Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT01221389 |
| Other study ID # |
OHREB#2010077-01H |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
March 2012 |
| Est. completion date |
March 2013 |
Study information
| Verified date |
May 2023 |
| Source |
Ottawa Hospital Research Institute |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Information on the management of casualties from the ongoing conflicts in Afghanistan and
Iraq has brought in to question the traditional approach to blood transfusion in hemorrhaging
patients. Present recommendations for when to transfuse plasma products is when coagulation
tests become abnormal. The proposed trial will investigate whether the more aggressive plasma
transfusion strategies as advocated from researchers based on the Central Asian conflicts is
valid. Since a study to determine the full impact of an altered plasma transfusion practice
would require thousands of patients, a feasibility trial is appropriate and is being
proposed. The hypotheses are thus:
Primary Hypothesis- A multicentre trial that investigates the earlier use of plasma in
patients with hemorrhagic shock going for emergency surgery will be feasible.
Secondary Hypotheses- The early use of a universal donor blood plasma (AB+ plasma) in
patients with shock due to blood loss (i.e. hemorrhagic) going for emergency surgery will
reduce overall exposure to the total number of blood donor products (so-called allogeneic
blood exposure). A reduction in allogeneic blood exposure would then reduce the total number
of blood transfusion-related complications. The early use of this plasma product is safe and
will not increase the incidence of blood clotting or other transfusion-related complications.
Description:
Investigations that have arisen from reviews of casualty management in the ongoing conflicts
in Afghanistan and Iraq have challenged the standard approach to blood transfusion in
hemorrhaging patients. Present recommendations are to ideally transfuse non-red blood cell
blood products as indicated by coagulation and other blood tests. In the event that testing
is not available or feasible, then clinical judgment is advised with two recommendations. The
first is that platelets are usually required after red blood cell (RBC) transfusions of one
blood volume (approximately 5 liters of blood loss); and the second is that plasma is not
usually required until RBC transfusion of well over one blood volume. Contrary to these
recommendations is evidence from these conflicts indicating that delays in plasma transfusion
or reduced plasma dosing are associated with increased mortality. Although the evidence is
primarily retrospective and at times circumstantial in nature, the relationship between
plasma administration and mortality appears to be causation rather than simple association.
Matching of injury severity and other important variables does not alter this conclusion. If
this conclusion is true, the question becomes whether or not the transfusion practice of
patients in a civilian setting should be changed.
The present plasma transfusion recommendations were largely based on studies of plasma
exchange patients and the use of data from the 1970's. In plasma exchange, patients have a
controlled removal of their plasma that is ultimately replaced with donor plasma.
Coagulopathy develops solely from the amount of plasma removal since no consumption of
factors exists. Hemorrhaging patients however lose coagulation factors both in shed blood and
due to ongoing consumption at sites of injury. Further, the hemodynamic instability and
hypovolemia experienced by hemorrhaging patients further exacerbates the reduction in
clotting factor levels. Prior to the late 1980's, hemorrhaging patients often received whole
blood transfusions. Whole blood, no longer used in most circumstances, contains approximately
1 unit of plasma in each unit. Thus, patients receiving whole blood will not develop a
coagulopathy as quickly as patients who receive the now standard packed red blood cell units.
Despite a lack of prospective studies and significant limitations of the supporting evidence,
the practice of waiting to administer plasma was rapidly adopted. Reasons for this were
several but included concerns about infectious transmissions, shortage of blood products and
the financial costs of the blood products. Regardless of the reasons for their development
however, the present transfusion recommendations including those for plasma may no longer be
applicable in all circumstances.
A strong argument against waiting for the coagulopathy to develop before treating is that the
consequences of the coagulopathy are so grave that they should be avoided. The coagulopathy
of hemorrhagic shock is a major component of the 'lethal triad' seen in hemorrhaging patients
(in conjunction with acidosis and hypothermia). The lethal triad has a very high mortality
rate (over 70%) with limited ability of physicians to treat it. Evidence supporting this
argument has primarily come from the conflicts in Central Asia. Several retrospective studies
have been published by the US Army Institute of Surgical Research that have not only
challenged this practice but have resulted in changes in how the US armed forces manage
trauma patients. The US military now uses plasma in a 1:1 ratio in their traumatized soldiers
(i.e. 1 unit of plasma given for every unit of packed RBC).
Major hemorrhagic injuries in non-military situations consist primarily of traumatic injuries
and major blood vessel (i.e. vascular) injuries. Although all of these injuries or problems
are not exactly the same as military casualties, there are major commonalities between these
population groups that allow the results of the military studies to be applicable to these
civilian populations. Retrospective and case-control trials in non-military trauma and in
ruptured abdominal aortic aneurysms (AAA) offer indirect evidence to support a different
plasma transfusion practice that is more akin to the military recommendations. Computer
simulations to model massive blood transfusion scenarios also gives credence to the premise
that traditional transfusion practice is incorrect for actively hemorrhaging patients and
advocates the earlier use of plasma.
A retrospective chart review of 5 years of the perioperative management of Priority 1 AAA
ruptures at The Ottawa Hospital was conducted with research ethics board approval. Of 145
reviewed cases, there was a 64% survival rate. The use of plasma occurred in over 75% of
patients and over 99% of patients were exposed to allogeneic blood products. Plasma use was
associated with poor outcomes and served as a marker for cases with higher blood loss and
blood product exposure. The use of plasma was however consistent with the present
recommendations and thus appeared to be reactive in nature, rather than proactive use.
A definitive trial that assesses the role of early plasma has not been performed.
Unfortunately, a study to determine the full impact of an altered plasma transfusion practice
would require thousands of patients. The emergency nature of these surgical patients would
also make the ability to randomize patients challenging. The goal of the present trial will
therefore be to assess the feasibility of such a trial. We need to assess the ability to
randomize patients, to prepare plasma and deliver it in a timely fashion. Further, the
logistics of having physicians to administer the study fluid (i.e. plasma or colloid control)
in a timely fashion will be determined. Finally, the ability to accurately measure outcomes
will be assessed.
