Pragmatic Prehospital Group O Whole Blood Early Resuscitation (PPOWER) Trial: A Prospective, Interventional,Randomized, 3 Year, Pilot Clinical Trial
Phase: PHASE3
Conditions: Hemorrhagic Shock
Sponsor: Jason Sperry

1 
 
Table of Contents 
ABBREVIATIONS .................................................................................................................................... 2 
PROTOCOL SYNOPSIS ......................................................................................................................... 3 
1. 
OBJECTIVE, SPECIFIC AIMS, BACKGROUND, AND SIGNIFICANCE ............................. 5 
1.1 
OBJECTIVE ................................................................................................................................ 5 
1.2 
SPECIFIC AIMS ......................................................................................................................... 5 
1.3 
BACKGROUND and RATIONALE .......................................................................................... 5 
1.4 
INNOVATION .............................................................................................................................. 6 
1.5 
SIGNIFICANCE .......................................................................................................................... 7 
2. 
RESEARCH DESIGN AND METHODS ...................................................................................... 7 
2.1 
CLASSIFICATION AND METHODOLOGICAL DESIGNS .................................................. 7 
2.2 
DETAILED DESCRIPTION OF STUDY DESIGN ................................................................. 8 
2.3 
STUDY INTERVENTION .......................................................................................................... 8 
2.4 
INTERVENTIONAL ARM .......................................................................................................... 9 
2.5 
STANDARD OF CARE ARM .................................................................................................. 10 
2.6 
RANDOMIZATION ................................................................................................................... 10 
2.7 
STANDARD OPERATING PROCEDURES ......................................................................... 11 
2.8 
STUDY ENDPOINTS ............................................................................................................... 11 
2.9 
STATISTICAL ANALYSIS ....................................................................................................... 13 
3. 
HUMAN SUBJECTS .................................................................................................................... 16 
3.1 
SUBJECT POPULATION........................................................................................................ 16 
3.2 
INCLUSION CRITERIA ........................................................................................................... 16 
3.3 
EXCLUSION CRITERIA .......................................................................................................... 16 
4. 
IRB APPROVAL AND FDA AMENDMENTS ........................................................................... 17 
5. 
RECRUITMENT AND INFORMED CONSENT PROCEDURES ........................................... 17 
5.1 
RECRUITMENT METHODS: ................................................................................................. 17 
5.2 
INFORMED CONSENT PROCEDURES ............................................................................. 18 
6. 
POTENTIAL RISKS AND BENEFITS ....................................................................................... 19 
6.1 
POTENTIAL RISKS ................................................................................................................. 19 
6.2 
ALTERNATIVE TREATMENTS ............................................................................................. 19 
6.3 
POTENTIAL BENEFITS .......................................................................................................... 20 
6.4 
DATA SAFETY MONITORING .............................................................................................. 20 
6.5 
RISKS MANAGEMENT PROCEDURES .............................................................................. 26 
7. 
COSTS AND PAYMENTS ........................................................................................................... 27 
8. 
QUALIFICATIONS AND SOURCE OF SUPPORT ................................................................. 28 
8.1 
QUALIFICATIONS OF THE INVESTIGATORS .................................................................. 28 
8.2 
SOURCES OF SUPPORT ...................................................................................................... 29 
9. 
REFERENCES .............................................................................................................................. 29 
 
 
 
 
 
 
 

2 
 
ABBREVIATIONS 
 
AE – Adverse Event 
AHTRs - Acute Hemolytic Transfusion Reactions 
AIS – Abbreviated Injury Scale 
ARDS – Acute Respiratory Distress Syndrome 
Cc – cubic centimeter 
CPR – cardiopulmonary resuscitation  
CRF – case report form 
DSMB – data safety monitoring board 
ED – emergency department 
ELISA - Enzyme-linked immunosorbent assay 
FFP – Fresh Frozen Plasma 
GSW – Gun shot wound 
HR – heart rage 
ICF – informed consent form 
ICU – intensive care unit 
IND – investigational new drug 
INR – international normalized ratio 
IRB – institutional review board 
IV - intravenous 
LAR – Legally Authorized Representative 
LTLR-WB - Low Titer, Leucocyte Reduced, Whole Blood 
mmHg – millimeter of mercury 
MOF – Multiple Organ Failure 
NI – Nonsocomial Infections 
non-WB – non- Whole Blood 
PI – Principal Investigator  
PLT -Platelets 
PRBCs – Packed Red Blood Cells 
PT – Prothrombin Time 
PTT – Partial Thromboplastin Time 
SAE – Serious Adverse Event 
SBP – Systolic Blood Pressure  
SOP – Standard Operating Procedure  
TACO – Transfusion Associated Circulatory Overload 
TEG - Thromboelastograph 
TRALI – Transfusion Related Acute Lung Injury 
 
 
 
 
 
 
 
 
 
 

3 
 
PROTOCOL SYNOPSIS 
 
Protocol Title: 
Pragmatic, Prehospital Group O, Whole Blood Early 
Resuscitation trial (PPOWER) 
Protocol Number: 
PRO17100053 
NCT Number: 
NCT03477006 
Version # and Date: 
Version 7 Dated 2020-02-04 
Clinical Phase: 
 
Phase 3 
Investigational Drugs: 
Low titer, platelet replete-leukocyte reduced, group O whole 
blood 
Trial Site: 
University of Pittsburgh 
IND Sponsor: 
Jason L. Sperry, MD, MPH  
Investigator: 
Jason L. Sperry, MD, MPH 
Co-Principal 
Investigator 
Darrell J. Triulzi, MD 
Sub-Investigators: 
Frank Guyette MD, MPH; Matthew Neal, MD; Mazen Zenati, 
MD, PhD; Mark Yazer, MD   
 
 
Research Facilities: 
UPMC Presbyterian/ Montefiore  
Clinical Laboratories: 
UPMC Presbyterian Shadyside CP PUH- UPMC Clinical 
Laboratory Building  
Study Rationale: 
Initiation of whole blood resuscitation in the prehospital setting 
and continued through the in-hospital phase of treatment to 
patients in hemorrhagic shock represents the most efficacious 
and ideal intervention post-injury. 
Study Objectives: 
The objective of this study is to determine whether LTLR-WB 
resuscitation in the prehospital setting with continuation 
through the in-hospital acute resuscitation phase of care will 
significantly reduce the morbidity and mortality attributable to 
hemorrhagic shock post-injury as compared to standard 
prehospital and in-hospital resuscitation practice. 
Study Hypothesis: 
Early whole blood transfusion initiated in the prehospital setting 
and continued through the in-hospital acute resuscitation 
phase of treatment will reduce the morbidity and mortality 
attributable to hemorrhagic shock post-injury as compared to 
standard prehospital and in-hospital resuscitation practice 
Study Aims: 
Specific Aim I: Determine the feasibility and most appropriate 
study population that will lead to a large multicenter clinical trial 
designed to evaluate the effectiveness of prehospital through 
in-hospital LTLR-WB as compared to standard care practice in 
patients at risk of hemorrhagic shock. 
 
Specific Aim II: Determine if prehospital through in-hospital 
LTLR-WB reduces 28-day mortality, multiple organ 
dysfunction, presenting coagulopathy, 24-hour resuscitation 
requirements and early mortality time points as compared to 

4 
 
standard of care prehospital and in-hospital resuscitation in 
patients at risk of hemorrhagic shock. 
 
Specific Aim III: Determine the primary drivers by which 
prehospital through in-hospital LTLR-WB improves clinical, 
resuscitative and hemostatic outcomes as compared to 
standard of care prehospital and in-hospital resuscitation in 
patients at risk of hemorrhagic shock. 
Study Design: 
The pilot study will be a 3-year, pragmatic, prospective, 
randomized, open label, pilot clinical trial utilizing a busy level 
1 trauma center with one of the busiest air medical services in 
the country where affiliations with local blood bank colleagues 
exist to provide cold storage LTLR-WB for the prehospital (up 
to 2 units) and in-hospital setting (up to 6 additional units), up 
to 8 units total. There are 14 helicopter bases which fly 
patients to Presbyterian Hospital at the University of 
Pittsburgh. 
 
Planned Sample Size:  
56 patients in each arm, 112 total patients 
Duration of Treatment: 
3 Years 
Major Inclusion Criteria:  1. Injured patients at the risk of Hemorrhage being transported 
from scene or referral hospital to a participating PPOWER trial 
site  
 
AND 
2A. Systolic blood pressure ≤ 90 mmHg AND tachycardia > 
108 bpm at scene, or at outside hospital or during transport.  
        OR 
2B. Systolic blood pressure ≤70 mmHg without tachycardia 
requirement, at scene or outside hospital or during transport. 
 
Major Exclusion 
Criteria: 
1. Documented age:  Age ≥90 or <18 years of age 
2. Inability to obtain intravenous or interosseous access 
3. Isolated fall from standing injury mechanism 
4. Known prisoner or known pregnancy 
5. Traumatic arrest with > 5 minutes of CPR without return of 
vital signs 
6. Brain matter exposed or penetrating brain injury (GSW) 
7. Isolated drowning or hanging victims 
8. Isolated burns without evidence of traumatic injury 
9. Referral Hospital In-patient admission  
10. Objection to study voiced by subject or family member at 
scene 
11. Wearing PPOWER opt-out bracelet 
Study Endpoints: 
The primary endpoints of this study are 1.) 28-day all-cause 
mortality as the safety and efficacy endpoint; 2.) enrollment 
and accrual rate as the feasibility endpoint. 
 

5 
 
1. 
OBJECTIVE, SPECIFIC AIMS, BACKGROUND, AND SIGNIFICANCE 
 
 OBJECTIVE 
 
The objective of this study is to determine whether LTLR-WB resuscitation in the prehospital 
setting with continuation through the in-hospital acute resuscitation phase of care will significantly 
reduce the morbidity and mortality attributable to hemorrhagic shock post-injury as compared to 
standard prehospital and in-hospital resuscitation practice. 
 
 SPECIFIC AIMS 
 
Hypothesis: The initiation of LTLR-WB resuscitation in the prehospital setting with 
continuation through the in-hospital acute resuscitation phase of care will significantly reduce the 
morbidity and mortality attributable to hemorrhagic shock post-injury as compared to standard 
prehospital and in-hospital resuscitation practice. 
 
Specific Aims: 
Specific Aim I: Determine the feasibility and most appropriate study population that will lead to 
a large multicenter clinical trial designed to evaluate the effectiveness of prehospital through in-
hospital LTLR-WB as compared to standard care practice in patients at risk of hemorrhagic shock. 
Specific Aim II: Determine if prehospital through in-hospital LTLR-WB reduces 28-day mortality, 
in-hospital mortality, multiple organ dysfunction, presenting coagulopathy, 24-hour resuscitation 
requirements and early mortality as compared to standard of care prehospital and in-hospital 
resuscitation in patients at risk of hemorrhagic shock. 
Specific Aim III: Determine the primary drivers by which prehospital through in-hospital LTLR-
WB improves clinical, resuscitative and hemostatic outcomes as compared to standard of care 
prehospital and in-hospital resuscitation in patients at risk of hemorrhagic shock. 
 
 BACKGROUND and RATIONALE 
 
Traumatic injury represents an incredible health care burden in the United States and 
worldwide.1 Hemorrhage is estimated to be responsible for over 40% of all trauma-related 
deaths.2,3 Ongoing traumatic blood loss is complicated by the well-known ‘lethal triad’ of 
coagulopathy, hypothermia and acidosis which results in further unbridled hemorrhage.4-11 
Uncontrolled bleeding, resultant shock and organ dysfunction remain the leading causes of early 
in-hospital mortality.12,13 Despite advances in trauma resuscitation, a paucity of therapeutic 
interventions are available early enough to reduce the downstream morbidity and mortality 
attributable to hemorrhage, shock and coagulopathy.14,15 
 
In-hospital resuscitation of traumatic hemorrhage has changed  over the past decade.16-21 
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).22 This reconstituted strategy has also been coined 
‘whole blood-like’ resuscitation despite being inferior compositionally to whole blood.23,24 The use 
of whole blood was historically the gold standard for treating hemorrhagic shock during World 
War I and II, prior to sweeping changes in blood banking practice.25  Whole blood use continues 
today and is thought to provide the bleeding patient the identical components they are losing with 
maximal resuscitative and hemostatic effects.26-30 
     Recent military experiences continue to show the benefits of fresh whole blood resuscitation 
demonstrating significant survival and hemostatic advantages.31-34 Whole blood has also been 

6 
 
postulated to improve microcirculatory hemodynamics, reduce the ‘storage lesion’ effect and 
minimize donor exposure risks.35 A recent civilian study has also demonstrated benefit using 
modified whole blood after arrival to the hospital where appropriate blood typing and cross 
matching was performed prior to transfusion.36 Due to the time sensitive nature of the treatment 
of hemorrhage, the ideal resuscitation intervention would entail use of a blood product containing 
all essential hemostatic components, closest to time of injury, where prevention or reversal of the 
devastating downstream consequences of shock and coagulopathy can occur. 
     Initiation of whole blood resuscitation in the prehospital setting and continued through the in-
hospital phase of treatment to patients in hemorrhagic shock represents this ideal intervention 
post-injury. Essential to the prehospital initiation of whole blood resuscitation in the civilian 
population is need for it to be transfused without the need for blood typing or cross matching. Of 
similar importance is the need for cold storage and recycling of any unused whole blood product, 
allowing maximal utility of this precious resource.     
     We hypothesize that the initiation of LTLR-WB resuscitation in the prehospital setting with 
continuation through the in-hospital acute resuscitation phase of care will significantly reduce the 
morbidity and mortality attributable to hemorrhagic shock post-injury as compared to standard 
prehospital and in-hospital resuscitation practice. Thus, a large pragmatic clinical trial is needed 
to definitively establish the efficacy and safety of whole blood resuscitation initiated in the 
prehospital setting. Only a high-quality clinical trial will provide the essential evidence to justify 
and provide the impetus for the use of this precious blood banking resource early post-injury. 
Because of the challenges associated with execution of these types of large trials particularly in 
the prehospital setting,38 it is essential to establish feasibility of this approach in a pilot study and 
provide experience to inform a definitive large, multicenter whole blood trial.  
 
 INNOVATION 
 
     Interventions that are initiated in the prehospital 
setting represent the forefront of traumatic injury 
research. The majority of such prehospital trauma trials 
are performed under the requirements of exception 
from informed consent for emergency research with 
regulatory 
oversight 
by 
the 
Food 
and 
Drug 
Administration (FDA) and Title 21, Code of Federal 
Regulations, Section 50.24 (21 CFR 50.24). Although 
the additional regulatory requirements of this type of 
research remain extremely arduous, the beneficial 
consequences of providing novel interventions during 
the earliest phase of treatment, within minutes from the 
time of injury, cannot be overstated. Treatment of hemorrhage is time sensitive79,80. The ability to 
initiate early whole blood resuscitation, containing all essential hemostatic components, at a time 
point where prevention or reversal of the downstream manifestations of shock and coagulopathy 
can occur is of paramount significance. It is this early prehospital therapeutic window where a 
reduction in the morbidity and mortality which complicates traumatic injury can be potentially 
realized. 
     Another innovative aspect of the proposed trial is the essential collaborative and 
multidisciplinary approach required to execute a prehospital initiated whole blood resuscitation 
interventional trial. Group O whole blood represents a precious resource to blood banks across 
the country. Essential to the clinical investigation of early whole blood resuscitation post-injury 
and the ultimate integration of whole blood into standard trauma practice is the collaborative 
relationship between trauma surgeons, blood banking specialists and prehospital administration 
and providers. It is this cohesive and cooperative rapport that maximizes patient benefit 
Fig 1. Study Organization 

7 
 
concurrently with appropriate blood product resource utilization.37 It will be the successful 
execution of this pilot trial that will provide the backdrop and impetus for these collaborative 
relationships to develop at other institutions.  
Whole blood transfusion following traumatic injury represents the ‘essential next step’ for the 
management of hemorrhagic shock post-injury. The potential significance of whole blood being 
provided in the prehospital setting brings this potential lifesaving hospital intervention to those 
patients who need it most, at the most beneficial time before hemorrhagic shock and 
coagulopathy begin to have their detrimental consequences.  
 
 SIGNIFICANCE 
 
     Early whole blood resuscitation has significant potential to prevent downstream manifestations 
of shock and coagulopathy, attenuate glycocalyx injury, improve microcirculatory hemodynamics 
and provide the most hemostatic and definitive resuscitation available.24,35,42,43 It is the ability to 
initiate needed whole blood in the prehospital setting to those patients who would benefit most, 
at the earliest time post-injury, before hemorrhagic shock and coagulopathy can result in their 
detrimental consequences, which underscores the significance of the impact of the study.       
     The University of Pittsburgh, Presbyterian Hospital has over the last 2 years initiated an urgent 
release whole blood transfusion program for trauma patients in hemorrhagic shock in our 
emergency department utilizing LTLR-WB identical to the proposed intervention for the pilot and 
large multicenter trial. We published data on the first 47 patients demonstrating the feasibility and 
initial safety of such a program.28 We have continued this program and have currently utilized 
LTLR-WB in over 187 patients with no safety concerns. We have simultaneously been monitoring 
LTLR-WB patients for hemolytic side effects from ABO mismatched whole blood.29 In 27 non-
group O patients, there were no significant differences in laboratory hemolysis markers. 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 pilot trial and future large multicenter trial. 
     The most obvious driver of potential outcome benefits for early LTLR-WB transfusion is that 
the hemorrhaging patient is receiving a robust resuscitative and hemostatic product identical in 
composition to what they are losing with the potential for a lower risk of coagulopathy. Early whole 
blood resuscitation has potential additional benefits which may drive outcome differences in those 
with hemorrhagic shock. Whole blood has been hypothesized to improved microcirculatory 
hemodynamics, reducing the sequelae of shock and anaerobic metabolism.35,68-71 Increasing 
evidence suggests that platelet function may be maintained or even improved with cold storage 
providing further hemostatic benefit.61,65 Plasma resuscitation alone or in conjunction with whole 
blood has increasingly been shown to benefit endothelial glycocalyx integrity and 
homeostasis.42,72 Importantly, plasma resuscitation has been shown to reduce Syndecan-1 
shedding, an endothelial glycocalyx constituent whose levels are known to be associated with 
inflammation and coagulopathy.43,72,73 Additional benefits may include minimization of donor 
exposure, as the requirements for whole blood storage and resuscitation would lower overall age 
of the transfused products as compared to balanced component resuscitation. 24,35,45,46 
2. 
RESEARCH DESIGN AND METHODS 
 
 CLASSIFICATION AND METHODOLOGICAL DESIGNS 
 
The pilot study will be a 3 year, pragmatic, prospective, randomized, open label, clinical 
trial utilizing a busy level 1 trauma center with one of the busiest air medical services in the country 
where affiliations with local blood bank colleagues exist to provide cold storage LTLR-WB for the 

8 
 
prehospital (up to 2 units) and in-hospital setting (up to 6 additional units), up to 8 units total. 
There are 14 helicopter bases which fly patients to Presbyterian Hospital at the University of 
Pittsburgh. Some of the busiest air medical bases in the system will be utilized for the pilot trial. 
The pilot trial may need fewer or more bases added as enrollment proceeds. The study is required 
to be open label due to the inability to blind blood or blood component transfusion. 
 
 DETAILED DESCRIPTION OF STUDY DESIGN 
 
Study Population:  The study population will consist of injured patients at risk of hemorrhage 
being transported via air medical services from the scene of injury or from referring hospital to a 
definitive care trauma center participating in the PPOWER pilot trial. Patients will be enrolled in 
the prehospital setting prior to trauma center arrival with continuation of LTLR-WB resuscitation 
or standard of care resuscitation during the in-hospital acute resuscitation phase of the study. 
 
Study Population Rationale: The most appropriate patient population who would benefit most 
from early, prehospital initiation of LTLR-WB are those with potentially survivable injuries, at risk 
of the detrimental complications attributable to hemorrhagic shock, using criteria which can be 
widely generalizable in the real-world prehospital setting. In the prehospital phase of treatment, 
complete characterization of injuries and injury severity is not possible. We have chosen inclusion 
and exclusion criteria based upon preliminary data obtained from the PAMPer study, a recently 
closed pragmatic prehospital trial at the University of Pittsburgh.40 The incidence of arrival shock 
(87%) and coagulopathy (41%), the need for large volume transfusion (36%) and the development 
of multiple organ failure (25%) and overall mortality (30%) utilizing the proposed inclusion and 
exclusion criteria, with appropriate modifications, will provide the most appropriate patient 
population to demonstrate the benefits of LTLR-WB resuscitation.  
     Group O whole blood represents a precious blood banking resource. There exists an even 
further limited supply of Rh negative, group O whole blood (6.6% of blood supply overall). Due to 
this supply limitation, the only feasible and sustainable approach for whole blood resuscitation is 
to utilize Rh positive group O whole blood, which is significantly more common (37.4% of blood 
supply overall).  
 
 STUDY INTERVENTION 
 
The study intervention will be the initiation of prehospital through in-hospital transfusion of 
LTLR-WB in patients meeting all inclusion and no exclusion criteria. Whole blood units will be 
obtained from a local FDA licensed blood center (LifeSource dba Central Blood Bank; Registration 
number: 2571073; License number: 1025). 
     Up to two units of LTLR-WB (O+) will be initiated in the prehospital phase of the study with an 
additional 6 units of LTLR-WB (O+) available during the in-hospital phase of the trial if indicated. 
 
Study Intervention Rationale: To provide the earliest and most robust intervention with 
appropriate concern for blood banking resource utilization, a prehospital and in-hospital phase 
intervention will be utilized. As whole blood resuscitation is most pertinent to patients with acute 
hemorrhage, we have limited the in-hospital acute resuscitation phase time period and the 
additional 6 units of LTLR-WB to 4 hours post-admission. This acute phase resuscitation period 
definition is based upon unpublished data from the recently completed PAMPer study at our 
institution.40 Over 79% of the blood products transfused in the first 24 hours occurred in the first 
4 hours following admission. 
 
Whole Blood Intervention: Blood from male only, group O+ donors will be collected using the 
FDA approved Terumo Imuflex® WB-SP blood bag system. With this collection system, whole 

9 
 
blood passes through a platelet sparing inline leukoreduction filter into a bag containing citrate 
phosphate dextrose solution.  Male only whole blood donors will be used in order to mitigate the 
risk of transfusion related acute lung injury (TRALI; estimated incidence ≈1:12,000). Whole 
blood collected with this system can be kept as such for up to 21 days when stored between 1-
6ºC.  Per blood bank protocol, the anti-A and anti-B antibody titers in each unit will be tested on 
a sample from every donor using an immediate spin saline tube method without incubation; only 
units where the titer of both anti-A and anti-B are <100 will be issued for the study and 
subsequent transfusion. All other required transmissible disease testing will also be performed 
on these LTLR-WB units before they are released, as per blood bank standard practice. The 
LTLR-WB units will have affixed on them the standardized Whole Blood product label thereby 
making them easily distinguishable from the other non-WB units in inventory.  
 
 INTERVENTIONAL ARM 
  
Prehospital Phase Interventional Arm: Two units of LTLR-WB (O+) will be stored at each 
helicopter base in temperature regulated blood bank approved refrigerators for up to 14 days, 
which is the period within which cold stored platelets are thought to retain maximal function. Two 
units of LTLR-WB will be transported on all air medical flights with prehospital staff in blood 
banking approved and verified coolers. The temperature of the blood will  be monitored throughout 
transit and storage in accordance with standard blood banking and Stat MedEvac procedures. 
Following 14 days without use, LTLR-WB will be replaced with new LTLR-WB units and the old 
products will be returned to the blood bank for recycling into PRBCs.. During transport, storage 
and during all flights standard STAT MEDEVAC protocols for storing and carrying blood products 
at the base and on the helicopters will be followed. While at the bases the blood units are stored 
in a dedicated blood refrigerator and moved to cooler for transport only when the aircraft is 
launched. The blood is packaged in the coolers with a thermometer for temperature maintenance 
to assure that they are maintained at 2-5 degrees Celsius at all times. The Clinical Protocol that 
is currently followed and will be followed for all blood products in the study can be found in 
Appendix 1. Our FDA approved blood bank will follow all regulations required by the FDA for safe 
blood and blood component transfusion. On day 15, after ensuring the WB unit had remained in 
temperature compliance and is otherwise eligible for recycling according to 21 CFR 640.2(c), the 
WB unit will be recycled into a PRBC unit following the standard operating procedures at the 
Centralized Transfusion Service in Pittsburgh. 
     Patients who meet all inclusion and no exclusion criteria at the scene, at a referral hospital or 
during transport and are randomized to the interventional arm will receive up to 2 units of LTLR-
WB (O+) en-route to a PPOWER participating trauma center based upon hemodynamic status 
using identical criteria as the Prehospital Standard of Care arm. If the intervention is completed 
during transport, standard operating procedures for the prehospital setting will be employed by 
the prehospital providers during the remaining flight. (Appendix 7) 
 
In-Hospital Phase Interventional Arm: Once enrolled in the interventional arm, prehospital 
providers will inform the trauma team of PPOWER enrollment and the randomization of the patient 
into the interventional arm (LTLR-WB administration arm). Upon arrival and on-going in-hospital 
LTLR-WB transfusion will be at the discretion of the trauma attending/team based upon the 
hemodynamic status of the patient, injury severity, need for therapeutic intervention, control of 
hemorrhage and on-going coagulopathy.  
     Patients enrolled in the interventional arm will only receive LTLR-WB if blood products are 
required during the acute resuscitation phase over the first 4 hours following admission (up to 6 
units of LTLR-WB). The acute resuscitation phase generally includes the first 4 hours from the 
time of admission. Six units of LTLR-WB will be available for urgent release in the emergency 
department and will be taken to the operating room as needed. In those patients with ongoing 

10 
 
hemorrhage who require blood products beyond the 8 units of LTLR-WB total (2 prehospital, 6 in-
hospital), a balanced component transfusion strategy will be employed identical to the standard 
of care arm of the study and usual care at the University of Pittsburgh.  
 
 STANDARD OF CARE ARM 
 
Prehospital Standard Care Arm: Patients who meet all inclusion and no exclusion criteria at the 
scene, at a referral hospital or during transport and are randomized to the standard of care arm 
of the study will receive resuscitation fluids, including crystalloid and PRBC infusion, per the 
current standard practice. 
 
In-Hospital Standard Care Arm: Once enrolled in the standard of care arm, prehospital 
providers will inform the trauma team of PPOWER enrollment and standard of care arm 
assignment upon arrival and on-going in-hospital 
blood component transfusion will be at the discretion 
of the trauma attending/team based upon the 
hemodynamic status of the patient, injury severity, 
need 
for 
therapeutic 
intervention, 
control 
of 
hemorrhage and on-going coagulopathy. Patients 
enrolled in the standard of care arm will receive 
products using a balanced component transfusion 
strategy (1:1:1 - fresh frozen plasma: packed red 
blood cells: platelets)22 with TEG directed adjustment 
if blood products are required for on-going 
resuscitation.82 Four units of uncrossmatched PRBCs will be available for urgent release in the 
emergency department. (Figure 2) 
 
 
 RANDOMIZATION 
 
Procedures Assuring Adherence to Randomized Assignment: Enrollment will occur in the 
prehospital phase of the trial and LTLR-WB or prehospital standard of care will be provided based 
upon randomization assignment. Prehospital providers will designate the patient as enrolled and 
notify receiving staff of the treatment arm. Research staff will be present upon arrival and will 
communicate directly with blood banking staff/anesthesia and the trauma team regarding the 
randomization arm of the patient. Once in-hospital, LTLR-WB randomized patients may receive 
LTLR-WB transfusion as indicated during this acute resuscitation phase of in-hospital care up to 
6 units in-hospital and 8 units of LTLR-WB total.  
 
Randomization and Blinding: A single stage cluster randomization scheme will be utilized. 
Designated air medical bases at the University of Pittsburgh will be block randomized and 
assigned to the LTLR-WB arm or Standard of Care (control) arm for 1 month time intervals. The 
cluster design will be at the level of the helicopter base.  The block scheme will vary randomly 
between 2 and 4 month block sizes over the period of enrollment for the trial. Randomization 
assignments will be determined prior to the start of the bases enrollment following the above 
single stage cluster design using standard computerized randomization software. 
Communication with the blood bank transportation services and each respective air base will 
occur and an annual schedule of randomization assignment will be distributed to each study air 
base. This specific randomization scheme is required due to the limited supply of O+ LTLR-WB 
and also due to the logistics and delivery of the intervention in the prehospital setting. The 
Fig 2. Schematic depicting randomization arm comparison 

11 
 
proposed pilot trial will be an open label trial as blood product transfusion requires appropriate 
documentation and essential look back procedures.  
 
 STANDARD OPERATING PROCEDURES 
 
Prehospital Standard Operating Procedures:  The University of Pittsburgh Medical Center is 
being utilized for this pilot trial because it is a level I trauma center with busy air medical transport 
services that is recognized for providing high level care of the injured patients. To minimize over 
exuberant crystalloid resuscitation during the prehospital phase of treatment after enrollment and 
randomization, further crystalloid use will follow a ‘goal directed’ standard operating procedure 
based upon published evidence from our institution.81  
 
In-Hospital Standard Operating Procedures:  For the pilot trial once 4 hours has passed 
without ongoing blood transfusion requirements, standard transfusion practice evidence in the 
ICU will be followed including standard evidence based guidelines for each respective 
institution.83  
 
Resuscitation Practice: Irrespective of randomized arm, resuscitation practice during the in-
hospital phase of care will be based upon the patient’s hemodynamic status, bleeding control 
status, laboratory analysis, physician decision making and/or coagulopathy. Although the 
current trial will characterize what is given (LTLR-WB vs. component resuscitation) during the 
acute resuscitation phase of management, indications, quantity, and the rapidity of blood 
product transfusion will be dictated by the clinical status of the patient as directed by the trauma 
and anesthesia teams as is done for all trauma resuscitations. 
 
 STUDY ENDPOINTS 
 
Principle Outcomes: The principle objectives for the pilot trial are to evaluate 1.) safety and 
efficacy and 2.) feasibility for a prehospital through in-hospital LTLR-WB resuscitation protocol 
that will lead to a large, multicenter clinical trial that can be performed under the requirements of 
exception from informed consent for emergency research with regulatory oversight by the Food 
and Drug Administration (FDA) and Title 21, Code of Federal Regulations, Section 50.24 (21 
CFR 50.24).  
 
Primary Outcome For Assessing Safety and Efficacy: The primary safety and efficacy 
outcome for the pilot trial will be all cause 28-day mortality. We will utilize data derived from our 
recently completed PAMPer trial, which utilized identical inclusion and exclusion criteria, for in-
hospital mortality estimates.    
 
Primary Outcome For Assessing Feasibility and Trial Performance: The primary feasibility 
outcome for the pilot trial will be enrollment and accrual rate. Secondary performance and 
feasibility outcomes will include a) Eligibility rates; b) Adherence rates for the protocol; c) Injury 
and patient characteristics enrolled in the trial; d) Frequencies of proposed clinical outcomes; e) 
Air medical base population differences. 
 
Secondary Clinical Outcomes Estimating Treatment Effectiveness and Safety: Over 28 
days or up to discharge following randomization, we will compare: 1) Multiple Organ Failure 
(MOF): Organ dysfunction will be evaluated via the Denver Post-Injury Multiple Organ Failure 
Score and characterized as both a rate (%) and as MOF free days.84,85 2) Mean Denver Post-
injury MOF Score: This continuous variable will be a much more sensitive measure of organ 
dysfunction for the pilot trial. 3) Arrival Shock Severity: We will compare presenting base deficit, 

12 
 
lactate and shock index (SI, heart rate/systolic blood pressure-bpm/mmHg) 4) Acute Respiratory 
Distress Syndrome (ARDS): We will compare pulmonary dysfunction using the Berlin definition 
for ARDS.86 5) Nosocomial Infection (NI): We will compare the incidence of pneumonia and 
blood stream infections. 6) Mortality: We will compare mortality rates at 3, 6 and 24 hours 
following arrival, all cause in-hospital and 28-day mortality. 7) Blood component transfusion and 
resuscitation requirements at 24 hours: We will compare overall blood component transfusion 
requirements and crystalloid/colloid resuscitation requirements across the two arms. 8) Acute 
Hemolytic Transfusion Reaction (AHTR): We will compare the incidence of AHTRs across study 
arms as defined by the CDC/National Healthcare Safety Network (NHSN) Hemovigilance 
Surveillance definition. (www.cdc.gov/nhsn) Length of hospital stay and intensive care unit stay. 
Length of stay and ICU resources will be descriptively compared. Patients will be followed for 28 
days from admission for the 28-day mortality outcome utilizing chart review, patient contact or 
utilization of the social security death index for those who cannot be contacted. 
 
Predefined Subgroup Analyses: Predefined subset analyses for the pilot trial will be 
performed looking at our primary outcomes (safety/efficacy and feasibility) in 1) Females > 50 
years of age versus study cohort with females < 50 years excluded ; 2) Patients who ultimately 
did or did not require in-hospital blood transfusion; 3) Patients with and without significant 
traumatic brain injury (Head abbreviated injury score- AIS >2); 4) Patients enrolled from the 
scene of injury versus those enrolled from a referral hospital; 5) Patients that require operative 
intervention in the first 24 hours; 6) Those patients with a preinjury history of anticoagulation / 
antiplatelet therapy; 7) Patients who ultimately did or did not require massive transfusion (≥ 10 
units blood in first 24hrs) 8)Patients who did or did not receive prehospital PRBCs.  
 
Clinical Outcome Definitions:  
Multiple Organ Failure (MOF): Organ dysfunction will be evaluated via the Denver Post-injury 
Multiple Organ Failure Score, a well-validated scoring system in injured patients and 
characterized as an incidence rate (%) and as MOF free days.84,87 Patients who are never 
admitted to the ICU or those with a length of ICU stay of less than 48 hrs will be considered to 
have a Denver score of 0. A summary of the Denver score may be calculated by summing the 
worst scores of each of the individual systems over the course of the ICU stay. A summary 
Denver score > 3 will be classified as MOF. Scores will be determined daily up until ICU 
discharge.87 Mean Denver Post-injury MOF Score: As the primary endpoint for the pilot trial, the 
3 highest (worst) daily Denver scores will be averaged and compared across the treatment 
arms. Patient not in the ICU will be given a score of 0.  Acute Respiratory Distress Syndrome 
(ARDS): The Berlin definition for mild ARDS (PaO2/FIO2, ≤ 300 mm Hg + timing, imaging and 
origin criteria) will be utilized as a threshold value to determine the incidence of ARDS and will 
be further stratified into Moderate (PaO2/FIO2, ≤ 200) and Severe (PaO2/FIO2, ≤ 
100).86(Nosocomial Infection (NI): The CDC criteria for the diagnosis of hospital acquired 
pneumonia and blood stream infection will be utilized (www.cdc.gov/nhsn) Mortality: We will 
derive the time to a mortality event from the time of admission for 6 hour and 24 hour mortality 
rates over the initial 24 hours. All cause in-hospital and 28-day mortality will be similarly 
determined from the date of admission. 7) Blood component transfusion and resuscitation 
requirements at 24 hours: Blood component transfusion needs per unit (PRBC, FFP, PLT) will 
be recorded over the first 24 hours of admission with 6-hour incremental totals. For every unit of 
LTLR-WB that is transfused each will be designated as 1 unit of PRBC, 1u of FFP and a single 
pack of platelets. Similar recording of crystalloid volume and colloid volume of the initial 24 
hours following admission will be undertaken. 8) Acute Hemolytic Transfusion Reactions: We 
will compare the incidence AHTRs (CDC NHSN Hemovigilance Surveillance definition) and will 
measure arrival serum haptoglobin levels. 9) Length of hospital and intensive care unit (ICU) 
stay: Length of stay will be determined from the date of admission for all enrolled patients. 

13 
 
 
Mechanistic Outcomes: The principle factors that may be responsible for beneficial clinical 
outcome effects associated with or attributable to LTLR-WB resuscitation when initiated early in 
the prehospital phase of injury are an important and essential objective of the proposed pilot 
trial. We will compare across treatment arms: 1) Coagulopathy:  Coagulopathy will be assessed 
via PT/PTT/INR and rapid Thromboelastography (r-TEG) measurements. 2) Platelet Function:  
We will assess platelet activation, aggregation, and adhesion via flow cytometry analysis, whole 
blood aggregometry measurements and flow chamber analysis under shear stress conditions, 
respectively in a subset of patients.88,89 3) Glycocalyx integrity: We will assess glycocalyx 
integrity by measuring serum concentrations of Syndecan-1 and Hyaluronan by ELISA at in-
hospital time points. 3) Donor Exposure, Age and Volume of Transfusion Products: During the 
prehospital and in-hospital acute resuscitation phase of the study the number donors from all 
transfused products blood products, the age of all LTLR-WB and PRBCs from the standard of 
care arm and overall transfusion volumes will be recorded and compared. 
 
Blood Sampling and In-Hospital Measurements: In-hospital phase blood sampling will occur 
upon arrival (+ 4 hrs) and at 12 hours (+/- 12hrs) and 24 hours (+/- 12hrs) from time of arrival. 
Timing of samples will need to be flexible based upon patient availability and logistic factors. 
This early in-hospital sampling will allow adequate assessment of the benefits of early LTLR-WB 
resuscitation and appropriate characterization of the proposed clinical and mechanistic 
outcomes. TEG analysis at arrival, 12hr and 24hr time points will be performed on a TEG® 5000 
Thromboelastograph® Hemostasis Analyzer.  
 
  STATISTICAL ANALYSIS 
 
     The overarching goals for the pilot trial are to evaluate safety, efficacy and feasibility of a 
LTLR-WB prehospital through in-hospital protocol to plan for the successful execution of a large, 
multicenter clinical trial. All analyses will be performed based on the intent-to-treat principle for 
the prehospital randomization and analyses will include all enrolled patients grouped by 
randomization assignment. This pilot study will guide the calculation needed for the large, multi-
center clinical trial and will provide estimation for intra-cluster correlation coefficient and sample 
size variation across clusters. We will report 95% confidence intervals for all measurements 
 
Safety and Efficacy Analysis: 28-day mortality is the primary safety and efficacy outcome and 
will be compared across randomized groups. Utilizing intention to treat principles we will 
compare the LTLR-WB and Standard of Care arms using a pooled Z test for comparing two 
independent proportions. We will additionally perform survival analysis for all mortality outcomes 
including 3hr, 6hr, 24hr, and 28day time points across the two arms of the study testing the 
differences using log rank test. 
 
Eligibility, Enrollment, and Subject Accrual Anlaysis: The feasibility of enrollment will be 
evaluated by determining 1) the number of patients that meet the eligibility criteria for the trial; 2) 
the proportion of eligible patients that can be randomized and 3) the proportion of eligible 
patients who are enrolled in the trial.  These proportions will be estimated directly as the 
observed ratio of numbers of patients, and 95% confidence intervals will be calculated to 
understand the likely range of values for a larger study with a comparable research protocol. 
The reasons why patients are not enrolled including frequencies of individual exclusions and the 
proportion of patients declining participation or not able to be randomized will be described. 
Rate of subjects’ accrual per month with 95% C.I. will be calculated. 
 

14 
 
Adherence and Minimization of Bias: Adherence rates for each treatment arm of the protocol 
will be ascertained as the proportion of enrolled patients who adhere to the intervention (LTLR-
WB vs. standard care) as assigned.  Estimated proportions and 95% confidence intervals will be 
created. The trial has been designed to negate intervention arm crossover and maximize follow-
up completion.  
 
Estimates for Trial Secondary Clinical Outcomes:  We will estimate the mean differences in 
the average Denver post-injury MOF score derived from the 3 highest daily scores between two 
treatment groups as the main clinical outcome for the pilot trial. We will also record and 
compare the overall proportion of patients who developed MOF based on Denver score > 3 and 
compare MOF free days. Similarly, the incidence of ARDS, NI, mortality (6hr, 24hr and 28 day) 
and hemolytic transfusion reactions will be recorded. We will perform survival analysis for all 
mortality outcomes. Blood component and resuscitation volumes over the initial 24 hours, length 
of ICU stay, days on a ventilator, and total hospital stay will be also be determined. Estimated 
proportions and means and 95% confidence intervals will be created for each outcome using 
the data from the entire pilot trial (i.e. combining the data from the two assigned treatment 
arms).  Absolute and relative differences for continuous levels and event rates by assigned 
treatment will be estimated and 95% confidence intervals will be calculated to identify potential 
treatment differences for safety and for study planning purposes. Subgroup analyses will be 
exploratory and be based on baseline factors specified prior to the initiation of the trial.  
 
The Following Outcomes Will Be Recorded: 
1. The average Denver post-injury MOF score derived from the 3 highest daily scores. 
Differences between these averages will be estimated across the study two arms. 
2. Proportion of patients who developed MOF based on Denver score > 3 and compare 
MOF free days across the study two arms. 
3. The incidence of ARDS, NI, mortality (6hr, 24hr and 28 day) and hemolytic transfusion 
reactions will be recorded and compared across the study two arms 
4. Survival analysis in relation to all causes of death. 
5. Blood component and resuscitation volumes over the initial 24 hours, 
6. Length of ICU stay, days on a ventilator, and total hospital stay will be also be 
determined. 
 
Statistical Distributions of Enrolled Sample of Patients: Descriptive statistics, including 
means, standard deviations, medians, interquartile ranges, minimums, maximums, and 
frequency distributions, will be examined for all relevant measures.  Transformations of 
measures will be considered based on distribution diagnostics and outlier analyses.  The 
baseline characteristics of the patients in the entire trial will be described and 95% confidence 
intervals will be calculated to identify potential differences in baseline characteristics. 
 
 
1. Estimated proportions and means and 95% confidence intervals will be created for each 
outcome using the data from the entire pilot trial (i.e. combining the data from the two 
assigned treatment arms).  
2. Absolute and relative differences for continuous levels and event rates by assigned 
treatment will be estimated and 95% confidence intervals will be calculated to identify 
potential treatment differences for safety and for study planning purposes. Subgroup 
analyses will be exploratory and be based on baseline factors specified prior to the 
initiation of the trial. 
3. Descriptive statistics, including means, standard deviations, medians, interquartile 
ranges, minimums, maximums, and frequency distributions, will be examined for all 
relevant measures.   

15 
 
4. Transformations of measures will be considered based on distribution diagnostics and 
outlier analyses.   
5. The baseline characteristics of the patients in the entire trial will be described and 95% 
confidence intervals will be calculated to identify potential differences in baseline 
characteristics. 
 
 
Sample Size Justification for Pilot Trial: Assuming a baseline in-hospital mortality risk of 33% 
in the control arm as was demonstrated in the recently completed PAMPer trial with all cause 
in-hospital mortality as the primary outcome, enrolling 56 patients in each arm, 112 total 
patients and using a 2 sided alpha of 0.05, the study will have a 80% power to detect a 22% 
(33% to 11%) or greater difference in in-hospital mortality. Based upon current PAMPer clinical 
outcome data and the additional benefit attributable to LTLR-WB when it is initiated in the 
prehospital setting, the current proposed mortality difference is clinically meaningful and of 
sufficient magnitude to influence clinical practice for a pilot trial. The above sample size will 
provide more than sufficient power for the originally planned feasibility outcomes as we have 
increased our sample size by 24%. The above power analysis was generated assuming 2 
sequential tests using the O’Brien-Fleming spending function to determine test boundaries 
which are depicted in the following table and graph. 
 
Details when Spending = O'Brien-Fleming, N1 = 56, N2 =56, P1 = 0.1100, P2 = 0.3300 
 
 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look Time 
Bndry 
Bndry 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
0.50 
-2.96259 
2.96259 
0.003051 
0.003051 
0.003051 
0.164669 
0.164669  
2 
1.00 
-1.96857 
1.96857 
0.049002 
0.046949 
0.050000 
0.636252 
0.800921  
Drift 2.81024 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 Based upon the busy air medical service at the University of Pittsburgh, the  bases to be 
utilized for the pilot trial, 61 patients who met all inclusion and exclusion criteria for the current 
proposed pilot trial, were admitted to Presbyterian Hospital, consented and were enrolled 
(www.pamperstudy.com) over a 12 month period 6/2015-5/2016. Based upon a planned 
enrollment period of 2.5 years, this sample size is feasible after accounting for consent rates 
and exclusions. 
1st Interim Analysis 
2nd Interim Analysis 

16 
 
3. 
HUMAN SUBJECTS 
 
 SUBJECT POPULATION 
 
The study population will consist of injured patients at risk of hemorrhage being 
transported via air medical services from the scene of injury or from referring hospital to a 
definitive care trauma center participating in the PPOWER pilot trial. Patients will be enrolled in 
the prehospital setting prior to trauma center arrival with continuation of LTLR-WB resuscitation or 
standard of care resuscitation during the in-hospital acute resuscitation phase of the study 
 
  INCLUSION CRITERIA 
 
1. Injured patients at the risk of Hemorrhage being transported from scene or referral hospital to a 
participating PPOWER trial site  
AND 
2A. Systolic blood pressure ≤ 90 mmHg AND tachycardia > 108 bpm at scene, or at outside 
hospital or during transport.  
        OR 
2B. Systolic blood pressure ≤70 mmHg without tachycardia requirement, at scene or outside 
hospital or during transport. 
 
 EXCLUSION CRITERIA 
 
1. Documented age:  Age ≥90 or <18 years of age 
2. Inability to obtain intravenous or interosseous access 
3. Isolated fall from standing injury mechanism 
4. Known prisoner or known pregnancy 
5. Traumatic arrest with > 5 minutes of CPR without return of vital signs 
6. Brain matter exposed or penetrating brain injury (GSW) 
7. Isolated drowning or hanging victims 
8. Isolated burns without evidence of traumatic injury 
9. Referral Hospital In-patient admission  
10. Objection to study voiced by subject or family member at scene 
11. Wearing PPOWER opt-out bracelet 
 
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 air medical crew to either 
directly witness or obtain documentation of eligibility criteria, due to the nature of the emergency 
pre-hospital setting, there may be occasions where the air medical crew must rely on verbal 
report of inclusion criteria, including qualifying vitals, from the referring hospital or ground crew. 
In these instances, if, after subsequent review of outside hospital and/or ground crew 
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 intention-to-treat 
principle.  
     In the event that a verbal report must be used in lieu of physical documentation or directly 
witnessing the qualifying vitals, documentation of the verbal report will serve as the source 
documentation for determining eligibility. Verbal reports will be documented in the air medical 
record and will detail the information reported and by whom. 

17 
 
4. 
IRB APPROVAL AND FDA AMENDMENTS 
 
The Investigator will obtain, from the University of Pittsburgh Institutional Review Board 
(IRB), prospective approval of the clinical protocol and corresponding informed consent form(s); 
modifications to the clinical protocol and corresponding informed consent forms, and 
advertisements (i.e., directed at potential research subjects) for study recruitment.    
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s).  In such circumstances, the 
Investigator will promptly notify the University of Pittsburgh IRB of the deviation. The 
Investigator should also notify the sponsor of this event.  
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR 
Parts 50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, 
substantial changes to a clinical protocol submitted under an FDA-accepted IND application, or 
in the event of the Investigator’s decision to modify the previously accepted clinical protocol, a 
Protocol Amendment will be submitted to the IND file for FDA review and comment prospective 
of implementation of the changes, as required.  Changes that require prospective submission 
include: 
o Any significant change in the design of the protocol (such as the addition or 
deletion of a control group). 
The addition of a new test or procedure that is intended to improve monitoring for, or reduce the 
risk of, a side effect or adverse event; or the dropping of a test intended to monitor the safety of 
the investigational drug. 
5. 
RECRUITMENT AND INFORMED CONSENT PROCEDURES 
 
 RECRUITMENT METHODS:  
 
Subjects will be enrolled under "Exception from Informed Consent for emergency 
situations." 
 
Subjects will be identified by prehospital air medical personnel at the scene, in transit or 
when being picked up from a referring facility. Subjects not enrolled by prehospital personnel 
but who meet all inclusion and no exclusion criteria may be identified and enrolled by research 
personnel after arrival to the ED and will be analyzed based on the arm assignment from which 
they originated per the intention to treat analytic plan. 
 
In cases where the subject is incapacitated and unable to provide direct consent and an 
appropriate 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 sent electronically (email, fax, DocuSign, etc.) to the LAR. The 
investigator 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 Principal 
investigator electronically. An electronic picture of the signed signature page.forwarded to the 
consenting Investigator, will be accepted.  The consent form may also be sent to the LAR via 
DocuSign, where the document can be reviewed in detail and digitally signed.  
 
We will also send a postage paid envelope to the LAR for returning of the original 
complete signed informed consent whenever consent is obtained via email or fax.  

18 
 
If initial consent is obtained via LAR, the study team will routinely monitor the subject for 
capacity to consent while still admitted to the hospital.  If it is determined by the Investigator, in 
conjunction with the assessment of the clinical team, that the subject has regained capacity, the 
Investigator will conduct the inform consent discussion and attempt to obtain continuing 
consent. 
 
 INFORMED CONSENT PROCEDURES  
 
We anticipate that the pilot study will be conducted under the auspices and requirements 
of exception from informed consent for planned emergency research with regulatory oversight by 
the Food and Drug Administration (FDA) and Title 21, Code of Federal Regulations, Section 50.24 
(21 CFR 50.24). This entails obtainment of an Investigational New Drug (IND) approval from the 
FDA, local IRB approval, community consultation, public notification, as well as notification of 
patients or their legally-authorized representative as soon as feasible after enrollment. Per 
regulation, we will attempt to obtain prospective informed consent from the subject or an 
appropriate LAR whenever feasible).  However, we anticipate that prospective informed consent 
will not be feasible for the majority, if not all, of subjects enrolled.  The patient and/or family 
member or LAR will be informed at the earliest feasible opportunity of the subject’s inclusion in 
the clinical trial, and the details of the trial. If obtaining informed consent is not feasible and a 
legally authorized representative is not reasonably available, the investigator has committed, if 
feasible, to attempting to contact the subject's family member who is not a legally authorized 
representative, and asking whether he or she objects to the subject's participation in the clinical 
investigation. The investigator will summarize efforts made to contact family members and make 
this information available to the IRB at the time of continuing review if requested. The investigators 
will utilize available information and resources, such as social workers or social work notes, to try 
to locate the patient's legally authorized representative. If that search is unsuccessful, a 
notification letter will be sent to the subject's authorized representative explaining the study and 
providing contact information for answering questions. The letter will be sent via registered mail 
or by UPS and documentation of the addressee and date of mailing will be kept. If the subject 
becomes competent during the study period then he/she will be approached by a study 
Investigator for notification of enrollment and a similar provision of an opportunity to opt out from 
ongoing participation at the earliest opportunity. At any circumstance a subject or their legally 
authorized representative will have an opportunity to opt out of ongoing participation without 
penalty or loss of benefits. If the subject dies before consenting, a letter notification will be sent to 
the subject's family member to inform them that the subject was enrolled in this study. 
Community consultation as outlined by the local IRB will be undertaken prior to IRB 
approval. Feedback from the community will be obtained by research personnel regarding any 
concerns they may have about potential enrollment. Bracelets will be made available that could 
be worn by members of the community who do not want to participate. Public notification and 
community consultation will be performed as directed by the local IRB and may include such 
methods as using random digit dialing telephone surveys of the proposed study community, 
targeted small group meetings, newspaper adds, bus add, social media, or consultation with 
community leaders. Due to ongoing participation and coordination of multiple large multicenter 
studies of this type, our institution has significant experience with community consultation and 
notification practices.  Our community consultation plan is attached as an appendix (Appendix 
3)  
The following document describes the PPOWER study plan for Waiver of Consent for 
Planned Emergency Research in compliance with 21 CFR 50.24.  We are requesting this waiver 
because these human subjects are in a life-threatening situation, current available treatment is 
unsatisfactory, and it is necessary to determine the safety and effectiveness of whole blood 
transfusion in the prehospital setting.  Obtaining informed consent is not feasible because the 

19 
 
subjects will be unable to provide consent due to their medical condition and the intervention will 
need to be administered before consent from a legally authorized representative is feasible.  
Public disclosure to the communities in which the clinical investigation will be conducted and from 
which the subjects will be drawn, prior to initiation of the clinical investigation, of plans for the 
investigation and its risks and expected benefits.  
6. 
POTENTIAL RISKS AND BENEFITS 
 
 POTENTIAL RISKS 
 
Risks Associated With LTLR-WB:  The whole blood product to be utilized starting in the 
prehospital environment in the pilot clinical trial is the identical product to be used in the hospital 
and identical to the current whole blood product that has been transfused in over 200 patients 
over the last 24 months at the University of Pittsburgh without evidence of complications or 
transfusion reactions. The primary risk with LTLR-WB is a hemolytic transfusion reaction which 
will be followed as an important secondary outcome. There have been no hemolytic transfusion 
reactions in over 200 patients transfused LTLR-WB at the University of Pittsburgh in the last 24 
months. The primary risks with any blood transfusion can be found in the Circular of Information 
prepared jointly by AABB, the American Red Cross, America’s Blood Centers, and the Armed 
Services Blood Program. Those primary acute immunologic complications include hemolytic 
transfusion reactions, immune mediated platelet destruction, febrile nonhemolytic reactions, 
allergic reactions, anaphylactoid reactions and transfusion-related acute lung injury (TRALI). 
Delayed immunologic complications include delayed hemolytic reaction, alloimmunization, 
posttransfusion purpura, transfusion-associated graft-vs-host disease. Nonimmunologic 
complications include transmission of infectious agents, bacterial sepsis, transfusion-associated 
circulatory overload (TACO), hypothermia and metabolic complications. 
 
The primary risk associated with transfusion of Rh+ blood into a woman of child-bearing potential 
(WCP) is hemolytic disease of the fetus and newborn (HDFN) of a future pregnancy.  
Complications of HDFN include fetal anemia, fetal hydrops, and in the most severe cases, fetal 
death.  However, the overall risk of poor fetal outcome in a future pregnancy for Rh- women that 
are administered Rh+ blood products has been estimated to be less than 0.5%90.  Of note, the 
incidence of a female being Rh- is only 15%.  This means that the majority of WCP are at no risk 
of Rh mismatch.  For those WCP that are at risk, the likelihood of poor fetal outcome is very small.   
 
 
6.1.2 Risk of Study Procedures 
 
Risk of breach of confidentiality: When the results of the research are published or 
discussed in conferences, no information will be included that would reveal subjects’ identities.  
The PI and other study personnel will ensure that the subject’s confidentiality will be maintained. 
Subject name and other identifiable information will be kept in a secure, locked, limited access 
area such as a password protected database. Subjects will be provided a unique study 
identification number.  
 
Risk of venipuncture: Any labs drawn for research will try to be coordinated with labs being 
drawn for conventional care. Any venipuncture performed will be done so using aseptic technique 
by a clinical team member trained in phlebotomy. 
 
 ALTERNATIVE TREATMENTS 
 

20 
 
Prehospital air medical standard of care resuscitation and in-hospital standard of care 
resuscitation will be employed.  
 
 POTENTIAL BENEFITS 
 
We anticipate that the benefits of getting whole blood may reduce bleeding in some 
patients, and possibly reduce overall blood transfusion requirements during the first day after 
injury. Prior studies have suggested that early whole blood transfusion may improve outcomes in 
patients with a lot of blood loss.  Whether the subject receives the early whole blood transfusion, 
s/he may also benefit from increased observation at the time points involved in the study.  
Ultimately subject participation may help us to improve prehospital treatment of trauma injuries.  
 
 DATA SAFETY MONITORING 
 
6.4.1 Data Safety Monitoring Board 
 
The Clinical Coordinating Center will be led by Dr. Sperry (PI) for the pilot trial with the 
assistance of MACRO and associated clinical research infrastructure at the University of 
Pittsburgh. Given the small size and resources allotted for the pilot trial, we will not have a formal 
Data Coordinating Center and the data coordination will be performed by the Clinical Coordinating 
Center. A Steering Committee chaired by Dr. Triulzi (Co-PI) will be charged with overseeing the 
study and make all major organizational and policy decisions. Committee members will include 
Dr. Sperry, Dr. Guyette and Dr. Zuckerbraun. This group will have conference calls as needed for 
smooth execution of the trial. Members of a Data Safety Monitoring Board (DSMB) will be 
appointed and will include experts in hematology, surgery (trauma/critical medicine), bioethics, 
and biostatistics.  Members will consist of persons independent of the investigators who have no 
financial, scientific, or other conflict of interest with the study.  Written documentation attesting to 
absence of conflict of interest will be required. 
Any perceived or real conflicts of interest will be submitted to the University of Pittsburgh 
Conflict of Interest office.  If required, a management plan will be instituted to manage the 
conflict of interest.  At this time, no one on the study team has a conflict of interest.  
 
6.4.2 Data Safety Monitoring Plan 
 
The proposed study will use the FDA definition of adverse events (AE) and serious 
adverse events (SAE). Any fatal or life threatening AE, which is unexpected and related or 
possibly related to study intervention, will be reported immediately to the IRB and may be followed 
by an additional letter detailing the nature of the SAE if needed. In the event that a participant 
either withdraws from the study or the investigators decide to discontinue a participant due to a 
SAE, the participant will be monitored by the co-PIs until (a) a resolution is reached (e.g., the 
problem has resolved or stabilized with no further change expected), (b) the SAE is determined 
to be clearly unrelated to the study intervention, or (c) the SAE results in death. Outcomes of 
related or possibly related SAEs will be regularly reported to the IRB, DSMB, and the sponsor. A 
summary of the SAEs that occurred during the previous year will be included in the annual 
progress report as well as in the annual IRB renewal. 
 
Our DSMB responsibilities are listed as an appendix (Appendix 2). The DSMB will monitor 
accruing data in order to confirm patient safety throughout the trial. All study personnel will be 
trained on the protection of human subjects.  Although the DSMB will make the final decision 
about the monitoring plan, we anticipate that the DSMB will evaluate the rate of adverse events 
between the treatment and control arms every 6 months during enrollment. The DSMB will also 
monitor primary, secondary study outcomes between the treatment and control groups including 

21 
 
main effects and a priori subgroups as specified elsewhere in the protocol. The DSMB will advise 
the investigators if a change in the protocol is warranted based on this monitoring. 
The Medical Monitor is required to review all unexpected serious adverse events and other 
unanticipated problems involving risk to subjects or others.  At a minimum, the medical monitor 
must comment on the outcomes of the event or problem and, in case of a serious adverse event, 
comment on the relationship to participation in the study.  The Medical Monitor may review 
unblinded data in order to assist with his review. 
Study Changes 
If the PI and study team plan to modify the study, they will submit the amendment to the 
University of Pittsburgh HRPO along with all study documents to be changed (i.e. protocol, 
consent form, etc.)  Once IRB approval is obtained, the study team will submit the changes to 
the NIH at the next reporting cycle unless earlier notification is warranted.  If it is a significant 
change, the PI will request approval by the NIH Program Officer and DSMB prior to 
modification.  Any changes will also be reviewed by the Office for Investigator-Sponsored IND 
and IDE Support (O3IS) for determination if the change requires prospective FDA review or if it 
can be submitted at annual report. 
 
Data Analysis Plan Overall guideline: 
1. Nature of this study: Pilot study 
2. Overall objectives: Evaluate safety, efficacy, and feasibility of a LTLR-WB prehospital 
thru in-hospital protocol. The study will provide estimation for intra-cluster correlation 
coefficient and sample size variation across clusters for the design for a future full scope 
large clinical trail 
3. Analysis Principle: Intent-to-treat for the prehospital randomization assignment. 
95% confidence intervals for all measurements  
Safety and Efficacy Analysis: 
 
1. In-hospital mortality is the primary safety and efficacy outcome and will be compared 
across randomized groups.  
2. LTLR-WB and Standard of Care arms will be compared using a pooled Z test of two 
independent proportions.  
3. Survival analysis will be conducting looking at median survival at 3hr, 6hr, 24hr, and 
28day time points across the two arms of the study testing the differences using log rank 
test.  
 
Eligibility, Enrollment, and Subject Accrual:  
 
The feasibility of enrollment will be evaluated by determining, ratio of the following 
parameters will be calculated along with 95% confidence intervals: 
  
1) the number of patients that meet the eligibility criteria for the trial;  
2) the proportion of eligible patients that can be randomized and  
3) the proportion of eligible patients who are enrolled in the trial.   
 
Additionally: 
 
1. The reasons of not enrollment will be recorded with related frequency and 
percentages.  

22 
 
2. Frequency of patients eligible but not enrolled will be recorded  
3. Frequency of patients randomized but not included in the study will be recorded 
4. Rate of subjects’ accrual per month with 95% C.I. will be calculated. 
5. Adherence rates for each treatment arm of the protocol will be ascertained and 
recorded as the proportion of enrolled patient who adhere to each of the study arms 
 
Interim Analysis  
 
The main points in the interim analysis: 
1. Monitor the eligibility, enrollment, and subject accrual as stated above. 
2. Safety and efficacy by looking for In-hospital mortality differences between LTLR-WB 
and Standard of Care arms and compared these ratios using a pooled Z test of two 
independent proportions. Stopping rules will be used in the study interim analysis.  
3. Survival analysis will be monitored in the interim analysis  
4. Secondary outcomes will be checked and related 95% C.I will be estimated across 
the study two arms. 
5. Unanticipated Events 
6. Protocol deviation 
Stopping rules  
The following stopping rules of O’brien-Fleming boundaries will be implemented in the 
interim analysis:  
Details when Spending = O'Brien-Fleming, N1 = 56, N2 =56, P1 = 0.1100, P2 = 0.3300 
 
 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look Time 
Bndry 
Bndry 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
0.50 
-2.96259 
2.96259 0.003051 0.003051 0.003051 0.164669 0.164669  
2 
1.00 
-1.96857 
1.96857 0.049002 0.046949 0.050000 0.636252 0.800921  
Drift2.81024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.3 Parameters to be Monitored by Local Study Team 
 
The following progress will be monitored throughout the course of the research to ensure 
the safety of subjects as well as the integrity and confidentiality of their data. 
1st Interim Analysis 
2nd Interim Analysis 

23 
 
 
• 
An evaluation of the progress of the research study, including subject recruitment 
and retention, and an assessment of the timeliness and quality of the data. 
• 
A review of collected data (including adverse events, unanticipated problems, and 
subject withdrawals) to determine whether there is a change to the anticipated 
benefit-to-risk assessment of study participation and whether the study should 
continue as originally designed, should be changed, or should be terminated. 
• 
An assessment of external factors or relevant information (eg. pertinent scientific 
literature reports or therapeutic development, results of related studies) that may 
have an impact on the safety and study participants or the ethics of the research 
study. 
• 
A review of study procedures designed to protect the privacy of the research subjects 
and the confidentiality of their research data. 
 
Summary of Reports 
 
A summary of the data and safety monitoring meetings will be reported to the University 
of Pittsburgh HRPO office during annual renewal and to the NIH as required.  The DSMB chair 
and NIH Program Officer will regularly receive reports of enrollment, demographics, AE/SAEs, 
and UAPs.   Annual IND reports will be submitted to the FDA via the University of Pittsburgh’s 
O3IS (Investigator-Sponsored IND and IDE Support Office).    
 
6.4.4 Frequency of Monitoring 
 
The Investigator will review subject safety data as it is generated. The Investigator, sub-
investigators, and the research staff will meet on at least a quarterly interval during the active 
recruitment phase of the study to re-evaluate study goals, subject recruitment, data coding and 
retention, documentation and identification of adverse events, complaints and confidentiality of 
subjects. There will be an evaluation of the progress of the research study, including assessments 
of data quality, time lines, participant recruitment, accrual, and retention. The Investigator will also 
review the outcome and adverse event data to determine whether there is any change to the 
anticipated benefit-to-risk ratio of study participation and whether the study should continue as 
originally designed or should it be re-evaluated and changed. 
 
6.4.5 Reportable Adverse Events 
 
Assessing and Reporting Adverse Events (AEs):  Enrolled subjects will be monitored for 
adverse events throughout the first 48 hours after hospital admission. Reporting forms will be 
submitted to the DSMB and IRB. Potential adverse events occurring within the first 48 hours after 
admission will be reviewed as to treatment arm and further classified by: a) Severity (life-
threatening, serious, non-serious); b) Expected vs. Unexpected; and c) Related, Possibly Related, 
Probably Not Related, or Definitely Not Related. For serious adverse events that are related or 
possibly related to the study or intervention, the coordinating center will notify the IRB and the 
DSMB as well as additional appropriate regulatory agencies and sponsor promptly. The 
coordinating center will tabulate and report compliance, data quality, and non-serious adverse 
events on a regular basis.  
     Expected adverse events are commonly observed in patients who are at risk of hemorrhage 
following traumatic injury and may or may not be attributable to the LTLR-WB. Clinical diagnoses 
of pneumonia, sepsis, cerebral bleeding, stroke, seizures, surgical interventions, complications 
due to specific injuries as well as other major medical or surgical complications are commonly 

24 
 
observed in these patients. They will be recorded as noted in the hospital discharge summary as 
complications and will not be reported as adverse events. 
 
6.4.6 Adverse Events Reporting Timeline 
 
A table summarizing reporting timelines is provided below: 
 
Organization 
Fatal/Life 
Threatening 
SUSAR 
Non-fatal, 
non-life 
threatening 
SUSAR 
SAE 
(expected 
and 
related) 
UP (not 
involving 
risk) 
UPIRTSO 
IRB 
24 hours 
10 working 
days 
No 
requirement 
No 
reporting** 
10 working days 
FDA 
7 calendar 
days 
15 calendar 
days 
No 
requirement 
No 
requirement 
14 days* 
NHLBI 
7 calendar 
days 
7 calendar 
days 
No 
requirement 
No 
requirement 
14 days* 
Medical 
Monitor 
24 hours 
7 calendar 
days 
No 
reporting 
No reporting 
14 days* 
DSMB 
24 hours 
7 calendar 
days 
At next 
meeting 
(every 6 
months) 
At next 
meeting 
(every 6 
months) 
14 days* 
 
*Reporting occurs only after an IRB determination of UPIRTSO has been received 
**No direct reporting is required; events are documented on a log that can be reviewed upon 
request 
 
Prehospital Transfusion Adverse Events/Look Back Standard Operating Procedure (SOP): 
a. Transfusion rate will be compatible with the patient’s condition. The patient will be monitored 
closely during the entire transfusion. The documented start and stop times are directly related 
to the actual transfusion of the component. Study coordinators will assume responsibility of 
additional vital signs and completion of the whole blood  
b. The patient medical record shall include the following: 
1. Name of the components transfused 
2. Donation identification number  
3. Date and time of transfusion (Start and Stop time) 
4. Pre and post transfusion vital signs 
5. The volume or # of units transfused 
6. The transfusionist’s name (paramedic) 
7. Documentation of related adverse events 
     c. Procedure for transfusion reactions:  
This is modified from UPMC policy for Blood Transfusions to be applicable for this study. 
1. Careful observation throughout the transfusion allows for early detection of 
adverse reactions and optimal treatment, if necessary. All reactions should be handled 
initially as possible hemolytic reactions and the transfusion must be stopped. Any adverse 
events associated with the transfusion of blood or blood components should be 
documented in the patient’s Medical Record and reported to the blood bank/ transfusion 
service. Prehospital providers initiating transfusion of blood products will monitor vitals 

25 
 
throughout transport. If clinical concern for a transfusion reaction occurs, the transfusion 
will be stopped, and supportive care will continue. The concern for a transfusion reaction 
will then be communicated to the trauma center staff. 
2. The most common clinical events accompanying or announcing transfusion 
reactions are, in order of decreasing frequency: 
a. Fever, with or without chills 
b. Skin symptoms, hives and/or itching or rash 
c. Chest pain 
d. Hypotension 
e. Nausea 
f. Flushing 
g. Respiratory Distress (wheezing, coughing or dyspnea) 
h. Bleeding at infusion site 
i. Hemoglobinuria 
j. Circulatory overload 
k. Anaphylaxis 
3. If an adverse reaction is suspected, the procedure below will be followed: 
a. Stop the transfusion 
b. Maintain IV access with Normal Saline and change the tubing. 
c. Notify the patient’s physician upon arrival to the ED and initiate immediate 
treatment as ordered. 
4. For all other blood products involved in a reaction, all blood products shall be 
stopped and a transfusion reaction investigation shall be initiated per standard blood 
bank guidelines 
5. Notify the Blood Bank of the suspected transfusion reaction. 
6. Collect a sample drawn from the patient as soon after the reaction was 
detected. Send a 6 mls pink top tube, labeled with a new Blood Bank armband to the 
Blood Bank along with the unused blood, blood bag with attached hard back copy of the 
transfusion tag, the IV tubing used and the top 2 copies of the Transfusion Reaction 
Investigation 3 part form. The back copy of the Transfusion Reaction Investigation form 
should remain in the patient’s chart as the initial report. A post transfusion reaction 
Urinalysis with Microscopic may also be ordered by the patient’s physician. 
7. The Blood Bank will complete the Transfusion Reaction initial report and notify 
the caregiver of the critical results. Pathology will evaluate the patient’s reactions, Blood 
Bank’s initial report, culture when indicated, and report will be documented in the 
patient’s medical record. Consultation between the Medical Director of the Transfusion 
Service, the patient’s physician and Risk Management is required when a fatal hemolytic 
transfusion reaction occurs. Further evaluation and FDA notification may be indicated. 
The participating centers Transfusion Service is responsible for peer review and blood 
utilization practice. 
8. Look back procedures: Since the plasma will be tracked through the 
participating centers Blood Bank/Transfusion service look back/product recall 
procedures will be conducted as per standard protocol (Appendix 6). 
 
6.4.7 Withdrawal of Subjects and Stopping Criteria: 
 
Assuming a baseline in-hospital mortality risk of 33% in the control arm as was 
demonstrated in the recently completed PAMPer trial (manuscript in preparation) with all cause 
in-hospital mortality as the primary outcome, enrolling 56 patients in each arm, 112 total 
patients and using a 2 sided alpha of 0.05, the study will have a 80% power to detect a 22% 
(33% to 11%) or greater difference in in-hospital mortality. Based upon current PAMPer clinical 

26 
 
outcome data and the additional benefit attributable to LTLR-WB when it is initiated in the 
prehospital setting, the current proposed mortality difference is clinically meaningful and of 
sufficient magnitude to influence clinical practice for a pilot trial. The above sample size will 
provide more than sufficient power for the originally planned feasibility outcomes as we have 
increased our sample size by 24%. The above power analysis was generated assuming 2 
sequential test are made using the O’Brien-Fleming spending function to determine test 
boundaries which are depicted in the following table and graph. 
 
Details when Spending = O'Brien-Fleming, N1 = 56, N2 =56, P1 = 0.1100, P2 = 0.3300 
 
 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look Time 
Bndry 
Bndry 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
0.50 
-2.96259 
2.96259 
0.003051 
0.003051 
0.003051 
0.164669 
0.164669  
2 
1.00 
-1.96857 
1.96857 
0.049002 
0.046949 
0.050000 
0.636252 
0.800921  
Drift 2.81024 
    
   
 
 
Discontinuation of the Clinical Trial:  
 
The investigator may withdraw a subject from participating in this research if 
circumstances arise which warrant doing so. The decision may be made either to protect the 
subject’s health and safety, or because the subject’s condition did not meet certain criteria needed 
for study inclusion.  
 
  RISKS MANAGEMENT PROCEDURES 
 
6.5.1 Protection Against Risks   
 
General Risks of Study Protocol and Procedures 
 
Data collected will include a review of the air medical patient care report(s), Emergency 
Department and electronic/ paper hospital records. Prehospital Data: Demographics, air medical 
response times (call receipt to arrival, arrival at patient side,) injury characteristics, vital signs, 
prehospital resuscitation volumes, prehospital interventions (needle decompression, chest tubes) 
O'Brien-Fleming Boundaries with Alpha = 0.05
Upper
Lower
Z Value
Look
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
1.4
1.9
2.4
1st Interim Analysis 
2nd Interim Analysis 

27 
 
referring hospital vitals, and interventions will be recorded. In-Hospital Data: Demographics, 
shock severity (base deficit, lactate), injury characteristics, ED vitals, ED interventions (chest 
tubes, intubation), injury severity, operative interventions and timing of interventions, injury 
severity score, ICU days, ventilator days, length of stay, multiple organ dysfunction scores (daily), 
nosocomial infectious outcomes, blood gas results, chest x-ray reads, transfusion of blood and 
blood components, resuscitation requirements, all primary and secondary outcomes will be 
recorded. 
 
Data Entry and Storage: MACRO and associated internet technology affiliates at the University 
of Pittsburgh will create web-based data entry platform to collect necessary information for the 
proposed pilot study.  
 
All research interventions/activities will be conducted in private patient care areas. The 
collection of sensitive information about subjects is limited to the amount necessary to achieve 
the aims of the research, so that no unneeded sensitive information is being collected. 
 
A Case Report Form will be completed for each subject enrolled into the clinical study. 
The Investigator will attest that all clinical and laboratory data entered on the CRF are complete, 
accurate and authentic using a signoff page within the data entry platform.  A key linking the 
subject to the code number will be kept locked in a secure location and will be available only to 
the investigators. The data and samples will be retained indefinitely and used for future testing.  
Data from this study, without the subject’s identity, may be reported in scientific meetings, articles 
or other appropriate communications.  
 
The Investigator will retain the data for the entire period of this study and will retain the 
specified records and reports for a minimum of 7 years after completion of the study.  Subject 
names or other directly identifiable information will not appear on any reports, publications, or 
other disclosures of clinical study outcomes. 
 
6.5.2 Protection Against Potential Risks of Experimental Intervention 
 
MACRO research coordinators for the pilot trial will document and verify all trauma arrivals 
via air medical transport for PPOWER enrollment. Those patients who met inclusion and 
exclusion criteria during air medical transport that were enrolled will be verified and those patients 
will undergo initial laboratory and blood sampling within the first hour of arrival. All requirements 
for notification for exception from informed consent for emergency research and Title 21, Code of 
Federal Regulations, Section 50.24 (21 CFR 50.24) will be explicitly followed (Appendix 4). 
 
Training and Participating Site Coordination: As the clinical coordinating center for the 
proposed pilot trial the University of Pittsburgh will be responsible for all research coordinator 
training, prehospital provider training and sample collection and storage. Research coordinators, 
prehospital providers and associated staff will be trained during the months prior to the trial start 
date regarding the scientific basis for the study, specific inclusion and exclusion criteria, sample 
collection and processing, prehospital procedures and SOPs, and rapid TEG performance. Trial 
enrollment and maintenance of data integrity will be assessed monthly using the web-based data 
platform. Trial screening, enrollment and data completeness and accuracy will be accessed at 
regular intervals via random patient audit. 
7. 
COSTS AND PAYMENTS 
 
Neither the participant, nor the insurance provider will be charged for the costs 
performed only for the purposes of this research study.  Subject will be charged in the usual 

28 
 
manner for any procedures performed as part of your standard medical care (care the subject 
would receive even if they were not participating in this research study). 
8. 
QUALIFICATIONS AND SOURCE OF SUPPORT 
 
 QUALIFICATIONS OF THE INVESTIGATORS 
 
Jason Sperry, MD MPH is a Professor of Surgery and Critical Care Medicine at the 
University of Pittsburgh and the PI for the ongoing DoD funded PAMPer and STAAMP multicenter, 
randomized, clinical trials which investigate prehospital plasma and tranexamic acid in the 
prehospital setting during air medical transport. Dr. Sperry is an authority on interventional clinical 
trials in the prehospital setting, coagulopathy, massive transfusion and clinical outcomes research 
and comparative effectiveness studies following traumatic injury. He is an executive board 
member of MACRO, the interdepartmental Multidisciplinary Acute Care Research Organization 
which will provide the clinical coordination for the LITES network. He is also a Co-investigator for 
NHLBI funded TACTIC and is the Chair of the multicenter trials committee for the American 
Association for the Surgery of Trauma (AAST) and on the executive committee for the National 
Trauma Research Repository (NTRR) under the direction of the National Trauma Institute (NTI).  
 
Frank Guyette MD, MPH is an Associate Professor of Emergency Medicine and is the Co-
PI for the ongoing DoD funded PAMPer and STAAMP trials at the University of Pittsburgh. Dr. 
Guyette is a ROC investigator and was the PI of the ROC (Biomarker Lactate for the Assessment 
of Trauma) BLAST study. He is board certified in EM and EMS and is the Medical Director for 
STAT MedEvac, the nation’s largest non-profit critical care transport group. His leadership roles 
in the EMS community include Chair of the Pennsylvania Chapter American College of 
Emergency Medicine (PACEP) EMS Committee, National Association of EMS physician 
(NAEMSP) Air Medical Committee, and the American College of Emergency Physician member 
of the board of directors of the Commission on Accreditation of Medical Transport Systems 
(CAMTS). Dr. Guyette also serves as a member of the EMS COMPASS Evidence Review Group 
participating in the development of evidence based prehospital performance measures. His area 
of expertise is prehospital clinical outcomes research with a focus and multiple publications on 
out of hospital critical illness, prehospital resuscitation, prehospital point of care testing, and 
emergency medical service education. 
 
 
Matthew Neal, MD is an Assistant Professor of Surgery at the University of Pittsburgh. His 
lab focuses on the mechanisms of organ failure and coagulopathy following trauma and 
hemorrhage. Specifically, he is interested in the role of innate immune activation in the regulation 
of hemostasis and thrombosis. He is particularly interested in platelet biology in sterile injury and 
sepsis. In addition, he has a translational research interest in outcomes following massive 
transfusion and the clinical assessment of coagulation defects in trauma and sepsis. 
 
Darrell J. Triulzi, MD is a Professor of Pathology and Medicine, University of Pittsburgh, 
with subspecialty training and board certification in Transfusion Medicine/ Blood Banking. He has 
been director of the Division of Transfusion Medicine at UPMC hospitals since 1991. He has 
participated as both PI and co-investigator in federally funded clinical studies in transfusion 
medicine and has numerous publications in the field. He is also Medical Director of the Institute 
for Transfusion Medicine, which provides transfusion support to UPMC hospitals through Central 
Blood Bank. 
 
Mazen Zenati, MD, PhD is an Assistant Professor at University of Pittsburgh. Dr. Zenati 
will assist with statistical analysis for this study. 
 
Mark Yazer, MD is a board-certified expert in transfusion medicine and full-time faculty at 
UPMC Department of Pathology. Dr. Yazer is an experienced clinical trialist and has participated 
in other NIH funded clinical trials. 

29 
 
 
 SOURCES OF SUPPORT 
 
Cold stored, low titer, platelet replete-leukocyte reduced, group O whole blood (LTLR 
WB), Federal Sponsor: National Institutes of Health Grant number 1R34HL135224-01A1 
9. 
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52. 
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anti-B caused by the transfusion of blood or blood components containing ABO-
incompatible plasma. Transfusion. 2013;53 Suppl 1:114S-123S. 
53. 
Crosby WH, Akeroyd JH. Some immunohematologic results of large transfusions of 
group O blood in recipients of other blood groups; a study of battle casualties in Korea. 
Blood. 1954;9(2):103-116. 
54. 
Barnes A. Transfusion of universal donor and uncrossmatched blood. Bibl Haematol. 
1980(46):132-142. 
55. 
Barnes A, Jr. Status of the use of universal donor blood transfusion. CRC Crit Rev Clin 
Lab Sci. 1973;4(2):147-160. 
56. 
Barnes A, Jr., Allen TE. Transfusions subsequent to administration of universal donor 
blood in Vietnam. JAMA. 1968;204(8):695-697. 

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57. 
Strandenes G, Austlid I, Apelseth TO, et al. Coagulation function of stored whole blood 
is preserved for 14 days in austere conditions: A ROTEM feasibility study during a 
Norwegian antipiracy mission and comparison to equal ratio reconstituted blood. J 
Trauma Acute Care Surg. 2015;78(6 Suppl 1):S31-38. 
58. 
Yazer MH, Glackin EM, Triulzi DJ, Alarcon LH, Murdock A, Sperry J. The effect of 
stationary versus rocked storage of whole blood on red blood cell damage and platelet 
function. Transfusion. 2015. 
59. 
Bostrom F, Sjodahl M, Wehlin L, Egberg N, Lundahl J. Coagulation parameters in 
apheresis and leukodepleted whole-blood plasma during storage. Transfusion. 
2007;47(3):460-463. 
60. 
Pidcoke HF, McFaul SJ, Ramasubramanian AK, et al. Primary hemostatic capacity of 
whole blood: a comprehensive analysis of pathogen reduction and refrigeration effects 
over time. Transfusion. 2013;53 Suppl 1:137S-149S. 
61. 
Pidcoke HF, Spinella PC, Ramasubramanian AK, et al. Refrigerated platelets for the 
treatment of acute bleeding: a review of the literature and reexamination of current 
standards. Shock. 2014;41 Suppl 1:51-53. 
62. 
Manno CS, Hedberg KW, Kim HC, et al. Comparison of the hemostatic effects of fresh 
whole blood, stored whole blood, and components after open heart surgery in children. 
Blood. 1991;77(5):930-936. 
63. 
Becker GA, Tuccelli M, Kunicki T, Chalos MK, Aster RH. Studies of platelet concentrates 
stored at 22 C nad 4 C. Transfusion. 1973;13(2):61-68. 
64. 
Cap AP. Platelet storage: a license to chill! Transfusion. 2016;56(1):13-16. 
65. 
Nair PM, Pidcoke HF, Cap AP, Ramasubramanian AK. Effect of cold storage on shear-
induced platelet aggregation and clot strength. J Trauma Acute Care Surg. 2014;77(3 
Suppl 2):S88-93. 
66. 
Montgomery RK, Reddoch KM, Evani SJ, Cap AP, Ramasubramanian AK. Enhanced 
shear-induced platelet aggregation due to low-temperature storage. Transfusion. 
2013;53(7):1520-1530. 
67. 
Skripchenko A, Gelderman MP, Awatefe H, et al. Automated cold temperature cycling 
improves in vitro platelet properties and in vivo recovery in a mouse model compared to 
continuous cold storage. Transfusion. 2016;56(1):24-32. 
68. 
Arslan E, Sierko E, Waters JH, Siemionow M. Microcirculatory hemodynamics after 
acute blood loss followed by fresh and banked blood transfusion. Am J Surg. 
2005;190(3):456-462. 
69. 
Barbee RW, Kline JA, Watts JA. A comparison of resuscitation with packed red blood 
cells and whole blood following hemorrhagic shock in canines. Shock. 1999;12(6):449-
453. 
70. 
Torres LN, Sondeen JL, Dubick MA, Filho IT. Systemic and microvascular effects of 
resuscitation with blood products after severe hemorrhage in rats. J Trauma Acute Care 
Surg. 2014;77(5):716-723. 
71. 
Torres LN, Pittman RN, Torres Filho IP. Microvascular blood flow and oxygenation 
during hemorrhagic hypotension. Microvasc Res. 2008;75(2):217-226. 
72. 
Kozar RA, Pati S. Syndecan-1 restitution by plasma after hemorrhagic shock. J Trauma 
Acute Care Surg. 2015;78(6 Suppl 1):S83-86. 
73. 
Pati S, Matijevic N, Doursout MF, et al. Protective effects of fresh frozen plasma on 
vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic 
shock are time dependent and diminish between days 0 and 5 after thaw. J Trauma. 
2010;69 Suppl 1:S55-63. 
74. 
Aufderheide TP, Nichol G, Rea TD, et al. A trial of an impedance threshold device in out-
of-hospital cardiac arrest. N Engl J Med. 2011;365(9):798-806. 

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75. 
Bulger EM, May S, Brasel KJ, et al. Out-of-hospital hypertonic resuscitation following 
severe traumatic brain injury: a randomized controlled trial. JAMA. 2010;304(13):1455-
1464. 
76. 
Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after 
traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg. 
2011;253(3):431-441. 
77. 
Nichol G, Leroux B, Wang H, et al. Trial of Continuous or Interrupted Chest 
Compressions during CPR. N Engl J Med. 2015;373(23):2203-2214. 
78. 
Brown JB, Sperry JL, Fombona A, Billiar TR, Peitzman AB, Guyette FX. Pre-trauma 
center red blood cell transfusion is associated with improved early outcomes in air 
medical trauma patients. J Am Coll Surg. 2015;220(5):797-808. 
79. 
Clarke JR, Trooskin SZ, Doshi PJ, Greenwald L, Mode CJ. Time to laparotomy for intra-
abdominal bleeding from trauma does affect survival for delays up to 90 minutes. The 
Journal of trauma. 2002;52(3):420-425. 
80. 
Howell GM, Peitzman AB, Nirula R, et al. Delay to therapeutic interventional radiology 
postinjury: time is of the essence. J Trauma. 2010;68(6):1296-1300. 
81. 
Brown JB, Cohen MJ, Minei JP, et al. Goal-directed resuscitation in the prehospital 
setting: a propensity-adjusted analysis. J Trauma Acute Care Surg. 2013;74(5):1207-
1212; discussion 1212-1204. 
82. 
Gonzalez E, Moore EE, Moore HB, et al. Goal-directed Hemostatic Resuscitation of 
Trauma-induced Coagulopathy: A Pragmatic Randomized Clinical Trial Comparing a 
Viscoelastic Assay to Conventional Coagulation Assays. Ann Surg. 2015. 
83. 
Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical 
trial of transfusion requirements in critical care. Transfusion Requirements in Critical 
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1999;340(6):409-417. 
84. 
Sauaia A, Moore EE, Johnson JL, Ciesla DJ, Biffl WL, Banerjee A. Validation of 
postinjury multiple organ failure scores. Shock. 2009;31(5):438-447. 
85. 
Ciesla DJ, Moore EE, Johnson JL, Burch JM, Cothren CC, Sauaia A. A 12-year 
prospective study of postinjury multiple organ failure: has anything changed? Arch Surg. 
2005;140(5):432-438; discussion 438-440. 
86. 
Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: 
the Berlin Definition. JAMA. 2012;307(23):2526-2533. 
87. 
Minei JP, Cuschieri J, Sperry J, et al. The changing pattern and implications of multiple 
organ failure after blunt injury with hemorrhagic shock. Crit Care Med. 2012;40(4):1129-
1135. 
88. 
Vogel S, Bodenstein R, Chen Q, et al. Platelet-derived HMGB1 is a critical mediator of 
thrombosis. J Clin Invest. 2015;125(12):4638-4654. 
89. 
Ding N, Chen G, Hoffman R, et al. Toll-like receptor 4 regulates platelet function and 
contributes to coagulation abnormality and organ injury in hemorrhagic shock and 
resuscitation. Circ Cardiovasc Genet. 2014;7(5):615-624. 
90. 
Yazer MH, Delaney M, Doughty H, et al. It is time to reconsider the risks of transfusing RhD 
negative females of childbearing potential with RhD positive red blood cells in bleeding 
emergencies. Transfusion. 2019;9999; 1-6.  doi:10.1111/trf.15569. 
 
 
 
 
 
 

34 
 
 
 
 
Clinical Protocol Appendix 1 Blood Product Maintenance 
 
CENTER FOR EMERGENCY MEDICINE OF WESTERN PENNSYLVANIA,  INC. 
STAT MEDEVAC 
Blood Product Maintenance 
                                   1. 
 Base site blood products will be inspected daily for adequate 
temperature maintenance  in the blood product storage refrigerator. 
Daily temperature checks will be documented  in conjunction  with the 
weekly circular graph temperature recording.   Blood products will also 
be properly signed out of the blood refrigerator  when indicated for 
missions and maintained at proper temperature  until transfused or 
returned to the refrigerator. 
2. 
Inventory/Expiration 
Tracking 
Log 
a.  All PRBC units must be logged on this sheet when received 
from the designated distribution  point: 
1.   STAT MedEvac 1- Washington Hospital Transfusion 
Services 
Lab 
2. STAT MedEvac 2 -Johnstown American Red Cross 
3.   STAT MedEvac 3- UPMC Passavant Cranberry  Blood Bank 
4. 
STAT MedEvac 4- UPMC McKeesport  Transfusion Services 
L
a
b 
5. STAT MedEvac 5- Uniontown Hospital Blood Bank 
6. STAT MedEvac 6- Clarion Hospital Blood Bank 
7. STAT MedEvac 7- UPMC Horizon Transfusion  Services 
L
a
b 
8. STAT MedEvac 8- UPMC Passavant Cranberry 
9. STAT MedEvac 9- American Red Cross 
10. STAT MedEvac 10- John Hopkins Hospital 
11. STAT MedEvac 11 -Altoona Hospital Blood Bank 
12. STAT MedEvac 13- Baltimore American Red Cross 
13. STAT MedEvac 14- UPMC Passavant Cranberry  Blood 
B
a
nk 
14. STAT MedEvac 15- Washington  Hospital Transfusion 
Services 
Lab 
15.  STAT MedEvac 16- UPMC Passavant Cranberry  Blood 
B
a
nk 
16. STAT MedEvac 17- UPMC Hamot 
17. STAT MedEvac 18- Children's National Medical Center 
Blood 
Bank 
b. 
Record the following information: 

35 
 
1.   Unit Number 
2.   Date placed in service 
3.   Date unit will expire 
4.   Date unit is to be returned (minimum  of 10 days prior 
to expiration date on blood products) 
5.   Initials of person confirming  ABO type and placing units 
into service. 
6.   Disposition of units (transfused,  wasted, or returned) 
7.   Location:- Note the receiving facility where patient receiving 
PRBCs transfusion was admitted. 
8.   Paperwork: Check that all appropriate  paperwork is 
complet
ed. 
9.   Comments:  As needed, and list flight number 
associated with blood product transfusion. 
10. Initials of person completing log regarding  unit disposition. 
 
3. 
 Daily Checks I Shift Responsibilities:  In order to prevent any problems 
with the recording chart to potentially go undetected  for as long as 24 
hours, check the chart midway through the shift for accurate 
documentation  of current day and time every shift. Any problems  
should be corrected immediately  and documented on the recording 
chart. 
a.   Temperature and Visual Inspection to be completed  on every 
shift recording the following information  on the Temperature 
Check and Visual Inspection  Sheet: 
1.   Date  
of 
inspection 
2.   Temperatures  as indicated 
a. Make sure temperature  reading on recording 
chart corresponds  with current day, time. 
b. Make sure stylus is making 
contact 
with 
recording chart. 
c. Notify Base Site Manager of any problems,  
i.e.: possibility of contamination,  temperature  
not maintained between 1o  C to 6° C, inability 
to get recording chart to function properly. 
3.   Refrigerator graph:  Confirm accurate documentation  of 
current day and time on the circular graph. Internal 
refrigerator temperatures  and chart temperatures must 
both be within acceptable range (1-6° C) and agree with 
each other :t1° 
a.   Any gaps or fluctuations  in temperature  on 
recording 
chart 
must 
have 
explanation  
documented  on chart followed by your initials. 
b.   A copy of all temperature  documentation  will be 
sent to the appropriate blood bank by the Base 
Site Coordinator  or base representative. 
4.   Contamination: Check each unit of blood for contamination 
and expiration date- i.e., if the red cell mass appears 
purple; if there is a zone of hemolysis: visible clots; if the 
plasma is murky; if plasma has a purple, brown,  or red 
discoloration; if there are signs of leakage or inadequate  
sealing. 
a. 
PRBC units that are questionable must be 

36 
 
quarantined  and recorded  as such in the 
comments section. 
b.  Notify the appropriate blood bank immediately 
of quarantined blood. 
c. 
 Exchange quarantined  units for replacement  units 
as soon as possible. 
5.   Confirm that blood is ''0"  negative or positive. 
6.   Confirm that blood is not due to expire by checking  
the inventory and expiration tracking log.  If blood is to 
be returned, follow blood product return/transfer 
procedure. 
7.   Confirm ice or commercial ice packs are available 
for transport. 
8.   Comments  
as 
needed 
9.   Initials of person doing inspection. 
b.   Ensure refrigerator is clean and in working order. 
 
3.      Visual Inspection: Check appearance for contamination, clots, 
discoloration, etc.  List as satisfactory or unsatisfactory. 
4. Initials: 
Your 
initials. 
5.   Comments: Insert flight number and patient name if 
blood product was transfused. 
7. 
Packing blood products for a mission 
a. 
Blood products are to be taken on every mission. 
b. 
Each unit should be in the plastic blood product bags 
c. 
 Place in the insulated cooler with commercial ice packs or ice and 
an appropriate thermometer. The units should be "sandwiched" 
between the ice using appropriate barriers to prevent the units 
from coming in direct contact with the ice. 
d. 
 If blood is not transfused, return it to the blood product 
refrigerator upon returning to base. Fill out remaining Columns 
6-10 of Blood Tracking Log 
8. 
Administration of blood products is to be carried out in strict 
accordance with STAT MedEvac Critical Care Protocols. 
9. 
Documentation of transfusion 
a.   When a unit is transfused during a mission make sure 
the appropriate information is relayed to the receiving 
facility including type and unit number. 
b.   Fill out appropriate blood bank forms for transfused products per 
Central Blood Bank I American Red Cross instructions. 
c. Upon return to the base, fill out the Blood Tracking Log for 
Columns 
6-10 
as 
instructed. 
10. 
Replacement of transfused blood products 
a.   Notify appropriate blood bank that you have transfused 
blood and specify the number of replacements needed. 
i. 
Notify STAT Com and the Medical Director on call of any 
delay in receiving replacement units of blood and 
document the delay via special report. 
11. 
Transfusion Complications 
a. Notify the receiving facility of the patient's signs and 
symptoms immediately upon arrival. 
b.  Upon returning to base, an Adverse Reaction special 
report should be completed. 

37 
 
11. 
Blood refrigerator alarms 
a.   Monthly Check- High and low temperature alarms to 
be checked on the first of every month. 
i.   Remove blood from refrigerator and place on ice in cooler. 
ii.     Remove probe from glycerol solution and place the probe 
on ice.  Temperature of probe will register below 1c  C within 
several minutes to activate alarm. 
iii.  The designated operator should call to advise of the Alarm. 
Activate the silence button on the blood product 
storage refrigerator after receiving phone call. 
iv.  
Then place probe in tepid water to test high 
temperature alarm (>6°). 
v.   Again, the designated operator should call to confirm alarm 
activation. Activate the silence button on the blood 
product storage refrigerator after receiving phone call. 
vi.   Initial and note "Alarm Test" on Temperature Graph. 
vii.   Document "Alarms Checked/Operational or Non­ 
Operational" 
in 
comment 
section 
of 
Daily 
Temperature Checks and Visual Inspection Logs. 
viii.   If alarms fail or no phone call is received from the designated 
operator keep blood on ice in cooler and notify the Base 
Site Manager immediately for guidance. 
c. 
 
 
Alarm 
Activation 
i. 
The blood bank refrigerator will alarm any time the 
temperature in it rises above 6°C or below 1 oc or 
electrical 
power is shut off to the refrigerator. 
ii. 
At the same time, the remote alarm will be activated at the 
Communications 
Specialist's 
switch 
board, 
the 
Communications Specialist will notify you by phone when 
the alarm activates. 
iii. 
When alarm goes off, try to find any obvious causes, i.e., 
door is open to refrigerator, refrigerator is unplugged, 
circuit breaker is off, or circulating fan is not working. 
iv. 
If cause cannot be found or corrected, removed blood 
and place it on ice in the cooler. 
v. 
Notify the Base Site Manager immediately of problem. The 
Base Site Manager will instruct you as to what to do with 
the units of blood. 
12. 
Quarterly Temperature Monitoring 
a. 
 Every quarter (March, June, September, and December) 
a verification of temperature maintenance of blood during 
emergency flights must be performed. 
b. 
The following steps are to be performed when testing 
the temperatures: 
1.  Store the bottle in your refrigerator along with the units 
of blood until needed. 
2.   When packing units for an emergency, record the 
thermometer reading, time packed, date and initials on 
the card provided. 
3.   Place the bottle into the cooler along with the blood. 
4.   Assure that all the blood units and the bottle are covered 
with ice. 

38 
 
5.  Upon return to base after flight, record the thermometer 
reading, time unpacked, date, and initials on the bottom 
of the card provided. 
6.  The acceptable range during transport is 1-10. 
                                                      c.   
A record of all results will be maintained at the base 
 
Appendix 2 Data and Safety Monitoring Board  
 
A Data and Safety Monitoring Board (DSMB) will be created to review this study.  After initial 
approval and at periodic intervals (to be determined by the committee) during the course of the 
study, the DSMB responsibilities are to: 
1. Review the research protocol, informed consent documents and plans for data and safety 
monitoring; 
2. Evaluate the progress of the study, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, 
adverse events, unanticipated problems, performance of the trial sites, and other factors 
that can affect study outcome; 
3. Consider factors external to the study when relevant information becomes available, such 
as scientific or therapeutic developments that may have an impact on the safety of the 
participants or the ethics of the study; 
4. Review clinical center performance, make recommendations and assist in the resolution 
of problems reported by the PI; 
5. Protect the safety of the study participants; 
6. Report on the safety and progress of the study; 
7. Make recommendations to the PI, and if required, to the DoD or FDA concerning 
continuation, termination or other modifications of the study based on the observed 
beneficial or adverse effects of the treatment under study; 
8. Monitor the confidentiality of the study data and the results of monitoring;  
9. Assist the PI by commenting on any problems with study conduct, enrollment, sample size 
and/or data collection. 
 
The DSMB will include experts in hematology, surgery (trauma/critical medicine), 
bioethics, and biostatistics.  Members will consist of persons independent of the 
investigators who have no financial, scientific, or other conflict of interest with the study.  
Written documentation attesting to absence of conflict of interest will be required. 
 
The University of Pittsburgh Office of Clinical Research, Health Sciences / CTSI will 
provide the logistical management and support of the DSMB.  A safety officer 
(chairperson) will be identified at the first meeting.  This person will be the contact person 
for serious adverse event reporting.  Procedures for this will be discussed at the first 
meeting. 
 
The first meeting will take place before initiation of the study to discuss the protocol, 
approve the commencement of the study, and to establish guidelines to monitor the study.  
The follow-up meeting frequency of the DSMB will be determined during the first meeting.  
An emergency meeting of the DSMB will be called at any time by the Chairperson should 
questions of patient safety arise.   
 
 
 
 

39 
 
Appendix 3 Community consultation plan draft 
 
 
 We will conduct public disclosure to the communities in which the clinical investigation will be 
conducted and from which the subjects will be drawn, prior to initiation of the clinical investigation, 
of plans for the investigation and its risks and expected benefits.  
The following section describes our notification procedures: 
• 
Website. The University of Pittsburgh has an already established web site – 
acutecareresearch.org-which was designed to maintain communication and provide 
updates about emergency studies. The website includes our phone numbers, and an 
email account for communication.  The website also has a dialogue box allowing 
anonymous email communication for persons who do not wish to leave their names.  
• 
Bumper ads on mass transit.  These ads will be visible to the entire metropolitan area, 
and are constantly in motion. The ads will direct viewers to our website.  
• 
Flyers. We will distribute flyers directing traffic to our local website. Flyers will be provided 
in hospital waiting areas and community bulletins boards. 
• 
Presentation to local paramedics, emergency physicians and medical directors. We 
will create an email list-serve using Campaign Monitor. We will add any community 
members that express interest in our research based on emails, calls, inquiries or 
referrals.  
 
Consultation (including, where appropriate, consultation carried out by the IRB) with 
representatives of the communities in which the clinical investigation will be conducted and from 
which the subjects will be drawn. 
The following section describes some of our consultation procedures: 
• 
Website. The University of Pittsburgh has an already established web site – 
acutecareresearch.org-which was designed to maintain communication and provide 
updates about emergency studies. The website includes our phone numbers, and an 
email account for communication.  The website also has a dialogue box allowing 
anonymous email communication for persons who do not wish to leave their names. Also, 
anyone wishing to “opt out” will be provided the lead coordinator’s number to call and will 
be provided with a bracelet to wear indicating they do not wish to be part of the PPOWER 
study. 
• 
Feedback from community will be recorded. Since the population eligible for enrollment 
includes all citizens in the study region it will not be possible to target any particular small 
group. Feedback from the community will be recorded by research personnel regarding 
any concerns they may have about potential enrollment. 
• 
Paper Surveys: Paper surveys will be placed in the trauma clinic, around campus and in 
the Emergency Department. The questions will be similar to the telephone survey. We will 
tally the results and present them to the IRB at the time of their community consultation 
plan evaluation.  

40 
 
• 
Presentation to Pennsylvania Emergency Health Services Counsel. This group 
reviews research for the State Department of Health. We will schedule to present at one 
of their meetings, solicit and record their feedback, and present these findings to the IRB.  
• 
Telephone calls. We will have the lead coordinator’s telephone number on the website 
for interested parties to call. All calls will be returned, and “opt out” bracelets sent to any 
requesting them. Any voiced protestations will be recorded and presented to the IRB.  
• 
Telephone Survey.  A very detailed telemarketing survey will be commissioned by Dr. 
Sperry and performed by Dr. Ricci’s group at the Graduate School of Public Health over 
a four-week period.  This survey will be completed for 500 households in the zip codes 
where we intend to conduct this study.  Demographics of the respondents will resemble 
the demographics of the region.  Respondents will discuss the study for 10-15 minutes 
with the interviewer. In previous communications of this nature, one of the most 
informative aspects of this exercise is the detailed, verbatim responses provided from 
individuals both in favor and opposed to this research.  This information will be provided 
to the IRB for review.  
 
• 
Opt out bracelets: Prehospital providers will be trained to identify “OPT OUT “bracelets 
and to not include these patients in our research study.  
 
• 
Jehovah’s Witness Congregations: In the past we have noted a special interest from 
Jehovah’s Witness Congregations in any blood product administration EFIC trials. 
Therefore, we plan to send a letter and instructions for an opt out bracelet to congregations 
in our community.  
 
In summary, we will make a significant effort to disclose the study to the public and to receive 
feedback from the community about the study. We will document all comments and reach as 
many people as possible. These results will be reported to the IRB. We will keep the research 
line open throughout the study for any comments. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

41 
 
Appendix 4 Requirements for Exception From Consent For Emergency Research 
 
We have outlined below each criterion stipulated in the regulations for this exception and how our 
study design applies to these criteria.  
 
(1) The human subjects are in a life-threatening situation, available treatments are 
unproven or unsatisfactory, and the collection of valid scientific evidence, which may 
include evidence obtained through randomized placebo-controlled investigations, is 
necessary to determine the safety and effectiveness of particular interventions.  
 
     The proposed trial is a randomized trial comparing the use of prehospital through in-hospital 
whole blood versus standard of care in patients in hemorrhagic shock following injury requiring 
air medical transport to a definitive trauma center. These patients are in a life-threatening situation 
with a mortality before discharge approaching 30-40% despite all efforts. The standard of care for 
management of these patients includes intravenous crystalloid and packed red blood cells while 
en-route to definitive care and component resuscitation once arrival occurs at the trauma center.  
     Importantly, prior studies have demonstrated that injured patients who require large volume 
blood transfusion have improved survival if transfusion of high or equal ratios of plasma and 
platelets to blood occurs. Evidence suggests that early blood component transfusion may reduce 
overall blood transfusion requirements and that addressing the coagulopathy which occurs early 
after injury improves outcome. This is essentially what whole blood resuscitation provides. 
 
(2) Obtaining informed consent is not feasible because:  
i. The subjects will not be able to give their informed consent as a result of their medical 
condition;  
ii. The intervention under investigation must be administered before consent from the 
subjects' legally authorized representatives is feasible; and  
iii. There is no reasonable way to identify prospectively the individuals likely to become 
eligible for participation in the clinical investigation.  
 
The study intervention needs to be administered en-route to a definitive trauma center from the 
injury scene or from a referring hospital (see discussion of therapeutic window below). In this 
uncontrolled setting, the hemorrhagic shock patient is unable to provide consent for study 
enrollment, is commonly unconscious or in extremis, and legal next-of-kin are often not 
immediately available at the scene, nor is it practical for the hospital provider to explain the study 
and receive consent while caring for the patient. Since we are studying patients with hemorrhagic 
shock following injury, there is no way to prospectively identify individuals who are likely to 
become eligible for this trial. 
 
(3) Participation in the research holds out the prospect of direct benefit to the subjects 
because:  
i. Subjects are facing a life-threatening situation that necessitates intervention;  
ii. Appropriate animal and other preclinical studies have been conducted, and the 
information derived from those studies and related evidence support the potential for the 
intervention to provide a direct benefit to the individual subjects; and  
iii. Risks associated with the investigation are reasonable in relation to what is known 
about the medical condition of the potential class of subjects, the risks and benefits of 
standard therapy, if any, and what is known about the risks and benefits of the proposed 
intervention or activity.  
 
(i) As defined, these patients are injured and in hemorraghic shock and are facing a potentially 

42 
 
life-threatening situation that requires immediate intervention.  
(ii) Previous human studies suggest the potential for a direct benefit to individual patients who are 
in hemorrhagic shock.  
(iii) Whole blood has been evaluated in the military and has been shown to offer a survival 
advantage. We have provided whole blood to over 230 patients without complication or incident. 
As discussed above, there are potential risks to subjects that may have not been observed in 
previous trials. We contend that these risks are reasonable in light of the potential benefits outlined 
in this proposal and the current poor outcome for patients with hemorrhagic shock. 
 
(4) The clinical investigation could not practicably be carried out without the waiver.  
 
This study could not be conducted without the waiver of consent due to the need to initiate the 
intervention in the prehospital setting en route to a definitive trauma center for patients in 
hemorrhagic shock at significant risk of mortality.  
 
(5) The proposed investigational plan defines the length of the potential therapeutic 
window based on scientific evidence, and the investigator has committed to attempting to 
contact a legally authorized representative for each subject within that window of time and, 
if feasible, to asking the legally authorized representative contacted for consent within that 
window rather than proceeding without consent. The investigator will summarize efforts 
made to contact legally authorized representatives and make this information available to 
the IRB at the time of continuing review. 
 
Patients in hemorrhagic shock following injury have been shown to develop progressive 
hypothermia, coagulopathy and acidosis leading to further recalcitrant hemorrhage and 
multisystem organ failure and death. The potential therapeutic window for addressing this process 
is during the initial resuscitation period, which occurs from arrival of the air medical transport 
provider on scene or at a referral hospital up until trauma center arrival. Since this is an 
immediately life-threatening situation, it will not always be possible to contact legal 
representatives at the time of study entry. We will make every effort to contact legal 
representatives after admission to the hospital to notify them that the patient was enrolled in a 
randomized trial. Research personnel will attempt to contact the subject’s legal authorized 
representative as soon as feasible and a summary of these efforts will be documented in the 
patient’s chart. If the subject becomes competent during the study period then he/she will be 
approached by research personnel for notification of enrollment.   
 
(6) The IRB has reviewed and approved informed consent procedures and an informed 
consent document consistent with Sec. 50.25. These procedures and the informed consent 
document are to be used with subjects or their legally authorized representatives in 
situations where use of such procedures and documents is feasible. The IRB has reviewed 
and approved procedures and information to be used when providing an opportunity for a 
family member to object to a subject's participation in the clinical investigation consistent 
with paragraph (a)(7)(v) of this section. 
 
All procedures and consent forms will be approved by the Institutional Review Board (IRB) of the 
study site prior to the onset of the trial.  
 
(7) Additional protections of the rights and welfare of the subjects will be provided, 
including, at least:  
i. Consultation (including, where appropriate, consultation carried out by the IRB) with 
representatives of the communities in which the clinical investigation will be conducted 

43 
 
and from which the subjects will be drawn;  
ii. Public disclosure to the communities in which the clinical investigation will be 
conducted and from which the subjects will be drawn, prior to initiation of the clinical 
investigation, of plans for the investigation and its risks and expected benefits;  
iii. Public disclosure of sufficient information following completion of the clinical 
investigation to apprise the community and researchers of the study, including the 
demographic characteristics of the research population, and its results;  
iv. Establishment of an independent data monitoring committee to exercise oversight of 
the clinical investigation; and  
v. If obtaining informed consent is not feasible and a legally authorized representative is 
not reasonably available, the investigator has committed, if feasible, to attempting to 
contact within the therapeutic window the subject's family member who is not a legally 
authorized representative, and asking whether he or she objects to the subject's 
participation in the clinical investigation. The investigator will summarize efforts made to 
contact family members and make this information available to the IRB at the time of 
continuing review. 
 
 
(i) Community consultation as outlined by the local IRB will be undertaken prior to IRB approval. 
Since the population eligible for enrollment includes all citizens in the study region it will not be 
possible to target any particular small group. Feedback from the community will be obtained by 
research personnel regarding any concerns they may have about potential enrollment. If 
requested, bracelets will be made available that could be worn by members of the community 
who do not want to participate. Public notification and community consultation will be performed 
as directed by the local IRB and may include such methods as using random digit dialing 
telephone surveys of the proposed study community, targeted small group meetings or 
consultation with community leaders. Our institution has significant experience with community 
consultation and notification practices.  
(ii) & (iii) Public disclosures will be performed both prior to study enrollment and at the completion 
of the study in the form of multimedia press releases organized by the investigators. These will 
include plans for the study including potential risks and benefits and a summary of the results of 
the study upon completion. In the event that the press releases are not widely circulated, 
advertisements will also be placed in local papers describing the study.  
(iv) The Data Safety Monitoring Board will function as an independent data monitoring committee 
who will exercise oversight of the study.  
(v) We expect that all patients who meet the enrollment criteria will be unconscious or in critical 
state that does not allow appropriate consent to occur. Any delay in medical care that would be 
required for the care provider to attempt to obtain consent from the patient’s legal guardian would 
be life threatening. Thus it will not be feasible to attempt to obtain informed consent during the 
initial therapeutic window. Requiring consent to review a hospital chart to determine the presence 
or absence of serious adverse events is likely to be associated with a biased estimate of the 
safety and efficacy of the intervention. Therefore we will use exception from consent for 
emergency research which includes public notification, community consultation, patient 
notification of enrollment, and provision of an opportunity to opt out from ongoing participation.  
 
 
 
 
 
 
 

44 
 
Appendix 5 Standard operation procedures for notification and consent in EFIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

45 
 
Appendix 6 Donor -Patient LOOKBACK 
 
 
Donor-Patient “Lookback” 
Pg.  45 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
DONOR-PATIENT “LOOKBACK” 
    APPROVALS 
All Approvals are maintained and controlled via Document Control Systems’ MC3 Portal™ Software. 
Please Refer to MC3 Portal™ for the current controlled revision and approval records. 
 
    SUMMARY OF THE MODIFICATIONS – See MASTERControl™ InfoCard Release Date 
List a summary of the modifications below.  Bullet outline is recommended. 
 
• 
Revised Principle:  Regulatory agencies require notification of consignees by donor centers of blood products from 
a donor who subsequently tests confirmed positive for HIV1, 2, HCV, or HTLV-I/II or is at risk for transmitting 
Creutzfeldt-Jakob disease (CJD).  Lookback will also be performed by CTS when notified by the blood center of 
donors confirmed positive for HBV, HTLV, WNV, Zika, and Ebola viruses and Babesia. 
 
• 
Revised Section II title and step II.A:  RECIPIENTS PHYSICIAN NOTIFICATION OF POSSIBLE 
VIRAL/CJD/PARASITIC INFECTION (HIV, HCV, HBV, HTLV, WNV, Zika, Ebola, CJD, Babesia Ebola)  
A. General Requirements:  FDA has specific lookback requirements for some infectious agents, e.g., HIV, HCV, 
CJD, while others are performed by CTS as being important for patient safety (HVB, HTLV, WNV, Zika, 
Ebola, Babesia).  The CTS Pittsburgh and Chicago physician will identify a transfusion recipient according to 
records available described in Section IV of this policy.  Transfusion Service physician will send the patient’s 
physician a letter or secure e-mail notifying him/her of the lookback.  HIV and HCV notifications are sent by 
certified mail or secure e-mail.  The rest of the notification letters are sent by regular mail or secure e-
mail. 
 
• 
Revised step II.B.1;  step II.B.5 rewritten 
B. Lookback Notification Process 
1. HIV and HCV lookback process:  A notification letter is sent along with a notification form by 
certified mail or secure e-mail. The physician must promptly return the enclosed notification form … 
5. CJD lookback notification process and criteria:  The blood center will notify CTS of components 
from donors that were found to have CJD, vCJD, suspected vCJD, risk factors for CJD, or if 
withdrawal is recommended in cases under investigation for vCJD (CJD diagnosis and age less than 
55). In those situations, consignee notification could enable the consignee to inform the physician, or 
other qualified personnel responsible for care of the recipients, so that recipient tracing and medically 
appropriate notification and counseling may be performed at the discretion of health care providers.  
CTS will notify the patient’s physician in writing by letter or secure email and request that he/she 
provides follow up to the transfusion service of the patient outcome.  Follow up notification is not 
required if no response is received.  If the patient is deceased, physician notification is not required. 
 
For transfusible components from a donor with one family member diagnosed with CJD, or with risk 
factors for vCJD, suspected vCJD (due to geographic risk deferral, transfusion in the U.K. or in France 
between 1980 and the present, or due to injection of bovine insulin), per FDA Guidance for Industry, it 
is not appropriate to conduct tracing and notification of recipients of prior donations. 
 
 

46 
 
(Continued on next page) 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
Donor-Patient “Lookback” 
Pg.  46 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
 
• 
Revised step V.A.4   
V. RECORDS 
A. The following documents are maintained in the lookback file.  
 
4. Certified mail receipts or print out of secure e-mail communication. 
D. Lookback records are maintained for 10 years.  
E. HCV and HIV lookbacks are discussed at Transfusion Committee meetings and they are documented 
in Transfusion Committee records.  
 
• 
Deleted Procedure Notes 2-4 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
 
Donor-Patient “Lookback” 
Pg.  46 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
 
PROCESS 
SYSTEM 
Investigation of Adverse Transfusion Effects, Information Management 
CRITICAL CONTROL POINT 
Documentation/Record Keeping, Supplier Qualification, Error/Accident Review, Internal Assessment, 
Process Improvement 
 
PRINCIPLE 
Regulatory agencies require notification of consignees by donor centers of blood products from a donor 
who subsequently tests confirmed positive for HIV1, 2, HCV, or is at risk for transmitting Creutzfeldt-
Jakob disease (CJD).  Lookback will also be performed by CTS when notified by the blood center of 
donors confirmed positive for HBV, HTLV, WNV, Zika, and Ebola viruses and Babesia. 
 
POLICY 
I. 
IDENTIFICATION OF INFECTED DONORS 
A. 
Units implicated in the lookback process are identified by the blood center according to 
their SOPs.  The transfusion service is notified in writing of the units and their shipping 
date.  Notification to external hospitals (non CTS facilities) is completed by the blood 
center, not the RCRL or CTS. 
 

47 
 
II. 
RECIPIENTS PHYSICIAN NOTIFICATION OF POSSIBLE VIRAL/CJD/PARASITIC 
INFECTION (HIV, HCV, HBV, HTLV, WNV, Zika, Ebola, CJD,Babesia) 
A. 
General Requirements 
FDA has specific lookback requirements for some infectious agents, e.g., HIV, HCV, 
CJD, while others are performed by CTS as being important for patient safety (HVB, 
HTLV, WNV, Zika, Ebola, Babesia).  The CTS Pittsburgh and Chicago physician will 
identify a transfusion recipient according to records available described in Section IV of 
this policy.  Transfusion Service physician will send the patient’s physician a letter or 
secure e-mail notifying him/her of the lookback.  HIV and HCV notifications are sent by 
certified mail or secure e-mail.  The rest of the notification letters are sent by regular mail 
or secure e-mail. 
B. 
Lookback Notification Process 
1. 
HIV and HCV lookback process:  A notification letter is sent along with a 
notification form by certified mail or secure e-mail. The physician must promptly 
return the enclosed notification form to the transfusion service indicating that 
they accept responsibility for patient notification.  In the case of HIV and HCV, 
patient notification includes the need for HIV or HCV testing and counseling.  If 
the transfusion service cannot locate the physician, does not receive the 
notification form from the physician, or the physician refuses to accept 
responsibility for notification, then the transfusion service is responsible for 
notifying the patient.  This is done by the CTS physician at CTS hospitals.  The 
FDA requires that the process of notification be completed within 12 weeks for 
HCV and HIV and reasonable attempts should be made.  In addition to the 
physician notification, the facility where the patient was transfused will be 
notified.  This notification will go to the transfusion committee or similar entity 
at the facility. 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against 
the current electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are 
considered uncontrolled documents except when issued by Quality Assurance as an official hard copy for use in lieu of 
MASTERControl™. 
 
Donor-Patient “Lookback” 
Pg.  47 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
2. 
HCV lookback notification criteria:  A reactive NAT result serves as one basis 
for initiating lookback.  Since confirmatory testing for HCV (RIBA) became 
unavailable in 2012, new FDA approved algorithms were developed for HCV 
notification.  Notification of transfusion recipients of prior collections from the 
same donor is not required when the donor is repeatedly reactive on the anti-
HCV screening assay but negative on a mini-pool or individual donation HCV 
NAT assay and non-reactive on a second anti-HCV screening assay.  Transfusion 
Services must make reasonable attempts to perform the notification within 12 
weeks when the donor is repeatedly reactive on the anti-HCV screening assay 
and positive on a mini-pool or individual donation HCV NAT assay or negative 
on the HCV NAT assay and reactive on the second anti-HCV screening assay.  
Notification for HCV is not required if the donor is deceased. 
3. 
HIV lookback notification criteria:  When testing for HIV is confirmed 
positive or NAT positive when the screening test is reactive and further testing is 
not available, or if under an IND or IDE is exempted for such use by FDA, you 

48 
 
must notify transfusion recipients of previous collections of blood and blood 
components at increased risk of transmitting HIV infection, or the recipient's 
physician of record or a legal representative or relative if the recipient is a minor, 
deceased, adjudged incompetent by a State court, or if the recipient is competent 
but State law permits a legal representative or relative to receive information on 
behalf of the recipient of the need for recipient HIV testing and counseling (see 
above), you  must make reasonable attempts to perform the notification within 12 
weeks after receiving the results of further testing for evidence of HIV infection 
from the collecting establishment .  If the recipient received a transfusion in the 
hospital and died without ever being discharged from the hospital, you must 
notify the recipient’s physician of record but it is left up to the clinician’s medical 
judgement as to whether or not to inform a family member. 
4. 
HBV lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that test confirmed positive for HBV on a 
current donation (surface antigen positive with positive neutralization and/or 
positive NAT).  CTS will notify the patient’s physician in writing by letter or 
secure email and request that he/she provides follow up to the transfusion service 
of the patient outcome and/or testing.  Follow up physician notification is not 
required if no response is received.  If the patient is deceased, physician 
notification is not required. 
5. 
CJD lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that were found to have CJD, vCJD, suspected 
vCJD, risk factors for CJD, or if withdrawal is recommended in cases under 
investigation for vCJD (CJD diagnosis and age less than 55). In those situations, 
consignee notification could enable the consignee to inform the physician, or 
other qualified personnel responsible for care of the recipients, so that recipient 
tracing and medically appropriate notification and counseling may be performed 
at the discretion of health care providers.  CTS will notify the patient’s physician 
in writing by letter or secure email and request that he/she provides follow up to 
the transfusion service of the patient outcome.  Follow up notification is not 
required if no response is received.  If the patient is deceased, physician 
notification is not required. 
 
For transfusible components from a donor with one family member diagnosed 
with CJD, or with risk factors for vCJD, suspected vCJD (due to geographic risk 
deferral, transfusion in the U.K. or in France between 1980 and the present, or 
due to injection of bovine insulin), per FDA Guidance for Industry, it is not 
appropriate to conduct tracing and notification of recipients of prior donations.  
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
Donor-Patient “Lookback” 
Pg.  48 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
 
6. 
HTLV I/II lookback notification process and criteria:  The blood center will 
notify CTS of components from donors that test confirmed positive for 
HTLV I/II.  CTS will notify the patient’s physician in writing by letter or secure 

49 
 
email and request that he/she provides follow up to the transfusion service of the 
patient outcome and/or testing.  Follow up notification is not required if no 
response is received.  If the patient is deceased, physician notification is not 
required. 
7. 
Zika virus lookback notification process and criteria:  The blood center will 
notify CTS of components from donors that test NAT positive for Zika virus.  
CTS will notify the patient’s physician in writing by letter or secure email and 
request that he/she provides follow up to the transfusion service of the patient 
outcome and/or testing.  Follow up notification is not required if no response is 
received. If the patient is deceased, physician notification is not required. 
8. 
WNV virus lookback notification process and criteria:  The blood center will 
notify CTS of components from donors that test NAT positive for WNV virus.  
CTS will notify the patient’s physician in writing by letter or secure email and 
request that he/she provides follow up to the transfusion service of the patient 
outcome and/or testing.  Follow up notification is not required if no response is 
received.  If the patient is deceased, physician notification is not required. 
9. 
Ebola virus lookback notification process and criteria:  The blood center will 
notify CTS regarding blood and blood components collected from donors later 
determined to have Ebola virus infection or disease.  CTS will notify the patient’s 
physician in writing by letter or secure email and request that he/she provides 
follow up to the transfusion service of the patient outcome and/or testing.  Follow 
up notification is not required if no response is received.  If the patient is 
deceased, physician notification is not required. 
10. 
Babesia lookback notification process and criteria:  The blood center will 
notify CTS of components from donors that test positive by EIA only or EIA and 
NAT.  CTS will notify the patient’s physician in writing by letter or secure email 
and request that he/she provides follow up to the transfusion service of the 
patient outcome and/or testing.  Follow up notification is not required if no 
response is received.  If the patient is deceased, physician notification is not 
required. 
 
III. 
CENTRALIZED TRANSFUSION SERVICE RECIPIENT IDENTIFICATION 
The transfusion service must identify the recipient of any of the implicated units.  The method of 
recipient tracing varies with the date of transfusion and the hospital. 
PUH/E&E/CHP - After May 21, 1999 - SafeTrace Tx contains all units receipts received.  
Between mid-October 1988 and May 20, 1999 - the PTS computer system or microfiche 
contains all units recipients received. 
Prior to PTS computer (1988) - unit inventory cards (3 x 5) were used to record each unit, 
to whom it was issued and the hospital.  Cards are stored in boxes stored in a warehouse 
at National Business Records Management (NBRM).  There are cards dating back at least 
to 1977. (see Notes for retrieving cards) 
MUH - Patients transfused after May 11, 1991 are in the PTS system.  MUH has no transfusion 
records prior to this date. 
ALLEGHENY GENERAL HOSPITAL - Patients transfused after May 21, 1999 are in SafeTrace 
Tx.  Patients transfused between August 20, 1994 and May 20, 1999 are in the PTS 
system.  Patients transfused prior to this date must be retrieved by AGH staff.  From 
September 17, 1988 to August 19, 1994 records are at AGH Information Systems 
(SunQuest System).  From March 14, 1979 to September 16, 1988 , records are in log 
books stored at AGH Stat lab.  Any additional records are stored at Iron Mountain.  A 
request for the required records should be sent to the medical director of the department 
of pathology and the LIS manager. 

50 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
 
Donor-Patient “Lookback” 
Pg.  50 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
 
SHADYSIDE HOSPITAL - Patients transfused after May 21, 1999 are in SafeTrace Tx.  Patients 
transfused between October 7, 1994 and May 20, 1999 are in the PTS system. Patients 
transfused on or prior to this date must be extracted by SSH staff. A request for the 
required records should be sent to the medical director of the department of pathology 
and the laboratory administrative director. 
WASHINGTON HOSPITAL - Patients transfused after May 21, 1999 are in SafeTrace Tx.  
Patients transfused between July 7, 1995 and May 20, 1999 are in the PTS system. 
Patients transfused prior to this date are in card files and will be retrieved by WH staff. A 
request for the required records should be sent to the medical director of the department 
of pathology and the lab manager. 
MCKEESPORT HOSPITAL - Patients transfused after May 21, 1999 are in SafeTrace Tx.  
Patients transfused between March 2, 1997 and May 20, 1999 are in the PTS system. 
Patients transfused on or prior to this date are in card files and will be retrieved by McK 
staff. A request for the required records should be sent to the medical director of the 
department of pathology and the lab manager. 
UPMC, SOUTH SIDE HOSPITAL - Patients transfused after May 21, 1999 are in SafeTrace Tx.  
Patients transfused between February 28, 1997 and May 20, 1999 are in the PTS system. 
Patients transfused on or prior to this date are in card files and will be retrieved by SOSH 
staff. A request for the required records should be sent to the medical director of the 
department of pathology and the lab manager. 
COMMUNITY MEDICAL CENTER - Patients transfused on or after October 5, 1999 are in the 
SafeTrace Tx system.  Patients transfused prior to this date are referred to the medical 
director/lab manager to obtain the required information. 
UPMC, ST. MARGARETS - Patients transfused after July 31, 2000 are in the SafeTrace Tx 
system.  Patients transfused on or prior to this date are referred to the medical director/lab 
manager to obtain the required information. 
MAGEE HOSPITAL - Patients transfused after December 10, 2000 are in SafeTrace Tx.  Patients 
transfused on or prior to this date are referred to the medical director/lab manager of the 
hospital. 
WEST PENN HOSPITAL - Patients transfused after November 19, 2000 are in SafeTrace Tx.  
Patients transfused on or prior to this date are referred to the medical director/lab 
manager of the hospital. 
LIFECARE HOSPITAL - Patients transfused after January 17, 2000 are in SafeTrace Tx.  
Patients transfused on or prior to this date are referred to the medical director/lab 
manager of the hospital. 
KINDRED HOSPITAL - Patients transfused after December 31, 1999 are in SafeTrace Tx.  
Patients transfused on or prior to this date are referred to the medical director/lab 
manager of the hospital. 
RCRL CHICAGO - Patient’s transfused after June 1, 2000 are in SafeTrace Tx.  For patient’s 
transfused prior to this date, LifeSource will contact the transfusing facility directly. 

51 
 
UPMC-BRADDOCK HOSPITAL – Patients transfused after September 16, 2001 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the lab manager of the 
hospital. 
FORBES REGIONAL HOSPITAL – Patients transfused after March 24, 2002 are in SafeTrace 
Tx.  Patients transfused prior to this date are referred to the lab manager of the hospital. 
UPMC PASSAVANT AND UPMC PASSAVANT CRANBERRY HOSPITAL – Patients 
transfused after October 31, 2004 are in SafeTrace Tx.  Patients transfused prior to this 
date are referred to the lab manager of the hospital. 
AGH-SUBURBAN CAMPUS – Patients transfused after March 15, 2006, are in SafeTrace Tx.  
Patients transfused prior to this date are referred to the lab manager of the hospital. 
UPMC MERCY – Patients transfused after December 1, 2008 are in SafeTrace Tx.  Patients 
transfused prior to this date are referred to the lab manager of the hospital. 
 LIFELINE – Patients transfused after December 1, 2009 are in SafeTrace Tx. 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
Donor-Patient “Lookback” 
Pg.  51 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
 
ADVANCED SURGICAL – Patients transfused after May 1, 2010 are in SafeTrace Tx. 
MEADVILLE MEDICAL CENTER – Patients transfused after March 15, 2012 are in SafeTrace 
Tx.  Patients transfused prior to this date are referred to the lab manager of the hospital. 
UPMC EAST – Patients transfused after July 2, 2012 are in SafeTrace Tx.  UPMC East has no 
transfusion records prior to this date. 
WHEELING HOSPITAL – Patients transfused after January 11, 2014 are in SafeTrace Tx.  
Patients transfused prior to this date are referred to the lab manager of the hospital. 
BELMONT COMMUNITY HOSPITAL – Patients transfused after January 29, 2014 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the lab manager of the 
hospital. 
ALLEGHENY VALLEY HOSPITAL – Patients transfused on or after March 15, 2014 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the medical 
director/lab manager of the hospital. 
CANONSBURG GENERAL HOSPITAL - Patients transfused on or after March 15, 2014 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the medical 
director/lab manager of the hospital. 
REYNOLDS MEMORIAL HOSPITAL – Patients transfused on or after July 28, 2014 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the medical 
director/lab manager of the hospital. 
JEFFERSON HOSPITAL – Patients transfused on or after April 25, 2015 are in SafeTrace Tx.  
Patients transfused prior to this date are referred to the medical director/lab manager of 
the hospital. 
WASHINGTON HEALTH SYSTEM-GREENE – Patients transfused on or after December 1, 
2016 are in SafeTrace Tx.  Patients transfused prior to this date are referred to the 
medical director/lab manager of the hospital. 
UPMC HORIZON-GREENVILLE – Patients transfused on or after January 17, 2017 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the medical 
director/lab manager of the hospital. 

52 
 
UPMC HORIZON-SHENANGO – Patients transfused on or after January 17, 2017 are in 
SafeTrace Tx.  Patients transfused prior to this date are referred to the medical 
director/lab manager of the hospital. 
UNIVERSITY OF ILLINOIS-CHICAGO – Patients transfused on or after February 15, 2014 are 
in SafeTrace Tx.  Patients transfused prior to this date are referred to the medical 
director/lab manager of the hospital. 
 
IV. 
CONFIRMING THE PATIENT AND IDENTIFYING THE PHYSICIAN 
A. 
Pittsburgh:  For patients since October 1988, the SafeTrace Tx has the patient's name, 
hospital number, birth date and sometimes the physician.  If the physician's name is not 
available in the computer, this must be obtained from the medical record.  For 
transfusions in the pre-computer era, the transfusion, the recipient, and the physician are 
verified by review of the medical record or by the PTS patient card.  Patient cards are 
stored in boxes stored in a warehouse at National Business Records Management 
(NBRM).  
B. 
Chicago:  Patients transfused after June 1, 2000 are in SafeTrace Tx.  If physician 
information is not in SafeTrace Tx, the transfusion entity will receive only the 
information available prior to this time. 
V. 
RECORDS 
A. 
The following documents are maintained in the lookback file: 
1. 
Notification letter from blood center 
2. 
Copy of certified letter notifying recipient’s physician (HIV, HCV)  
3. 
Documentation indicating physician’s acceptance of responsibility for   patient 
notification (HIV, HCV only) 
4. 
Certified mail receipts or a print out of secure e-mail communication  
5. 
Documentation of patient notification if performed by the transfusion service 
medical director 
B. 
Documentation of notification of the patient’s physician 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
 
Donor-Patient “Lookback” 
Pg.  8 of 8 
Doc #:  ITxM-CS-00795 
Revision:  16 
Department:  ITxM Clinical Services 
 
C. 
Documentation of notification of the patient by his/her physician should be maintained in 
the patient's medical record  
D. 
Lookback records are maintained for 10 years. 
E. 
HCV and HIV lookbacks are discussed at Transfusion Committee meetings and they are 
documented in Transfusion Committee records. 
 
PROCEDURE NOTES 
1. 
Electronic records in SafeTrace Tx date back to May 20 of 1999.  Prior to this date, information 
may be retrieved using the Cognos PTS Archive reports if data is available. 
REFERENCES 
1. 
21CFR 610.47(b)(3) 
2. 
21CFR 610.46 

53 
 
3. 
Guidance for Industry “Lookback” for Hepatitis C Virus (HCV):  Product Quarantine, Consignee, 
Notification, Further Testing, Product Disposition, and Notification of Transfusion Recipients 
Based on Donor Test Results Indicating Infection with HCV, December 2010.  Updated August 
2017. 
4. 
21CFR 610.46 
5. 
Guidance for Industry:  Use of Nucleic Acid Tests on Pooled and Individual Samples from 
Donors of Whole Blood and Blood Components, Including Source Plasma, to Reduce the Risk of 
Transmission of Hepatitis B Virus, October 2012. 
6. 
Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob 
Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products.  Guidance for 
Industry, May 2010.  Updated January 2016. 
7. 
“Lookback” for Hepatitis C Virus (HCV):  Product Quarantine, Consignee Notification, Further 
Testing, Product Disposition, and Notification of Transfusion Recipients Based on Donor Test 
Results Indicating Infection with HCV, August 2007.  Updated December 2010. 
8. 
Guidance for Industry:  Donor Screening for Antibodies to HTLV-II.  August 1997. 
 
AUTHOR 
Darrell J. Triulzi, M.D., and Linda F. Hahn, MPM, MT(ASCP)SBB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current 
electronic version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

54 
 
Appendix 7: 
 
 
 
 
 
 
Whole 
Blood 
   Pre-Hospital 
Emergency 
Department 
In-hospital 
Meets 
inclusion 
and 
exclusion 
criteria  
Start 
Component 
Resuscitation 
Up to 6 Units 
of Whole 
Blood  
Standard 
care 
PPOWER Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

55 
 
APPENDIX 8: Tables that will be used to summarize study data and 
comparisons: 
 
Table1: Demographics and injury 
 
Overall 
Arm A 
Standard of Care 
n= 
Arm B 
LTLR-WB 
n= 
 
Age 
Mean ± SD 
Median (IQR) 
 
 
 
 
Sex  
Males,  frequency(%) 
Females frequency(%) 
 
 
 
 
Race 
White: 
Black: 
Others: 
 
 
 
 
BMI 
 
 
 
 
Major comorbidity 
1. 
2 
3. 
4. 
 
 
 
 
Smoking 
 
 
 
 
Intoxicated (alcohol) 
 
 
 
 
GCS 
 
 
 
 
Mechanism of injury 
 
 
 
 
Blunt vs 
Penetration 
 
 
 
 
ISS 
 
 
 
 
AIS 
 
 
 
 
Head trauma 
 
 
 
 
Distance from scene to 
hospital 
 
 
 
 
Transferred  
 
 
 
 
sedated 
 
 
 
 
Intubated 
 
 
 
 
ED Disposition 
 
 
 
 
Procedures 
 
 
 
 
 
Table 2: Safety and Efficacy 
 
 
Overall 
Arm A 
Standard of Care 
Arm B 
LTLR-WB 
Testing 
In hospital Mortality 
Frequency (%) 
 
 
 
 
 

56 
 
In hospital Mortality 
Proportion in each arm 
 
 
 
 
Z test of 
independent 
proportion 
Median survival at  
3hr 
6hr 
24hr 
28days 
 
 
 
 
Log rank test 
 
 
Table 3: Eligibility, Enrollment, and Subject Accrual 
 
Overall 
Arm A 
Standard of Care 
Arm B 
LTLR-WB 
95% C.I 
Patients that meet the eligibility 
criteria for the trial 
Frequency, (%) and Proportion 
 
 
 
 
Eligible patients that can be 
randomized 
Frequency, (%) and Proportion 
 
 
 
 
Eligible patients who are 
enrolled in the trial 
Frequency, (%) and Proportion 
 
 
 
 
Patients eligible but not 
enrolled  
Frequency, (%) and Proportion 
 
 
 
 
Patients randomized but not 
included in the study  
Frequency, (%) and Proportion 
 
 
 
 
Rate of subjects’ accrual per 
month 
Frequency, (%) and 
Proportion/ month 
 
 
 
 
Adherence rates for each 
treatment arm 
Frequency, (%) and Proportion 
 
 
 
 
Reasons of not enrollment  
1. 
2. 
3. 
4. 
5.  
Frequency, (%) and Proportion 
 
 
 
 
 
Table 4: Estimates for Trial Secondary Clinical Outcomes 
 
Overall 
Arm A 
Standard of Care 
Arm B 
LTLR-WB 
95% C.I 
Average Denver post-injury 
MOF score derived from the 3 
highest daily scores. 
 
 
 
 
MOF free days across the 
study two arms 
 
 
 
 

57 
 
ARDS 
(Frequency, (%) and Proportion) 
 
 
 
 
NI 
(Frequency, (%) and Proportion) 
 
 
 
 
Mortality 
6hr  
24hr  
28day 
(Frequency, (%) and Proportion) 
 
 
 
 
Hemolytic transfusion 
reactions 
(Frequency, (%) and Proportion) 
 
 
 
 
Median Survival analysis for in 
relation to all causes of death 
 
 
 
 
Blood component transfused 
the initial 24 hours (units) 
PRBC:  
Plasma: 
Platelets: 
Cryoprecipitate:  
 
 
 
 
Total resuscitation volumes 
over the initial 24 hours 
(Units) 
 
 
 
 
Length of ICU stay 
(Days) 
 
 
 
 
Days on a ventilator 
(Days) 
 
 
 
 
Total hospital stay 
(Days) 
 
 
 
 
 
Table 5: Unanticipated Events 
 
Unanticipated Events 
Reporting: grade/severity, 
PI Assessment: 
Related/unrelated 
 
Overall 
F(%) 
Arm A 
Standard of Care 
F(%) 
Arm B 
LTLR-WB 
F(%) 
 
1. 
 
 
 
 
2. 
 
 
 
 
3. 
 
 
 
 
4. 
 
 
 
 
5. 
 
 
 
 
 
 
 
 
 
 
 
 

58 
 
 
Table 6: Protocol deviation 
Protocol deviation 
Overall 
F(%) 
Arm A 
Standard of Care 
F(%) 
Arm B 
LTLR-WB 
F(%) 
 
1. 
 
 
 
 
2. 
 
 
 
 
3. 
 
 
 
 
4. 
 
 
 
 
5.