome is a 
reduction in serum biomarkers associated with glycocalyx breakdown (syndecan-1, sTM), 
endothelial leakage (sFLT-1, VEGF, sTM), sympatho-adrenal activation (NE, epinephrine), and 
inflammation (VEGF, sRAGE, HMGB-1, IL-6, 8, 10, 1α, 1β) in the plasma group. A rodent model 
has shown evidence of glycocalyx restoration after 2 hours of resuscitation with plasma as 
compared to crystalloid.15 Biomarkers will be drawn at 0, 2, end of initial bolus of fluid 
administration, 6, 12, and 24 hours to evaluate their trend in response to plasma versus crystalloid 
resuscitation. Timing of biomarker lab draw at the end of the initial fluid bolus will be variable since 
termination of fluid resuscitation depends on patients’ clinical response. Lactic acid will be drawn 
per standard of care to guide resuscitation. Standard labs for critically ill patients (such as 
complete blood count, basic metabolic panel, and arterial blood gases) will be obtained per STICU 
protocol. See Table 2 for timing of biomarker lab draws. Funding for measuring biomarkers will 
be obtained from an additional source if the grant is awarded. 
Secondary 
outcomes 
include 
additional volume of 
fluid 
 required 
for 
resuscitation after the 
initial bolus of study 
fluid 
(crystalloid  or 
plasma) within the first 
24 
hours 
of 
resuscitation, time on vasopressors, time until lactate normalization, ventilator days, ICU-free 
days, and hospital length of stay. Organ dysfunction will be measured including acute lung injury 
and acute renal failure. Standardized definitions will be used as outlined in the method of 
operation used in previously conducted trials by our group.28 Potential harms of plasma 
administration 
will 
be 
assessed 
including 
symptomatic 
and 
asymptomatic 
venous 
thromboembolisms, transfusion-related allergic reactions, febrile non-hemolytic transfusion 
reaction, delayed-serological transfusion reactions, and transfusion-associated circulatory 
overload. Risk/safety evaluation will be performed at half recruitment (13 randomized patients). 


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Blinding: The healthcare provider will not be able to be blinded to the study intervention. The 
outcome assessors will be blinded when feasible, and the laboratory technicians and statisticians 
will be blinded. 
Sample Size: We propose to enroll 26 patients (13 in each treatment arm) for the pilot randomized 
study to obtain unbiased estimates of treatment effect. We propose to enroll up to 100 patients to 
the observational study arm. Because this is a feasibility pilot study, we do not provide a power 
analysis for any outcomes since no formal hypothesis testing will be conducted. Instead, we will 
calculate estimates of treatment effect and 95% confidence intervals for all measures. We will 
also calculate probabilities of treatment benefit/harm using Bayesian analyses and conservative 
neutral priors. These estimates will inform the design of a future larger trial. 
Statistical Analysis: Because this is a pilot, efficacy trial, we will perform both a per-protocol and 
an intention-to-treat analysis. Both frequentist and Bayesian analysis will be performed. For the 
primary outcome and all continuous outcomes (using variable transformations if needed), we will 
use mixed models that include group and time period as covariates with a random subject effect. 
We will report group differences and 95% CIs from these models. For binary outcomes, a log 
binomial (or Poisson in case of non-convergence) will be used to estimate relative risks and 95% 
CIs. Hazard ratios and 95% CIs will be reported for time-to-event comparisons. For the Bayesian 
analysis, neutral conservative priors (that exclude large treatment effects almost never seen with 
medical interventions) will be used to estimate the probability of both benefits and harms, as 
defined by our primary and secondary outcomes. 
 
 
 
 
References 
1. 
Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International 
Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 
2017;45(3):486-552. 
2. 
Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in 
severe sepsis and septic shock, patterns and outcomes: an analysis of a large national 
database. Intensive Care Med. 2017;43(5):625-632. 
3. 
Johansson P, Stensballe J, Ostrowski S. Shock induced endotheliopathy (SHINE) in 
acute critical illness - a unifying pathophysiologic mechanism. Crit Care. 2017;21(1):25. 
4. 
Chignalia AZ, Yetimakman F, Christiaans SC, et al. The Glycocalyx and Trauma: A 
Review. Shock. 2016;45(4):338-348. 
5. 
Ince C, Mayeux PR, Nguyen T, et al. The Endothelium in Sepsis. Shock. 
2016;45(3):259-270. 
6. 
Chelazzi C, Villa G, Mancinelli P, De Gaudio AR, Adembri C. Glycocalyx and sepsis- 
induced alterations in vascular permeability. Crit Care. 2015;19:26. 
7. 
Hou PC, Filbin MR, Wang H, et al. Endothelial Permeability and Hemostasis in Septic 
Shock: Results From the ProCESS Trial. Chest. 2017;152(1):22-31. 
8. 
Ostrowski SR, Berg RM, Windelov NA, et al. Coagulopathy, catecholamines, and 
biomarkers of endothelial damage in experimental human endotoxemia and in patients 
with severe sepsis: a prospective study. J Crit Care. 2013;28(5):586-596. 
9. 
Oberholzer A, Souza SM, Tschoeke SK, et al. Plasma cytokine measurements augment 
prognostic scores as indicators of outcome in patients with severe sepsis. Shock. 
2005;23(6):488-493. 


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10. 
Torres Filho IP, Torres LN, Salgado C, Dubick MA. Plasma syndecan-1 and heparan 
sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after 
different resuscitation fluids. Am J Physiol Heart Circ Physiol. 2016;310(11):H1468- 
1478. 
11. 
Nelson A, Johansson J, Tyden J, Bodelsson M. Circulating syndecans during critical 
illness. APMIS. 2017;125(5):468-475. 
12. 
Holcomb JB, del Junco DJ, Fox EE, et al. The prospective, observational, multicenter, 
major trauma transfusion (PROMMTT) study: comparative effectiveness of a time- 
varying treatment with competing risks. JAMA Surg. 2013;148(2):127-136. 
13. 
Robinson BR, Cotton BA, Pritts TA, et al. Application of the Berlin definition in 
PROMMTT patients: the impact of resuscitation on the incidence of hypoxemia. J 
Trauma Acute Care Surg. 2013;75(1 Suppl 1):S61-67. 
14. 
Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal trauma resuscitation causes 
more cases of abdominal compartment syndrome. Arch Surg. 2003;138(6):637-642; 
discussion 642-633. 
15. 
Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a 
rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289-1295. 
16. 
Rahbar E, Cardenas JC, Baimukanova G, et al. Endothelial glycocalyx shedding and 
vascular permeability in severely injured trauma patients. J Transl Med. 2015;13:117. 
17. 
Straat M, Muller MC, Meijers JC, et al. Effect of transfusion of fresh frozen plasma on 
parameters of endothelial condition and inflammatory status in non-bleeding critically ill 
patients: a prospective substudy of a randomized trial. Crit Care. 2015;19:163. 
18. 
Chang R, Holcomb JB, Johansson PI, Pati S, Schreiber MA, Wade CE. Plasma 
Resuscitation Improved Survival in a Cecal Ligation and Puncture Rat Model of Sepsis. 
Shock. 2017. 
19. 
Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 Statement: Updated 
guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 
2010;63(8):834-840. 
20. 
Zanotti Cavazzoni SL, Dellinger RP. Hemodynamic optimization of sepsis-induced tissue 
hypoperfusion. Crit Care. 2006;10 Suppl 3:S2. 
21. 
Moore LJ, Jones SL, Kreiner LA, et al. Validation of a screening tool for the early 
identification of sepsis. J Trauma. 2009;66(6):1539-1546; discussion 1546-1537. 
22. 
Wawrose R, Baraniuk M, Standiford L, Wade C, Holcomb J, Moore L. Comparison of 
Sepsis Screening Tools' Ability to Detect Sepsis Accurately. Surg Infect (Larchmt). 
2016;17(5):525-529. 
23. 
Tinmouth A. Assessing the Rationale and Effectiveness of Frozen Plasma Transfusions: 
An Evidence-based Review. Hematol Oncol Clin North Am. 2016;30(3):561-572. 
24. 
Gui J, Yang Z, Ou B, et al. Is the Collapsibillity Index of the Inferior Vena Cava an 
Accurate Predictor for the Early Detection of Intravascular Volume Change? Shock. 
2017. 
25. 
Investigators A, Group ACT, Peake SL, et al. Goal-directed resuscitation for patients 
with early septic shock. N Engl J Med. 2014;371(16):1496-1506. 
26. 
Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for 
septic shock. N Engl J Med. 2015;372(14):1301-1311. 
27. 
Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early 
septic shock. N Engl J Med. 2014;370(18):1683-1693. 
28. 
Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood 
cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR 
randomized clinical trial. JAMA. 2015;313(5):471-482. 


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29. 
Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen 
saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 
2010;303(8):739-746. 


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Appendix A: 
List of Data Elements 
Demographics 
• 
Age 
• 
Gender 
• 
Race 
• 
Ethnicity 
• 
Height/Weight/BMI 
 
Past Medical History 
• 
Admitting Diagnosis (type of injury - blunt/penetrating) 
• 
Concomitant medical conditions/diseases 
• 
Current home medications 
 
Hospital Information 
• 
Admission date/time (ED and STICU/SIMU) 
• 
Time of injury 
• 
Type of injury 
• 
Pre-hospital treatment (LSIs) 
• 
Initial resuscitation therapy (blood products, IR, OR, LSIs) 
• 
Vital signs 
• 
Degree of pretibial edema 
• 
Laboratory results 
• 
Diagnostic procedure results 
• 
Daily STICU/SIMU data ( i.e. ventilator settings, vital signs) 
• 
Vasopressor use (medication, dose) 
• 
Blood products and fluids 
• 
Sepsis diagnostic information 
• 
Operative and endovascular interventions 
• 
Complications (ARDS, AKI, venous thromboembolic events, sepsis, severe sepsis, septic 
shock, transfusion reactions, infections, multi-organ failure, pneumonia) 
 
Discharge Information 
• 
Date/time of discharge 
• 
Disposition 
• 
ISS 
• 
AIS 
• 
Cause of death (as applicable) 
• 
Number of ventilator days 
• 
Number of ICU days