TRALI
Acute onset within 6 h after a blood transfusion
PaO2/FiO2 <300 mmHg
Bilateral infiltrative changes on the chest X-ray
No sign of hydrostatic pulmonary edema (PAOP <18 mmHg or CVP <15 mmHg)
No other risk factor for ALI present
Possible TRALI
Other risk factors for ALI present
Although this definition appears straightforward, a complicating factor is that the characteristics of TRALI are indistinguishable from ALI due to other causes, such as sepsis, major surgery, or lung contusion. Using this definition would rule out the possibility of diagnosing TRALI in critically ill patients with an underlying ALI risk factor who have also received a transfusion. To identify such cases, the term “possible TRALI” was developed (Table 15.1), which allows for the presence of another risk factor for ALI.
15.1.2 Pathogenesis
TRALI is suggested to be a “two-hit” event [3]. The “first hit” is the underlying condition of the patient resulting in priming of the pulmonary neutrophils. The “second hit” is the transfusion of a blood product. With regard to the causative factors in the blood product, TRALI can be divided in antibody-mediated TRALI and non-antibody-mediated TRALI. Antibody-mediated TRALI is caused by the passive infusion of human leukocyte or human neutrophil antibodies (HLA or HNA) originating from the donor and directed against the antigens of the recipient. Non-antibody-mediated TRALI is caused by the transfusion of stored cellular blood products (red blood cells and platelet concentrates). During storage, proinflammatory mediators accumulate in the blood product. Also, erythrocytes and platelets undergo morphological changes during aging. Both factors have been associated with the onset of TRALI in experimental and observational studies [4–8]. Although the “two-hit” model covers most of the TRALI cases, not all antibody-positive units result in TRALI, even in the presence of the corresponding antigen [9]. Furthermore, antibody-containing blood products were able to induce TRALI in healthy volunteers, i.e., in the absence of a “first hit” [10, 11]. For this reason, a threshold model has been proposed for antibody-mediated TRALI. The threshold model expands on the “two-hit” model by explaining susceptibility of the recipient to develop TRALI [12]. In relatively healthy patients (with a weak “first hit”), a strong antibody incompatibility or high volume of antibodies is needed to overcome the threshold. Conversely, in severely ill patients (with a strong “first hit”), already a weak antibody incompatibility or just a low volume of antibodies is able to overcome the threshold. Both models provide an explanation for the high incidence of TRALI among critically ill patients and have been confirmed by preclinical and clinical studies [13–19].
15.2 Incidence of Transfusion-Related Acute Lung Injury
The incidence of TRALI is high among critically ill patients. The incidence is significantly higher compared to general ward patient populations [20]. An explanation for this difference may be that a “first hit” is often present in critically patients. Furthermore, critically ill patients are often exposed to blood transfusion [21]. The incidence of TRALI in the critically ill has been studied in a few large prospective trials. The estimated incidence of TRALI was around 2% in a cohort of transfused cardiac surgery patients admitted to the ICU [18]. The incidence of TRALI in the general ICU patient population is estimated between 5 and 8 % of transfused patients [13, 17]. Patients admitted to the ICU because of a gastrointestinal bleeding have the highest reported incidence of TRALI, with up to 15 % in transfused patients [22]. In comparison, studies performed in patient populations on the general ward and national hemovigilance reports show incidences of TRALI varying between 0.001 and 0.01 % per product transfused, while ICU studies report up to 1 % per product transfused [15, 23].
15.3 Risk Factors for Transfusion-Related Acute Lung Injury
15.3.1 Patient-Related Risk Factors
It is conceivable that risk factors for ALI are also risk factors for TRALI, given that the “two-hit” model of TRALI holds that priming of lung neutrophils at the time of transfusion can occur by a proinflammatory response of any origin (Table 15.2) [12]. Risk factors associated with both TRALI and ALI include sepsis, mechanical ventilation, massive transfusion, and a positive fluid balance (Table 15.2).
Table 15.2
Patient-related risk factors for transfusion-related acute lung injury
Reference | Type of study | Odds ratio [CI] (when given) | |
|---|---|---|---|
Sepsis | |||
[24] | Retrospective | N/A | |
[13] | Prospective | N/A | |
[17] | Retrospective | OR 2.5 [1.2–5.2] | |
Shock | |||
[15] | Prospective | OR 4.2 [1.7–10.6] | |
Mechanical ventilation | |||
[25] | Retrospective | N/A | |
[17] | Retrospective | OR 3.0 [1.3–7.1] | |
Peak pressure >30 cm H2O | [15] | Prospective | OR 5.6 [2.1–14.9] |
Cardiac surgery | |||
Emergency | [17] | Retrospective | OR 17.6 [1.8–168.5] |
Elective | [15] | Prospective | OR 3.3 [1.21–9.2] |
Time on bypass | [26] | Prospective | OR 1.0 [1.0–1.03] |
Hematologic malignancy | |||
[24] | Retrospective | N/A | |
[17] | Retrospective | OR 13.1 [2.7–63.8] | |
[27] | Retrospective | N/A | |
Massive transfusion | |||
[17] | Retrospective | OR 4.5 [2.1–9.8] | |
Positive fluid balance | |||
[15] | Prospective case | OR 1.17 [1.08–1.28] (increment per L) | |
Liver failure | |||
[22] | Retrospective | OR 13.1 [2.7–63.8] | |
Liver transplant surgery | [15] | Prospective | OR 6.7 [1.3–35.7] |
Patients on mechanical ventilation seem particularly prone to develop lung injury after transfusion of a blood product [25, 28]. In experimental TRALI, mechanical ventilation synergistically augmented lung injury, which was enhanced by the use of injurious ventilator settings [16]. In line with this, it was found that high-peak airway pressures (>30 cm H2O) contribute to an increased TRALI risk [15]. Together, injurious mechanical ventilation seems to aggravate the course of a TRALI reaction.
In addition to pulmonary hits, systemic inflammatory conditions are often present in critically ill patients. Sepsis has been identified as a risk factor for TRALI in several studies in ICU patients [13, 17]. Also, the presence of shock prior to transfusion increases TRALI risk [15]. Coronary artery bypass grafting increased risk for TRALI about eight- to tenfold compared to the general patient population [17, 27]. This may be due to use of cardiopulmonary bypass [18].
There are also distinct differences between risk factors for TRALI and ALI due to other causes. There are risk factors for TRALI which are not commonly associated with ALI, such as hematologic malignancy and liver disease [22]. It is not known why these conditions strongly predisposes to TRALI, other than that these patients often receive plasma-rich products. Vice versa, well-known ALI risk factors such as pancreatitis or pneumonia were not identified as risk factors for TRALI, suggesting that TRALI is part of the ALI spectrum, but also has distinct entities.
15.3.2 Mitigating Risk of TRALI by Taking an Individualized Patient Approach
Appropriate management of critically ill patients has decreased risk of ALI. The same may hold for TRALI. The recent identification of TRALI risk factors enables ICU physicians to take an individualized approach toward their patients in need of a transfusion. Patient-focused strategies which may decrease the risk of TRALI include maintaining a restrictive fluid balance. A benefit of fluid restriction has also been shown in ALI patients and indeed suggests that fluid overload may play a role in TRALI pathogenesis [29]. However, shock prior to transfusion should also be avoided when possible. Decreasing airway pressures and maintaining low tidal volume ventilation in patients on mechanical ventilation prior to transfusion are a sensible approach, although not proven to be effective in mitigating TRALI risk in clinical trials.
15.3.3 Blood Product-Related Risk Factors for TRALI
The presence of donor anti-leukocyte antibodies in the transfused product is implicated in TRALI. Involved antibodies are mainly directed against HLA class I, HLA class II, or HNA. In a study in patients on general hospital wards, blood product-related risk factors were the transfused volume of high-titer cognate HLA class II antibody and the volume of high-titer HNA antibody [15].
Whether storage of blood products increases risk of TRALI is not clear. Bioactive lipids which increase during storage of red blood cells and platelet concentrates were shown to induce TRALI in animal models [5, 6]. A retrospective clinical study of ten TRALI patients linked the occurrence of TRALI with transfusion of blood products containing bioactive lipids [30]. However, this finding was not confirmed in other studies [15, 18]. Besides shedding of bioactive substances, red blood cells undergo changes in morphology and function during storage, including decreased chemokine scavenging and increased adhesion to the endothelium, which thereby may promote microvascular pathology in the lung [4]. However, these data are limited to preclinical TRALI models.
15.3.4 Mitigating Risk of TRALI by Modifying Blood Products
Pregnancy is the most important cause of sensitization in the donor population and 10–40 % of previously pregnant women have HLA antibodies [31]. A predominantly male donor strategy for preparation of fresh frozen plasma resulted in a reduction, but not abrogation, of TRALI cases [32, 33]. Of note, as long as a male-only donor policy is only implemented for plasma products, antibody-mediated TRALI due to red blood cell transfusion and pooled platelets are not prevented.
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