Trial Information

The Incidence of Transfusion-Related Acute Lung Injury (TRALI) Following Blood Product Transfusion in Patients Undergoing Elective Orthopedic-Oncology Procedures

Background

The transfusion of blood products is occasionally complicated by acute lung injury (ALI),
which can progress to the acute respiratory distress syndrome (ARDS). Such
transfusion-related acute lung injury, abbreviated TRALI, has been defined by both a
National Heart, Lung, and Blood Institute (NHLBI) working group, and by a Canadian consensus
conference (CCC), as new ALI occurring during or within six hours after a transfusion [1-2].
This definition is based entirely on clinical and radiological criteria and includes [2-4]:

1. ALI, as defined by [4]:

A. The sudden onset of respiratory distress symptoms (dyspnea). B. Hypoxemia: as
defined by a ratio of partial pressure of arterial oxygen to the fraction of inspired
oxygen (PaO2/FiO2) below 300mmHg, or oxygen saturation (SpO2) below 90% on room air, or
other clinical evidence of hypoxemia C. Bilateral infiltrates on frontal chest X-ray,
without cardiomegaly. D. No clinical evidence of left atrial hypertension (congestive
heart disease).

2. No preexisting ALI before transfusion.

3. During or within 6 hr after transfusion of any blood product.

4. No temporal relationship to an alternative risk factor for ALI. All types of blood
products have been associated with TRALI, however, the plasma-rich components, such as
fresh frozen plasma (FFP), whole blood, packed red blood cells (PC) and platelets, have
been most frequently implicated [3, 5-10].

Prolonged storage of transfused products, use of FFP, and the presence of an underlying
condition such as recent surgery, cytokine treatment, thrombocytopenia, massive blood
transfusion, hematologic malignancies or cardiovascular disease requiring cardiopulmonary
bypass (CABG) surgery, and active infection have been reported as risk factors for the
development of TRALI [11-18].

The pathogenesis of TRALI involves the presence of anti-leukocyte antibodies and/or
biologically active lipids from cell membrane fragments (and cytokines) in the donor's
blood, triggering an inflammatory response within the recipient's pulmonary
microvasculature, which in turn leads to lung injury [2,13,16,19-27].

The incidence of TRALI is not well established [28]. Nevertheless, using the NHLBI/CCC
definition of TRALI, several retrospective studies reported the incidence of TRALI to be one
case for every 1000-2400 units transfused [29-30]. This incidence estimate of 0.04% to 0.1%
(or up to 0.85% among transfused patients) is comparable to other estimates from earlier
studies that used older case definitions [6,12,31]. The only prospective cohort clinical
surveillance study to use current diagnostic guidelines for TRALI reported an 8% incidence
of TRALI in their intensive care unit (ICU) [32]. These data suggest that passive reporting
systems greatly under-estimate the number of TRALI cases.

Even though underdiagnosed, TRALI is currently the leading cause of transfusion-related
mortality in the United States [1,7,11]. The estimated mortality rate for recognized TRALI
is 5%-8% [20]. However, most survivors recover completely with appropriate supportive care
and can receive additional blood products in the future [11,20].

Due to the lacking epidemiology, and the increasing significance of TRALI as a major
transfusion-associated complication, we stress the need for additional prospective
surveillance studies.

Taken together, we wish to conduct a prospective observative study in order to evaluate the
incidence of TRALI among patients undergoing elective orthopedic-oncology procedures. This
patients' population receives blood product transfusions frequently, and may thus provide an
adequate cohort for such study.

Study Objectives This work aims to study the prevalence of TRALI-associated morbidity and
mortality in patients undergoing elective orthopedic-oncology procedures, and are transfused
with blood products in the perioperative period.

In addition, we wish to evaluate whether:

A.The incidence of TRALI is higher in patients operated for malignancies (versus benign
neoplasms) B.The incidence of TRALI is higher in patients treated with
C.chemotherapy/radiation prior to surgery (versus non-treated) The incidence of TRALI is
increasing with older blood products

Methods Study design An informed consent will be obtained from all orthopedic-oncology
patients scheduled to have an elective surgery, except for those who require minor
procedures (e.g., biopsies) which normally do not require transfusions. Diuretics and oral
hypoglycemics will be discontinued the day prior to surgery, as dictated by the routines in
our patients.

Peri-operative management Anesthetic and surgical management as well as blood product
transfusion will adhere to standard practice.

Postoperatively, the patients will be transferred to the post-anaesthesia care unit and
later to the orthopedic-oncology department, unless otherwise indicated.

In the postoperative period, departmental routines will guide blood product transfusions,
pain management and fluid therapy.

Monitoring of patients who received transfusions

Every patient that receives blood products will be included in the study, whether it
occurred pre-operatively, intra-operatively or post-operatively as long as they are
hospitalized. For these patients we will document:

A.General demographics, including chronic diseases, medications and treatments (e.g.,
chemotherapy/radiotherapy).

B.Blood product information, including type, dosage and storage age. C.Intra- and
post-operative data, including operative time, volume of crystalloids (and colloids) given
during surgery and afterwards, urine output, the need for vasopressors, inotropes or
diuretics, re-intubations, transfer to ICU and hospital length of stay (LOS).

For each unit of blood product transfused, we will commence patient monitoring for the next
6 hours. If several units are given in a sequel we will monitor the patient since the
beginning of the first transfusion until 6 hours after the last transfusion. Monitoring will
include:

1. Clinical symptoms of dyspnea.

2. PaO2/FiO2, or SpO2 on room air if arterial line is not obtainable - every 2 hours or
when indicated by clinical signs.

2.1. If PaO2/FiO2< 300mmHg, or SpO2< 90% on room air, or clinical signs of lung injury
occur - chest X-ray will be obtained and diagnosed by two radiologists.

3. Hb (gr/dl) will be assessed according to the physician's decision.

Study size In the orthopedic-oncology department of Tel Aviv Sourasky Medical Center
approximately 550 patients are operated annually, about 20% of whom receive transfusions.
Accordingly, the study is planned for 5 years. Therefore the anticipated sample size is
approximately 550 patients.