Shock, Whole Blood and Assessment of TBI- S.W.A.T.- Linking Investigations in Trauma and Emergency Services (LITES) Task Order 2
Conditions: Hemorrhagic Shock, Traumatic Brain Injury
Sponsor: University of Pittsburgh

 
Task Order 2: Shock, Whole blood and Assessment of TBI (SWAT) 
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LITES Task Order 2: Shock, Whole blood and Assessment of TBI (SWAT). Version 5 dated 2019-12-04 
 
Executive Summary 
 
     The LITES Network is an operational trauma center consortium which has the expertise, track 
record and confirmed capabilities to conduct prospective, multicenter, injury care and outcomes 
research of relevance to the Department of Defense (DoD). 
     Hemorrhage and Traumatic Brain Injury (TBI) are responsible for the largest proportion of all 
trauma-related deaths. It is the poly-trauma patient who suffers both hemorrhagic shock and 
traumatic brain injury where a paucity of evidence exists to direct treatment, limiting the 
development of beneficial trauma practice guidelines. 
     The use of Whole Blood (WB) for early trauma resuscitation has been touted as the ‘essential 
next step’ in the evolution of trauma resuscitation.  Despite its historical and more recent use, little 
is known regarding WB’s benefit relative to the ‘current practice’ ratio-based blood component 
therapy in the acutely bleeding patient, and even less is known regarding its effects in patients 
with TBI. 
 
AIM#1: Evaluate patient centered outcomes associated with early whole blood resuscitation 
practice as compared to component resuscitation in poly-trauma patients with hemorrhagic shock 
and further characterize outcome benefits in those with traumatic brain injury.  Whole blood 
Clinical Practice Guidelines will be prepared, including staff training resources, and provided for 
use by the Government. 
 
AIM#2: Characterize blood pressure and resuscitation endpoints during the acute resuscitation 
phase of care and the associated/attributable outcomes for traumatic brain injury in patients with 
hemorrhagic shock. 
 
General Hypothesis #1: Whole blood resuscitation will be associated with improved mortality and 
resuscitation outcomes in poly-trauma patients and long term neurological outcome in those 
patients with traumatic brain injury as compared to those resuscitated with component therapy. 
 
General Hypothesis #2: Differences in prehospital and acute phase resuscitation systolic blood 
pressure will be associated with differential outcomes in patients with traumatic brain injury at 
discharge and at 6 months. 
 
Study Design: The LITES network will perform a multicenter, prospective, observational cohort 
study over a 4-year period to determine the impact of whole blood resuscitation in trauma patients 
with hemorrhagic shock at risk of large volume resuscitation with and without TBI.  Early whole 
blood resuscitation will be compared to standard component resuscitation. The study will also 
further characterize blood pressure and resuscitation endpoints in poly-trauma  
 

 
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patients with traumatic brain injury. Trauma sites with appropriate characteristics will be selected 
within the LITES Network across the country. 
 
Study Setting: The study will be performed utilizing busy level I trauma centers within the LITES 
Network located across the country, at sites where either whole blood has currently been 
incorporated into standard of care or where component blood transfusion is being utilized for 
patients in hemorrhagic shock at risk for large volume resuscitation. 
 
Study Population: The study will focus on patients who suffer blunt or penetrating injury, 
transported to a Task Order 002 participating LITES trauma center with evidence of hemorrhagic 
shock at risk of large volume blood resuscitation. 
 
Background 
 
     The LITES Network is an operational trauma center consortium which has the expertise, track 
record and confirmed capabilities to conduct prospective, multicenter, injury care and outcomes 
research of relevance to the Department of Defense (DoD). Clinical trials from the point of injury 
in the prehospital arena through the trauma bay and operating theatre, through ICU and beyond 
discharge are feasible and critical to the overall goals of the network. Novel capabilities include 
prehospital point of care testing for shock severity and sequential coagulopathy measurements. 
The network and leadership have a track record of Exception From Informed Consent (EFIC) 
trials for planned emergency research and expertise with those injury subtypes including 
traumatic brain injury, hemorrhagic shock and coagulopathy of trauma, poly-trauma and severe 
extremity trauma. In addition to the track record and proven capabilities, the LITES Network uses 
a central IRB and efficient methods to minimize time, resources, cost and regulatory burdens to 
improve recruitment, consent rates and ease of data acquisition in order to promote successful 
execution of those task orders provided to the network from the DoD.     
 
     Traumatic injury represents an incredible health care burden in the United States and 
worldwide.1 Hemorrhage and Traumatic Brain Injury (TBI) are responsible for the largest 
proportion of all trauma-related deaths.2-4 Despite advances in trauma resuscitation and brain 
injury management, few therapeutic interventions are available to reduce the downstream 
morbidity and mortality attributable to these injury patterns.5-7 It is the poly-trauma patient who 
suffers both hemorrhagic shock and traumatic brain injury where a paucity of evidence exists to 
direct treatment, limiting the development of beneficial trauma practice guidelines.  
 
    Ongoing traumatic blood loss is complicated by trauma induced coagulopathy which results in 
further unbridled hemorrhage and resultant shock and organ dysfunction.8-17 Secondary to 
increasing evidence and knowledge, in-hospital resuscitation of traumatic hemorrhage has  

 
Task Order 2: Shock, Whole blood and Assessment of TBI (SWAT) 
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changed over the past decade to reduce the coagulopathic response to ischemia and tissue 
injury.18-23 The underlying principle of current resuscitation practice focuses on preventing or 
reversing the effects of coagulopathy with the early use of a balanced component transfusion 
strategy (1:1:1 - plasma: packed red blood cells: platelets).24 This reconstituted strategy has also 
been coined ‘whole blood-like’ resuscitation despite being inferior from a compositional standpoint 
relative to Whole Blood (WB).25-26 The use of WB was historically the gold standard for treating 
hemorrhagic shock during World War I and II, prior to sweeping changes in blood banking 
practice.27 The use of WB for early trauma resuscitation is making a resurgence, primarily based 
upon the military experience28-32 and has been touted as the ‘essential next step’ in the evolution 
of trauma resuscitation.26,33  Despite its historical and more recent use, little is known regarding 
WB’s benefit relative to the ‘current practice’ ratio based blood component therapy in the acutely 
injured patients and even less is known regarding its effects in patients with TBI.    
 
     Permissive hypotension has been thought to improve outcome in injured patients with 
hemorrhagic shock in the prehospital and acute resuscitation phase of treatment allowing for the 
ability to obtain surgical control of bleeding while minimizing ongoing hemorrhage.34-37 Despite 
this benefit for hemorrhagic shock patients, hypotension has been consistently shown to be 
associated with worse outcomes in patients with TBI.38-40 Interestingly, newer animal data 
suggests permissive hypotension may be beneficial in a swine TBI model.41 The majority of prior, 
high level TBI trials have excluded patients with concomitant hemorrhagic shock. Prospective 
evidence and long term TBI outcome data are lacking for these complex poly-trauma patients and 
the most appropriate blood pressure and most efficacious resuscitation target for patients with 
TBI and acute hemorrhage remain poorly characterized.   
 
Preliminary Data 
     Based upon the belief that early whole blood resuscitation represents the most efficacious 
hemostatic resuscitation product for the management of hemorrhage, the University of Pittsburgh 
started initially with 2 units and demonstrated feasibility and 
safety of a WB early resuscitation program30,42 and now has 4 
units of cold stored, low titer, platelet replete-leukocyte 
reduced, group O-WB for urgent release in the emergency 
department, without the need for blood typing or cross 
matching, for patients in hemorrhagic shock. We have 
currently transfused over 169 patients with over 296 units of 
WB without evidence of safety concerns. We plan to increase 
our urgent release availability to 6 units of WB within the next 
6 months. We have simultaneously been monitoring  
 
Figure 1 

 
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LITES Task Order 2: Shock, Whole blood and Assessment of TBI (SWAT). Version 5 dated 2019-12-04 
WB patients for hemolytic side effects from ABO mismatched whole blood.42 In 27 non-group O 
patients, there were no significant differences in laboratory hemolysis markers. (Figure 1) These 
preliminary and published data verify the feasibility and safety of this type of intervention in 
patients with hemorrhagic shock, providing the backdrop for the successful execution of the 
proposed observational cohort. Other trauma centers in the LITES Network are initiating and 
executing similar WB programs which we will utilize for the current proposal.  
 
Objectives/Specific Aims/Hypothesis 
 
     Due to the need to robustly characterize the safety and efficacy of cold-stored, urgent release, 
whole blood resuscitation in poly-trauma patients and provide essential insight into the most 
appropriate resuscitative target for injured patients with both hemorrhagic shock and TBI, we 
propose the following primary AIMs. 
 
AIM#1: Evaluate patient centered outcomes associated with early whole blood resuscitation 
practice as compared to component resuscitation in poly-trauma patients with hemorrhagic shock 
and further characterize outcome benefits in those with traumatic brain injury. 
  
AIM#2: Characterize blood pressure and resuscitation endpoints during the acute resuscitation 
phase of care and the associated/attributable outcomes for traumatic brain injury in patients with 
hemorrhagic shock. 
 
Hypothesis #1A: Whole blood resuscitation will be associated with a lower 4 hour mortality in 
poly-trauma patients as compared to those resuscitated with component therapy. 
 
Hypothesis #1B: Whole blood resuscitation will be associated with a lower incidence of 12 hour 
and 24 hour mortality, a lower incidence of death from exsanguination, incidence of MOF, 
nosocomial infection, improved transfusion ratios, lower overall blood transfusion requirements 
and shorter time to hemostasis as compared to those resuscitated with component therapy. 
 
Hypothesis #1C: Whole blood resuscitation will be associated with an improved Glasgow 
Outcome Score-Extended at 6 months post injury as compared to those resuscitated with 
component therapy in patients with traumatic brain injury. 
 
Hypothesis #2A: A nadir prehospital and acute phase resuscitation systolic blood pressure 
greater than or equal to 120 mmHg will be associated with improved traumatic brain injury 
outcomes at discharge and at 6 months. 
 

 
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Hypothesis #2B: The magnitude of the dose depth curve of systolic blood pressure during the 
prehospital and acute phase resuscitation will be associated with neurological outcome 
differences at discharge and at 6 months following traumatic brain injury. 
 
Research Design and Methods  
 
Study Design: The LITES Network will perform a multicenter, prospective, observational cohort 
study over a 4 year period to determine the impact of whole blood resuscitation in trauma patients 
with hemorrhagic shock at risk of large volume resuscitation with and 
without TBI.  Early whole blood resuscitation will be compared to 
standard component resuscitation. The study will also further 
characterize blood pressure and resuscitation endpoints in poly-
trauma patients with traumatic brain injury. Six trauma sites with 
appropriate characteristics will be selected from network sites across 
the country. (Figure 2) 
 
Study Setting: The study will be performed utilizing busy level I 
trauma centers from within the LITES Network located across the 
country, at sites where either whole blood has currently been 
incorporated into standard of care or where component blood 
transfusion is being utilized for patients in hemorrhagic shock at risk for large volume 
resuscitation. Due to the paucity of trauma centers who are currently utilizing whole blood for 
trauma patients as standard of care, the potential to incorporate additonal sites may be required 
over time.  
 
Study Population: The study will focus on patients who suffer blunt or penetrating injury, 
transported to a Task Order 002 participating LITES trauma center with evidence of hemorrhagic 
shock at risk of large volume resuscitation. 
 
Inclusion Criteria: Patients with blunt or penetrating injury who meet the following criteria: 
1, 2, and 3  
 
1) Has 2 or more of any of the following: 
a. Hypotension (systolic blood pressure ≤ 90 mmHg) in the prehospital setting or 
within 60 minutes of hospital arrival, 
b. Penetrating mechanism, 
c. FAST abdominal ultrasound is positive or equivocal or deferred by clinical team 
due to emergent visit to Interventional Radiology or a need for emergent 
laparotomy, thoracotomy, or vascular exploration. 
Figure 2  

 
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d. Heart Rate ≥ 120 in the prehospital setting or within 60 minutes of hospital 
arrival. 
 
AND 
2) Taken to the Operating Room (laparotomy, thoracotomy or vascular exploration) or 
Interventional Radiology within 60 minutes of arrival. 
AND 
3) Blood/blood component transfusion in prehospital setting, ED or OR within 60 minutes 
of arrival. 
 
 
Exclusion Criteria: 
1) Age < 15 
2) CPR > 5 consecutive minutes without ROSC 
3) Penetrating brain injury with brain matter exposed 
4) ED death 
5) Known pregnancy 
6) Known Prisoners 
 
Inclusion and exclusion criteria will be assessed based on available information at the time of 
enrollment.  Although all reasonable efforts will be made by the prehospital crew to either directly 
witness or obtain documentation of qualifying vitals, due to the nature of the emergency pre-
hospital setting, there may be occasions where the prehospital medical crew must rely on verbal 
report of inclusion criteria, including qualifying vitals, from the referring hospital or EMS agency.  
In these instances, if, after subsequent review of outside hospital and/or EMS agency 
documentation, it is determined that the subject did not meet inclusion criteria and/or met 
exclusion criteria, the subject will remain enrolled in the study based on the information available 
at the time the subject was enrolled in the study. 
 
Recruitment and Consent 
Initial blood sampling must be performed as early as possible after arrival (0 (+ up to 2), 4 (+/- 2) 
and 24 hours (+/- 12)). Because the initial early samples will be drawn before many subjects are 
able to consent due to their illness, and before surrogate decision-makers are typically available 
to consent, we are requesting waivers of consent to be used for: A) initial medical record review 
to verify eligibility, and B) 3 blood samples will be taken within 36 hours of arrival. A Waiver of 
HIPAA Authorization is also requested for the extraction of research data from the medical record 
during the first 36 hrs of admission. Subjects whose medical conditions improve to the point of 
being able to make their own medical decisions will sign a consent to continue further study-
related procedures. Subjects who remain critically ill, receiving continuous or intermittent 
sedatives, who are obtunded/disoriented from illness or injury, or are unable to dictate their own 
care will have proxy consent obtained from their previously appointed power of attorney (if one 

 
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LITES Task Order 2: Shock, Whole blood and Assessment of TBI (SWAT). Version 5 dated 2019-12-04 
exists) or the subject’s legally authorized representative. If there is no designated LAR, a proxy 
will be selected consistent with state laws.  
 
Waiver of Consent [A]       Medical record review for the identification of potential subjects 
 
The research involves no more than minimal risk to the subjects [45 CFR 46.116 (d)(1)]. 
 
The screening procedure poses minimal risk to the subjects. It involves a chart review to 
determine eligibility that will be performed on the medical records or by the attending/treating 
clinician(s).  
 
The only risk is breach of confidentiality that will be minimized by removing all patient identifiers 
and replacing them with a research code number; and storing the coded, de identified data on a 
secure pass word protected data base behind a University firewall. 
 
The waiver or alteration will not adversely affect the rights and welfare of the subjects [45 CFR 
46.116 (d)(2)]. 
 
Access to and use of patient medical record information will be limited to the research study 
investigators and their staff who already have access to this PHI based on the clinical 
responsibilities of the principal investigator that extends to their research teams. 
 
The research could not practicably be carried out without the waiver or alteration [45 CFR 46.116 
(d)(3)]. 
 
It is not practicable to try to obtain consent simply to identify eligible patient participants 
 
Whenever appropriate, the subjects will be provided with additional pertinent information after 
participation [45 CFR 46.116 (d)(4)]. 
 
It is unlikely that any information pertinent to the trauma patient's care will be obtained through 
this limited recruitment activity. 
 
Waiver of Consent [B]  Blood sampling during the first 36 hrs of admission. 
 
The research involves no more than minimal risk to the subjects [45 CFR 46.116 (d)(1)]. 
 
Blood samples for this study will be obtained in conjunction with draws for clinical care whenever 
possible. In cases where it is not possible to coordinate research sample collection with clinical 
sample collection, trauma patients will already have an existing central line that can be utilized to 

 
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obtain the sample or venipuncture will be performed by clinically trained personnel using aseptic 
techniques.  
 
Obtaining three 20 ml samples of blood will pose only minimal risk to these patients as collection 
of the samples 
will 
be via 
existing 
vascular 
access 
using 
aseptic 
techniques. 
The risk of a breach of confidentiality will be minimized by removing all patient identifiers and 
replacing them with a research code number; and storing the coded, de-identified data on a 
secure pass word protected data base behind a University firewall. 
 
The waiver or alteration will not adversely affect the rights and welfare of the subjects [45 CFR 
46.116 (d)(2)]. 
 
The acquisition of blood samples will be performed by trained and experienced research staff, 
under the oversight of the Principal Investigator, a physician with a research focus on 
coagulopathy, massive transfusion and clinical outcomes of traumatic injury 
 
The research could not practicably be carried out without the waiver or alteration [45 CFR 46.116 
(d)(3)]. 
 
Understanding the early response to whole blood administration, component therapy and 
hemorrhagic shock is an important focus of this proposal since early factors influence later events 
such as the development of multiple organ failure. Identifying and discovering which early 
mechanistic biomarkers might influence outcomes in this population is an important part of this 
study.   
 
Samples are required in the first 36 hours in order to determine the underlying mechanisms of 
whole blood benefit, which is one of the main objectives of the study. Sampling needs to occur 
approximately at the time of whole blood transfusion and soon after. Whole blood and component 
arm transfusion, in these severely injured trauma patients, will for the majority of patients occur 
within the first 4 hours of admission. Sampling at the proposed time points in the first 36 hours 
are essential and have to occur in relationship to this early whole blood and component 
transfusion window. Sampling beyond these early time points will not allow the main objectives of 
the study to be accomplished. 
 
Whenever appropriate, the subjects will be provided with additional pertinent information after 
participation.  [45 CFR 46.116 (d)(4)]. 
 
Subjects whose medical conditions improve to the point of being able to make their own medical 
decisions will sign a HIPAA-compliant consent to continue further study-related procedures. 
Subjects who remain critically ill, receiving continuous or intermittent sedatives, who are 

 
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obtunded/disoriented from illness or injury, or are unable to dictate their own care will have proxy 
consent obtained in compliance with local regulations. 
  
A Waiver of HIPAA Authorization is also requested and justified, to be used in conjunction 
with the Waiver of Consent [B], for the extraction of research data from the medical record.  
 
To ensure that this research use of the PHI involves no greater than minimal risk to privacy, 
describe your plan to protect patient-subject identifiers from improper use or disclosure. 
[45 CFR 164.512 (i)(2)(ii)(A)(1)] 
 
All electronic data will be stored on a secure password protected server. Each subject will be 
given a unique study identifier, which will be used for all patient samples and all clinical data 
sheets. The key to identify subjects with their unique study number will be kept on a secure drive 
and only accessed by the PI, co-investigators or their designees according to the University of 
Pittsburgh and UPMC policies. 
 
Describe your plan to destroy patient-subject identifiers at the earliest opportunity 
consistent with the research.  Indicate at what point in the research those identifiers will 
be destroyed.  If applicable, provide a health, research or legal justification for retaining 
the identifiers. [45 CFR 164.512 (i)(2)(ii)(A)(2)] 
 
At the time of data entry, all patient identifiers will be stripped and the data will be entered in a 
computerized database by code study number and all other records will be destroyed. Any info 
collected in hard copies will be secured in a locked area until data entry is completed. Only the 
PI, co-investigators or their designees will have access to this password protected database.  A 
linkage to the actual patient will be kept on a separate secure password protected server.Provide 
your assurance that this information will not be reused or disclosed to any other person 
or entity (i.e., other than the listed investigators and their research staff), except as 
required by law, for authorized oversight of the research study, or for other research for 
which the IRB has granted a waiver of the written HIPAA authorization. [45 CFR 164.512 
(i)(2)(ii)(A)(3)] 
 
All information generated in the course of the study will be accessed by the investigators or their 
designees according to the local site policies. Any sharing outside the University will be done with 
deidentified data. 
 
Why could this research not practicably be conducted unless the waiver of written HIPAA 
authorization is granted? [45 CFR 164.512 (i)(2)(ii)(B)]. 
 

 
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Understanding the early response to whole blood administration, component therapy and 
hemorrhagic shock is an important focus of this proposal since early factors influence later events 
such as the development of multiple organ failure. Thus it will be necessary to establish baseline 
parameters during this time point, in order to assess the effect of whole blood versus component 
blood products on outcomes such as time to hemostasis, nosocomial infection or transfusion 
reaction. Extraction of research data during this early period will be essential to understand these 
processes. 
 
Why could this research not practicably be conducted without access to and use of the 
identifiable medical record information? [45 CFR 164.512 (i)(2)(ii)(C)]. 
 
It is not possible to conduct this time-sensitive research in the Emergency Department and ICUs 
unless we are able to collect real time data to meet the outcomes associated with whole blood vs 
blood component therapy such as time to hemostasis, nosocomial infection, transfusion reaction 
and multiple organ failure.  
 
Explain why the nature and amount of the medical record information that will be collected 
is felt to be the minimum necessary in order to conduct this research study. [45 CFR 
164.514 (d)]. 
 
Only medical information that is pertinent to the outcomes will be collected. 
 
If no appropriate legally authorized representative can be identified, the subject’s ability to provide 
direct consent will be assessed until the time of hospital discharge. For subjects with some 
decision-making ability but who still require proxy consent, subjects’ assent for participation may 
be obtained verbally. If the subject improves to the point of being capable of his or her own medical 
decision-making, the subject’s consent will be obtained to continue participation. A copy of the 
informed consent document may be placed in the medical record. The original informed consent 
document will be kept with the study records in a locked file cabinet and a copy given to the 
subject or the subject’s legally authorized representative. Consent and proxy consent will be 
obtained by the investigators listed on the first page of the consent document or properly trained 
research staff.  
 
In cases where the LAR is not present in the hospital, the consent will be obtained by phone/fax 
or electronically. The study will be discussed with the LAR over the telephone. If the LAR agrees, 
the consent form (ICF) will be e-mailed or faxed or texted to the number provided by the LAR. 
The research staff will go over the ICF with the Legally Authorized Representative. If the LAR 
agrees to participate in the research, the LAR will sign the ICF and send back to the research 
staff by fax, text or scanned by e-mail. In cases where the proxy does not have access to a 
scanner or fax, they may take an electronic picture of the signed signature page and forward the 

 
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same to research personnel. If obtaining informed consent is not feasible and a legally authorized 
representative is not reasonably available, the informed consent will be sent via trackable means. 
The letter will be sent via trackable means and documentation of the addressee and date of 
mailing and the delivery confirmation with will be kept in the study folder. The subject or their LAR 
will return the consent using a study provided postage paid envelope. If a signed consent 
document is not obtained, we don’t receive any signed no research activities will be performed 
nor data will be extracted from the medical record, beyond 36 hours period covered by the 
Waivers of Consent and HIPAA.  Samples and data acquired under those Waivers will be 
retained.  
 
Whole Blood Transfusion Sites: Busy, Level 1 trauma centers from within the LITES Network will 
be selected based upon the ability to enroll patients with the proposed inclusion and exclusion 
criteria who have already implemented or are in the direct process of implementing an urgent 
release whole blood resuscitation protocol and are able to perform all necessary requirements for 
the planned prospective cohort study proposed. Those sites with the capabilities to deliver at least 
4 units of WB will be selected for participation with preference given to ≥ 6 units urgent release 
WB capabilities. WB sites will be selected based upon the ability to enroll 33% of patients for the 
overall cohort study. As WB resuscitation becomes increasingly more widely adopted, there exists 
the potential to include additional WB sites from within the network as respective institutional 
practice changes over the 4 year time point of the study. Similarly, there exists the potential to 
incorporate additional trauma sites into the LITES network based upon their abilities to enroll poly-
trauma patients in hemorrhagic shock and the utilization of WB resuscitation. As different trauma 
sites may utilize differing WB products with different titer levels, matching processes, and 
leukocyte reducing capabilities, these WB characteristics will be documented for all sites and for 
all WB units and respective patients enrolled.  
 
Component Transfusion Sites: Busy, Level 1 trauma centers from within the LITES Network will 
be selected based upon the ability to enroll patients with the proposed inclusion and exclusion 
criteria who currently utilize initial ratio based resuscitation (1:1:1 or 1:1:2) for patients at risk of  
large volume transfusion and are able to perform all necessary requirements for the planned 
prospective cohort study proposed. There is the potential for sites to differ based upon their 
current massive transfusion protocol and these standard practices will be documented for each 
site.  
 
Primary TBI Subgroup Stratification: Presence or absence of Traumatic Brain Injury (TBI) will be 
the principle subgroup stratification for the study. Presence of TBI will be based upon CT imaging 
results (classification: subarachnoid, subdural, intracerebral hemorrhage, intracranial injury, 
epidural, +/- shift, multifocal with specific classification) and TBI severity will be characterized and 
grouped by GCS, Abbreviated Injury Severity (AIS) coding, ICD-10 head region severity scores 

 
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and Rotterdam CT scores. The data coordinating center will collect de-identified serial head CT 
images (first two performed) from all participating sites in patients with a head abbreviated injury 
score of 2 or greater (head AIS >2). These images will allow the determination of Rotterdam CT 
head scores to appropriately classify traumatic brain injury severity. Serial head CTs (first two) 
will also be assessed for progression of injury. An independent and blinded neuroradiologist from 
the University of Pittsburgh will provide the classification of brain injury. 
 
Due to the nature of the population being studied, there will be patients who have clinically evident 
TBI but who do not have a head CT completed due to clinical intervention being a higher priority 
than diagnostic imaging. Often when patients require urgent clinical interventions, diagnostic 
scans (including CTs) are deferred until the patient is stabilized and the emergent issue is 
resolved.  Unfortunately, this means that sometimes a patient expires during intervention, and a 
CT is never obtained.  Therefore, patients who present in extremis with a clinically obvious TBI 
(eg: unhelmeted motorcyclist, falls from height, etc.) will be included in the TBI sub-group even if 
they do not have head CTs completed.  
 
Primary Study Outcome: The cohort study will be principally powered using 4 hour mortality as 
the primary outcome. This outcome was found to be significantly different across treatment arms 
in the recent PROPPR trial and early mortality time points have recently been recommended and 
deemed most appropriate for hemorrhagic shock clinical trials.24,43 Promoting survival beyond this 
time period may represent the critical period that is required for an injured patient to be transported 
to a higher echelon of care, particularly when injury occurs in austere environments. 
 
Secondary Non-TBI Clinical Outcomes: Secondary clinical outcomes will include 12 hr mortality, 
24hr mortality, 28 day mortality, time to hemostasis (defined by a WB or PRBC transfusion rate; 
≤ 
1unit/hour 
and 
surgeon 
directed 
intraoperative 
assessment), 
death 
from 
exsanguination/hemorrhage, blood and blood component transfusion requirements (over 1st four 
hours and total at 24hrs), Multiple Organ Failure, nosocomial infection, transfusion reaction, 
venous thromboembolism (VTE), ICU free days and ventilator free days. 
 
TBI Specific Outcomes: For the overall TBI subgroup, the principle outcome will be 6 month 
Extended Glasgow Outcome Scale (GOS-E). Additional TBI specific outcomes will include 
hemodynamic parameters (serial systolic and diastolic blood pressure and heart rate 
measurements), prehospital, arrival, serial and discharge Glasgow Coma Scale scores, need for 
craniectomy/craniotomy, need for mannitol administration, need for paralysis, need for barbiturate 
coma, need for hypertonic saline administration, need for ICP monitoring, ICP pressures (initial, 
max daily x 7 days), TBI progression based upon serial CT imaging in initial 48 hours and 
Galveston Orientation and Amnesia Test (GOAT score) at discharge. Each accrual site will 
transfer the TBI patient’s name, contact information, and basic injury characteristics, GOAT 
results, and discharge disposition  to the Clinical Coordinating Center in Pittsburgh. 

 
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Suicidal or emotionally distressed participants: If a participant reports suicidal ideation during the 
GOS-E, a risk assessment will be performed immediately by a trained neuropsychological 
technician under the supervision of a licensed neuropsychologist. If the participant is found to 
NOT be at imminent risk, resources will be given to the participant in the form of the Suicide 
Hotline and The Brain Injury Association of America website URL.  The technician will compose 
a 'Note To File' detailing their assessment and will make the other study team members aware of 
their assessment. If the participant is found to be at imminent risk, the technician will encourage 
the participant to go to their nearest local emergency room. These actions will be noted in the 
case file. 
 
Predefined Subgroups: Predefined subset analyses in addition to principle TBI subgroup analysis 
will be performed looking at 1) patients enrolled from the scene of injury versus those enrolled 
from a referral hospital, 2) patients with a preinjury history of vitamin K antagonist medication 
versus those without, 3) patients with preinjury history of antiplatelet medication versus those 
without, 4) patients with preinjury history of novel anticoagulant use versus those without, 5) 
patients who ultimately did or did not require massive transfusion (≥ 10 units blood in first 24hrs), 
6) patients who ultimately did or did not meet a critical transfusion threshold of ≥ 4 units PRBCs 
or whole blood in a 2 hour time period, 7) patients who ultimately did or did not require ≥ 6 units 
blood in first 24hrs, 8) patients who did or did not receive leukocyte reduction WB products, 9) 
TBI patients who did or did not receive a craniectomy/ craniotomy, 10) TBI patients who did or did 
not require ICP monitoring. It is recognized that the study is not appropriately powered for these 
subgroup comparisons and the results and conclusions formulated from these subgroup analyses 
will be considered exploratory in nature and will not be used as a basis for treatment 
recommendations. 
 
 
 
 
 
 
 
Specific Outcome Definitions: 
 
Denver MOF Score: The appropriate classification and timing of mortality will be captured 
in the data elements collected as described above. 
Of similar importance is the morbidity which ensues 
for those who survive their initial injury. Data 
elements that include the ability to calculate the 
Denver post-injury multiple organ failure score44-47 
will be collected over the first 7 days for those who 
are admitted to the ICU > 48 hours. (Figure 3) A total 
score > 3 will be considered MOF and the daily score 
will be determined up until post-injury day 7 or ICU 
discharge. Patients not residing in the ICU will be 
given a score of 0. If data elements are missing on 
specific days, the individual score for that missing 
component will be obtained from the prior day’s 
laboratory values.    
Figure 3.  

 
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Nosocomial Infection/Sepsis Data Elements: Nosocomial infections and sepsis outcomes 
will be derived from microbiology records and based upon positive culture evidence 
including bronchoalveolar specimens, blood cultures, wound cultures, organ space 
cultures and urinary tract cultures. Over the first 30 days of admission, quantification and 
location of specimen and classification of organism (Gram+, Gram-, species) will be 
collected. Quantitative thresholds for ventilator associated pneumonia, catheter related 
blood stream infections and urinary tract infection will be utilized as determined by the 
most recent CDC criteria and guidelines (www.cdc.gov/nhsn). 
 
Time to Hemostasis: The time to hemostasis outcome variable will be determined by the 
by the ability to reach a nadir transfusion requirement of 1 unit of WB or PRBCs in a 60 
minutes time period in the first 4 hours following arrival. Surgeon directed time to 
hemostasis will also be collected during the case. In the absence of the ability to obtain 
hemostasis by either of these criteria within the first 4 hours, the patient will be designated 
a ‘non-hemostasis’ patient. 
 
Death from Exsanguination/Hemorrhage: Those patients who succumb on the operating 
table, IR suite or ICU due to uncontrolled coagulopathy or hemorrhage in the first 4 hours  
from arrival will have their mortality classified as exsanguination/hemorrhage. This will be 
determined by the individual trauma surgeon at the time of the event.  
 
Acute Hemolytic Transfusion Reaction: We will utilize and characterize acute hemolytic 
transfusion reactions as defined by the CDC/National Healthcare Safety Network (NHSN) 
Hemovigilance Surveillance definition (www.cdc.gov/nhsn). 
 

 
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Galveston Orientation and Amnesia Test 
(GOAT): For TBI subjects, we will obtain the 
GOAT score at the time of discharge and the 
calculated score per standard methods.48 
(Figure 4) GOAT is a 10-item questionnaire 
used 
to 
quickly 
assess 
post-traumatic 
amnesia following head injury. The GOAT is 
read orally to the patient and may be easily 
administered at the bedside. The total score 
accounts for orientation of person, place, and 
time, and recollection of events pre and post- 
injury. Cutoff scores are available to identify 
abnormal, borderline, and normal orientation 
and it will additionally determine if a subject is 
able 
to 
provide 
continuing 
participation 
consent if consented by proxy. 
Extended Glasgow Outcome Scale (6 months-
GOSE): For TBI subjects, the GOSE score will 
be obtained at 6 months +/- 1month by hone 
survey or direct patient contact, whichever is 
feasible. For those TBI subjects who were 
unable to consent at discharge, the GOAT will 
be administered to assess their ability to 
provide 
direct 
consent, 
prior 
to 
the 
administration of the GOSE.  When the 
assessment is done by phone, the verbal 
consent of participants who have regained the ability to consent, will be obtained to allow 
the GOSE to be completed. The score is able to characterize 6 month functional status 
into 8 well defined categories as shown in (Figure 5).  
 
Classification of Mortality: Classification of the underlying mechanisms responsible for 
mortality are essential to appropriately characterize regional variation and preventable 
morbidity and mortality. Classification of mortality outcomes will be assigned at the level 
of the enrolling institution by the respective Site Investigator. A predefined list of mortality 
classifications will be provided and adjudicated upon at the site level and will include 1) 
Hemorrhage/Exsanguination, 2) TBI/herniation, 3) Multisystem Organ Failure, 4) Sepsis, 
5) ARDS, 6) Coagulopathy, 7) Cardiac Arrest with 1-6, 8) Pulmonary Embolism, 9) 
Withdrawal of Care as well as other pertinent causes of injury related death. 
 
Figure 5  
Figure 4 

 
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Clinical Laboratory Endpoints: Measurements of hemostasis (TEG, PT/PTT, INR; 0 hour(+ up to 
2 hours), 4 hour (+/-2 hours) and 24 hour (+/-12 hours)) for all patients and hemolysis labs (LDH, 
haptoglobin, bilirubin; 0 hour (+up to 2 hours), 4 hour (+/- 2 hours), and 24 hour (+/- 12hours)) for 
all patients will be obtained. Plasma samples for mechanistic outcomes will be drawn, stored, 
aliquoted and banked. The timing of all laboratory draws will follow local state and central IRB 
guidelines and local IRB guidelines at those sites who do not cede those guidelines to the central 
IRB at the University of Pittsburgh. The specific planned timing of draws are shown in (TABLE 
1).   
 
Screening/Outcome Data and Sample Collection: Patients will be screened for inclusion and 
exclusion criteria for the cohort study at the time of or soon after trauma center arrival and will 
undergo early blood sampling (Arrival + up to 2hrs). LITES Network sites selected for the 
prospective cohort study will have the capabilities to follow the patient to the OR, IR suite or ICU 
to obtain samples/labs and to record and monitor ongoing resuscitation, blood and blood 
component transfusion, mortality time points, time to hemostasis and death due to exsanguination 
for up to 4 hours from arrival or 
until hemostasis is obtained or 
patient death occurs. Due to the 
early 
requirement 
of 
initial 
blood samples for this cohort 
study, a waiver of consent for 
the initial patient screening and 
early blood draws (first 36hrs 
post-injury) will be obtained 
from the 
 central IRB. When available, 
blood samples will be drawn 
from an indwelling catheter 
(arterial or venous). If no 
indwelling catheter is available, 
then 
venipuncture 
will 
be 
performed following standard 
state and IRB requirements. 
Clinical laboratory samples will 
be sent at each LITES Network 
site 
following 
each 
sites 
laboratory guideline/requirements. Blood samples for storage will be drawn, centrifuged, 
separated, processed, and stored at -80°C for batched shipping. The schedule of proposed data 
and sampling can be found in (TABLE 1). 
 
TABLE 1. 
 
 
 
 
Procedures/Measurements 
Prehospital 
Arrival (+up to2 
hours) 
4 hours (+/-2 hours) 
post admission 
24 hours (+/-12 
hours) post 
admission 
At discharge 
At 6 months (+/- 1 
monht) 
Whole blood administration 
 
x 
X 
 
 
 
Component therapy administration 
 
x 
X 
 
 
 
Resuscitation data (WB, component 
transfusion) 
x 
x 
X 
x 
x 
 
Survival 
 
x 
X 
x 
x 
x 
Mechanistic Banked Samples 
 
x 
X 
x 
 
 
Hemostasis (PT, INR, TEG) 
 
x 
X 
x 
 
 
Hemolysis Labs                                               
(Lactate Dehydrogenase, haptoglobin, 
bilirubin) 
 
x 
X 
x 
 
 
Mechanistic Biomarkers 
 
x 
X 
x 
 
 
CBC 
 
x 
x 
x 
 
 
Serial Vitals (GCS, Blood pressure, Heart 
rate)  
x 
x 
X 
x 
 
 
GOAT (Galvenston Orientation Amnesia 
Test) + 
 
 
 
 
x 
 
Extended Glasgow Coma Scale+ 
 
 
 
 
 
x 
+TBI Subjects 

 
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Clinical Coordinating Center: Clinical Coordination specific for Task Order 002 will be performed 
by MACRO (Multidisciplinary Acute Care Research Organization) and its dedicated research 
team at the University of Pittsburgh, including all regulatory requirements, provider and 
coordinator training and monitoring. 
 
Institutional Review Board: A central IRB will be utilized at the University of Pittsburgh for the 
regulatory needs of the prospective observational cohort. All current LITES Network sites have 
IRBs which have experience and engagement with central IRB procedures. A waiver of initial 
consent up to 36 hours for screening and early sampling will be obtained from the central IRB 
allowing early sampling prior to consent. 
 
Data Coordinating Center (DCC): Data Coordination specific for Task Order 002 will be performed 
by the DCC and led by Dr. Wisniewski at the Graduate School of Public Health at the University 
of Pittsburgh. The DCC will coordinate all data collection and entry, management, security and 
confidentiality, data archiving, quality control and electronic medical record biomedical informatics 
as needed, as well as plan, coordinate and assist with all statistical analyses. 
 
Data Collection: Based upon the ability to appropriately execute AIMs I and II, the associated 
hypotheses generated and the primary and secondary outcomes proposed, the following data will 
be obtained on enrolled patients: 
 
Demographic and Injury Data: Age, gender, race/ethnicity, socioeconomic status, 
mechanism of injury, ISS, AIS scores, serial vitals (blood pressure, heart rate, respiratory 
rate), presence of TBI, ICU days, ventilator day, length of hospital stay, patient medication 
and past medical history.  
Prehospital Data: Time of injury, scene time, serial vital signs (GCS, blood pressure, 
heart rate, respiratory rate), transport characteristics, times and description of prehospital 
interventions (intubation, lines), medications, medic qualifications, crystalloid fluids, blood 
or blood component transfusion, adjuncts including tranexamic acid. 
ED Data: Arrival time, serial vitals (GCS, blood pressure, heart rate, respiratory rate), 
procedures, meds, resuscitation requirements (crystalloid, blood or blood component), 
adjuncts including tranexamic acid, factor VII, PCC, fibrinogen, ED disposition. 
OR Data: Procedures, operations, resuscitation requirements (crystalloid, blood or blood 
component), type of anesthesia, vasopressor requirement, adjuncts including tranexamic 
acid, factor VII, PCC, fibrinogen, disposition, serial vitals (blood pressure, heart rate), OR 
disposition, core temperature. 
Resuscitation Data: Whole blood resuscitation, time of transfusion, WB characteristics 
(titer, blood type, matched/unmatched, leukocyte reduced, platelet sparing), component 
blood resuscitation, time of transfusion, transfusion ratios, adjuncts including tranexamic 
acid, factor VII, PCC, fibrinogen. 

 
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Outcome Data: 4 hour, 6 hour and 24 hour mortality, MOF score (7days), nosocomial 
infection, acute hemolytic transfusion reaction, cause of mortality, time to hemostasis, 
venous thromboembolism (VTE). 
TBI Data: Serial GCS, TBI severity (AIS codes), TBI classification (subarachnoid, 
subdural, intracerebral hemorrhage, epidural, +/- shift, multifocal with specific 
classification) 
TBI 
progression, 
ICP 
data, 
operative 
intervention, 
paralysis, 
benzodiazepine coma, hypertonic resuscitation, GOAT and GOSE at discharge and 6 
months respectively. 
 
Eligible patients for the prospective cohort study will have de-identified data configured for 
compilation into the web based data entry platform with appropriate and all security measures in 
conjunction the DCC.  
 
Mechanistic Banked Samples: Samples within the 0 hour (+ up to 2 hours), at 4 hours (+/- 2 hours) 
and 24 hours (+/- 12 hours) will collected and stored for analyses. We will perform batched sample 
analyses of enrolled patient subgroups +/- coagulopathy and +/- TBI across the receipt of WB vs. 
component therapy. We will measure markers of endothelial cell injury including Syndecan-1 and 
Hyaluronan, markers of neurological injury and neuron cell death including S100B protein and 
Neuron Specific Enolase (NSE), and end points of coagulopathy including Thrombin-antithrombin 
complex (TAT), activated Protein C (aPC), tissue Plasminogen Activator (tPA) and Plasminogen 
Activator Inhibitor (PAI-1). 
 
Sample Tracking, Management and Storage: After sample obtainment, processing and storage, 
samples will initially be batched sent to the University of Pittsburgh biological sample repository 
where it will be tracked, managed and stored until the necessary translational or mechanistic  
measurement are performed. The CCC and DCC have a long track record of coordinating such 
processes. 
 
Power Analysis: The prospective cohort study will utilize time to 4 hour mortality for its primary 
outcome to power the study. Based upon the 6 LITES Network sites admission history that will be 
utilized and their respective volume of hemorrhagic shock patients meeting inclusion and 
exclusion criteria and a 3.5 year enrollment time period, we plan to initiate sampling on 1,050 
patients over the enrollment time period of the study. With an 85% consent rate which is an 
estimate based upon prior studies of similar nature, we will consent for participation 892 patients 
for the study. With an estimate baseline rate of 4 hour mortality of 11.1 % derived from the 
PROPPR study, there will be 90% power to detect a hazard ratio of 1.9. 
 
Calculations are based on the primary aim of the study based on the following assumptions: 
• 
Type I error rate of 0.05 
• 
Two-sided alternative hypothesis  

 
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• 
6 sites will be involved, three whole blood and three component sites 
• 
Each site will enroll 175 participants in 3.5 years of enrollment, of which, 85% will be 
eligible for the study (149) 
• 
The calculations are based on Cox proportional hazard model 
• 
A 4 hour event rate in the control (non-whole blood) group of 0.111 
The power calculations for these secondary aims are presented below.  When reporting the 
results of the analyses, caution will need to be taken with respect to the interpretation of the 
findings since they are secondary in nature.  
 
The secondary outcomes in Aim 1B include binary outcome, continuous outcomes, and time to 
event outcomes. For the binary outcomes, the odds ratio that can be detected is presented in 
Table 1. For the continuous outcome, the effect size that can be detected is 0.13. Finally, for the 
time to event outcomes, the hazard ratio that can be detected over a range of event rates in the 
control group is also presented in Table 1.  
Table 1: Detectable Effect Sizes Event Rate in the Control Group 
Event Rate 
              .1 
.2  
.3  
.4  
.5  
 .6  
Odds Ratio  
1.76  
1.56  1.49  1.46  1.46  1.48  
Hazard Rate  
2.69  
1.70  .37  
.30  
.27  
.30 
 
• 
For Aim 1C, a nonparametric analysis of variance will be used to compare the distribution 
of the GOS-E between the two groups. An effect size of 0.17 could be detected.  
• 
For aim 2A, a nonparametric analysis of variance will be used to compare the distribution 
of the GOS-E between the two groups. An effect size of 0.28 could be detected.  
• 
For aim 2B, a nonparametric correlation coefficient will be used to assess the association 
between GOS-E and the area under the systolic blood pressure curve. For each, a 95% 
confidence interval with a width of 0.19 can be estimated.  
• 
For all secondary analyses, the type I error rate was set to 0.05, with a two-sided 
alternative hypothesis, and 90% power. For the Aim 1, the sample size will be 1,190. For 
Aim 2, the sample size will be limited to those with a traumatic brain injury. For the 
purposes of this study, this is expected to be 35% or a total of 417 participants. 
Analyses 
  
AIM#1: The analysis will begin by describing the baseline demographic and clinical characteristics 
of the overall population and then stratified by whole blood usage. The characteristics will be 

 
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compared among those who receive and who do not receive whole blood. For discrete variables, 
proportions will be generated and a chi-square test will be used to test for differences between 
the proportions. For continuous characteristics, means (medians) and standard deviations 
(interquartile ranges) will be calculated and t-tests (Wilcoxon) will be used to compare the means 
(distributions) among those who receive and do not receive whole blood. 
 
Hypothesis#1A: For the primary outcome, the time to death will be generated for each participant.  
Kaplan-Meier curves will be generated for each treatment group and a log-rank test will be used 
to compare the distribution of the cumulative proportion.   A hierarchical Cox-proportional hazards 
regression model will be used to control for the within-institution clustering. The hierarchical Cox-
proportional hazards regression model will then be used to assess the independent impact of 
whole blood on time to death after controlling for the clustering effect and potential confounding 
effects of baseline characteristics. The model will include main effects for whole blood usage and 
a propensity score for receiving whole blood. The propensity score for the use of whole blood will 
be generated using a boosted logistic regression model. The dependent variable in the model will 
be the use of whole blood and the independent variables will be the baseline characteristics of 
the population. The Cox-proportional hazards model will be used to estimate the cumulative 
probability of death 4 hours. 
 
Hypothesis#1B: The analytic approach for the secondary outcomes included in Hypothesis#1B 
will vary based on the type of outcome. For binary outcomes (e.g., 12 hour and 24 hour mortality, 
death from exsanguination, incidence of MOF, nosocomial infection), the same analytic approach 
that was carried out for Hypothesis 1a will be implemented.   
 
For continuous outcomes (e.g., transfusion ratios, blood transfusion requirements) a two-
sided t-test for correlated means will be used to compare the means between those receiving and 
not receiving whole blood. A hierarchical analysis of variance model will be used to control for the 
within-institution clustering. The model will be used to assess the independent impact of whole 
blood after controlling for the clustering effect and the potential confounding. The model will 
include main effects for whole blood usage and propensity for receiving whole blood.   
 
Finally, for time to event analyses (e.g., time to hemostasis), a bivariate hierarchical Cox 
proportional hazards regression model will be generated to compare the time to event between 
those receiving and those not receiving whole blood. Again, the hierarchical model will be used 
to control for within-institution clustering. In a second step, to determine the independent effect of 
whole blood after controlling for potential confounding effects, the propensity score will be added 
to the model. 
 
Hypothesis#1C: A two-sided z-test for correlated proportions will be used to compare the 
distribution of GOS-E proportions between those receiving and not receiving whole blood. This 

 
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LITES Task Order 2: Shock, Whole blood and Assessment of TBI (SWAT). Version 5 dated 2019-12-04 
test will be used to control for the within-institution clustering. A hierarchical polytomous logistics 
regression model will then be used to assess the independent impact of whole blood after 
controlling for the clustering effect and the potential confounding effects of baseline 
characteristics. The model will include main effects for whole blood usage and propensity for 
receiving whole blood. 
 
AIM#2: The analyses for the second aim will be restricted to the subset of participants who will be 
characterized as having a traumatic brain injury.   
 
Hypothesis#2A: The analysis will begin by comparing the baseline characteristics of those with a 
prehospital and acute phase resuscitation systolic blood pressure greater than or equal to 120 
mmHg to those who do not. For discrete variables, proportions will be generated and a chi-
squared test will be used to test for differences between the proportions. For continuous 
characteristics, means (medians) and standard deviations (interquartile ranges) will be calculated 
and t-test (Wilcoxon) test will be used to compare the means (distributions) among those who 
receive and do not receive whole blood.   
 
A two-sided z-test for correlated proportions will be used to compare the distribution proportions 
of GOS-E at 6-months between those with a prehospital and acute phase resuscitation systolic 
blood pressure greater than or equal to 120 mmHg to those who do not. A hierarchical polytomous 
logistics regression model will be used to control for the within-institution clustering. The model 
will be used to assess the independent impact of whole blood after controlling for the clustering 
effect and the potential confounding effects of baseline characteristics. As was done in Aim#1A, 
the propensity for a prehospital and acute phase resuscitation systolic blood pressure greater 
than or equal to 120 mmHg will be generated using a boosted logistic regression model which will 
include all baseline characteristics, including site and whole blood usage.  The same analytic 
approach will be used to measure outcomes at discharge except a hierarchical logistic regression 
model will be used. 
 
Hypothesis#2B: The area under the curve of systolic blood pressure during the prehospital and 
acute phase resuscitation will be generated for each study participant. The analysis will begin by 
comparing the baseline characteristics with the area under the curve. For discrete variables, 
bivariate linear regression models will be generated (area under the curve as the dependent 
variable and the discrete baseline characteristic as the independent variable). For continuous 
characteristics, the correlation will be assessed.   
 
Hierarchical models will be used to adjust for within-institution clustering. Hierarchical bivariate 
linear regression models will be used to assess the association of baseline characteristics 
associated with area under the curve. A stratified propensity analysis will be used to estimate the 
association of area under the curve with GOS-E at six months. A hierarchical linear regression 

 
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model will be generated using the area under the curve as the dependent variable and the 
baseline characteristics as independent variables to generate an estimated area under the curve 
(propensity score) for each subject. The population will then be separated into five strata of equal 
sample size, based on the propensity. Within each stratum, the association of the area under the 
curve with outcome will be assessed using a hierarchical polytomous logistic regression model 
(outcome: GOS-E at six months, independent variable:  area under the curve).   
 
To determine the association across strata and if the association differs across strata, a 
multinomial polytomous regression model with GOS-E at six months as the outcome, area under 
the curve, an indicator of stratum, and the two-way interaction as independent variables will be 
fit.   
 
The same analytic approach will be used to measure outcomes at discharge except a hierarchical 
logistic regression model will be used.   
 
Subgroup Analysis: The general approach to assess the homogeneity of a treatment effect across 
subgroup will be to include an interaction term between the treatment variable and the 
characteristics defining the subgroup in the regression model. A statistically significant interaction 
term would indicate that the null hypothesis of a homogenous effect would be rejected indicating 
a differential effect of the treatment across the subgroups. For example, when examining the 
homogeneity of the effect of whole blood on the primary outcome among those with and without 
a traumatic brain injury, the hierarchical logistic model will be modified to include a main effect for 
traumatic brain injury and the two-way interaction between whole blood use and traumatic brain 
injury. 
 
Interim Analysis: There will be two aspects of the interim analysis. First, for efficacy, the Lan and 
Demets approach will be utilized to conduct the interim efficacy analysis. This approach is 
preferable over other approaches because it is flexible to the number of interim analyses 
conducted during the course of the study. The Lan and DeMets approach requires the use of a 
spending function to allocate the type I error to the interim analysis. The O’Brien and Fleming 
spending function which minimizes the type I error allocated to the interim analysis, saving the 
vast majority for the primary analyses will be used. For the proposed interim analysis, assuming 
that 50% of the study will be completed, it is estimated that the type I error allocated to the interim 
analysis will be 0.005, leaving 0.048 of the type I error for the primary outcome analysis. 
  

 
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Time Line: The study will occur over a 4 year period with a 6 month start up period, an interim 
analysis at 2 years and a 3.5 year enrollment period. 
 
 

 
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