Introduction

Transfusion-related acute lung injury (TRALI) is a rare complication presenting as respiratory distress during or after transfusion of blood components,16) but is a serious and potentially fatal complication of transfusion, and mortality rates of 5% to 25% have been reported.8) A TRALI was first described as a clinical entity in 1985, but it is recently recognized as a leading cause of morbidity and mortality following transfusion.3)16) The exact incidence of TRALI is unknown, and TRALI is also believed to be under-diagnosed and under-reported. Widely varying incidence rates of TRALI have been reported in the literature. It is estimated to occur in 0.014~0.08% of all units of transfused blood components or in 0.04~0.16% of all transfused patients.16)19)26)

All blood products have been associated with TRALI, including whole blood, packed red cells, platelet products, fresh frozen plasma, and cryoprecipitate.4)

The cause of this uncommon syndrome is not clearly elucidated, but two hypotheses have been proposed. Most commonly, it is caused by donor human leukocyte antigen (HLA) antibodies that react with recipient antigens, so called immune-mediated hypothesis. Another hypothesis proposes

a role for biologically active compounds accumulated during storage of blood products, which are capable of priming neutrophils in TRALI patients.4)

In neurosurgical field of practice, aneurysmal subarachnoid hemorrhage (SAH) is peculiar to the other illness, because patients with aneurysmal SAH are likely to receive more amount of blood component and tend to mdevelop respiratory complication seemingly due to sympathetic over-discharge or fluid over-loading. In these patients, respiratory complications such as acute lung injury and the acute respiratory distress syndrome account for significant morbidity and mortality.12) Although there were several studies regarding pulmonary complications after

SAH,6)7) TRALI has not been systematically reported in the neurosurgical literatures. Awareness of TRALI has been increased, nevertheless its occurrence is still under-reported.

It is attributed to a lack of uniformity in definition and methods of surveillance. Transfusion of blood components is a common practice, and therefore making an exact diagnosis and prompt treatment of TRALI becomes crucial.

The aim of the present study is to identify the incidence of TRALI in patients with aneurysmal SAH as well as to determine the risk factors for TRALI.

Materials & Methods

Patient Selection and Variables

This retrospective study was conducted on in-patients of Neurosurgical department at our institute, facilitating 15 beds in neurosurgical intensive care units and 70 beds in the Neurosurgical ward. All patients with ruptured aneurysmal SAH who had been admitted between Jan. 2006 and Dec.

2008, were eligible for the study. All cases were retrieved through electronic medical record system (OCS) and electronic radiologic system (PACS). During this period, a total of 237 patients with aneurysmal SAH were admitted at our department.

For the purpose of this study, the following cases excluded; coil embolization, delayed microsurgical treatment (>72 hours from the ictus), proven history of head injury or severe infection, a previous history of SAH or other form of stroke, other underlying lesions including tumor, arteriovenous malformation, and other vascular malformations. We also excluded patients who died within 72 hrs of admission to the hospital. As a result of this exclusion, 154 patients who underwent early microsurgical treatments within 72 hours from the ictus for the ruptured

aneurysms were enrolled in this study.

Collected data included as followings; demographic variables, Glasgow coma scale (GCS) score, Hunt-Hess grade, Fisher grade, whether mechanical ventilation was applied or not, and if so duration of mechanical ventilation, hypervolemic therapy, presence of vasospasm, underlying

medical disease, and length of intensive care unit (ICU) stay. With relevant to the transfusion, following parameters including type of blood product, number of blood components, total amount of transfused blood components, preoperative complete blood count (CBC), postoperative

CBC, use of other form of volume expander were also reviewed.

Criteria for the diagnosis of TRALI

According to the American-European Consensus

Conference (AECC) in 2004, a TRALI was defined as cases in which (1) acute lung injury as evidenced by: acute onset of relevant signs/symptoms, hypoxemia (PaO2/FiO2 < 300 or SpO2 < 90% on room air), bilateral infiltrates on chest radiography without cardiomegaly, no clinical evidence of left arterial hypertension (Fig. 1); (2) no preexisting acute lung injury before transfusion; (3) evidence of lung function compromise during or within 6 hours of transfusion; (4) no temporal relationship to an alternative risk factor for acute lung injury (circulatory fluid overload, atrial fibrillation, etc.).9)

Statistical Analysis

Continuous variables were expressed as mean±standard deviation, and categorical variables as percentages. The chisquare test and Student t-test were first used where appropriate, significance was set at a probability value of 0.05, and 95% of confidence interval (CI) was calculated.

Statistical comparisons were made between patients with and without TRALI. Data analysis was performed using SPSS 13 (SPSS Inc., Chicago, Il). The multivariate analysis was performed to identify risk factors for TRALI and to calculate the odds ratio (OR) and 95% CIs.

Results

A total of 237 patients with aneurysmal SAH had been admitted during the past 3-year study period, and among them, 154 patients were enrolled in our study. Of these, 9 patients met criteria for diagnosis of TRALI, and the incidence of TRALI was 0.06%. All patients with TRALI presented with respiratory distress and severe hypoxemia, often accompanied by visible cyanosis. The reactions usually occurred within 4 hours of transfusion, and there were no

other evident causes for the respiratory failure.

Among 836 blood product units transfused during this study period for 154 patients with aneurismal SAH, 508 (61%) were packed red blood cells, 150 (18%) were platelets and 178 (21%) were fresh-frozen plasma. The mean age was 53.44±12.08 years (range, 40~69 years), and there was female preponderance with a gender ratio of 5:4 (55%:45%).

The median number of transfused erythrocyte (red blood cell; RBC) unit was 3 (1 to 15). One out of 9 patients with TRALI received massive transfusion (at least 10 units) during the exposure period. The most frequent underlying diseases were hypertension and diabetes mellitus. One patient with TRALI had initial GCS score less than 8. Every TRALI patient was managed with mechanical ventilation, and the mean duration of mechanical ventilation was 6.1±

3.02 days (Table 1).

Table 2 describes aneurysm location and transfused blood components in 9 patients with TRALI. Posterior communicating artery was the most common site of aneurysm. Two variables that have statistical significance in univariate analyses (Table 1) also had independent risk factors for TRALI (Table 3). Fisher grade III & IV and total amount of transfused units much more than 1200cc were associated with the development of TRALI. On the contrary to our initial thought, sex, Hunt-Hess Grade IV & V, preoperative hemoglobin less than 13, postoperative hemoglobin less than 11, volume expander use, hypertension, and diabetes were not significantly associated

with TRALI.

Discussion

Transfusion-related acute lung injury (TRALI) is an easily under-diagnosed complication after transfusion, but it is the second most common cause of transfusion-related mortality.22) In the present study the incidence of TRALI was 0.01% (9 in 836) for all transfused components, and 0.06% (9 in 154) for all transfused patients with aneurysmal SAH.

Packed blood cells were transfused to all these patients. Three out of 9 patients with TRALI had history of freshfrozen plasmas transfusion. Only one patient received packed blood cells, fresh-frozen plasmas, and platelets altogether. The incidence of TRALI in our study was

compatible to the others. The incidence of TRALI varies from 0.014~0.08% of all units of transfused blood components, or in 0.04~0.16% of all transfused patients.16)20)

Implicated blood components include packed blood cells, whole blood, fresh frozen plasma, cryoprecipitate, platelets, and others.11)14)18)19) Interestingly however, albumin has not

been associated with TRALI.15)

The pathogenic mechanism of TRALI is not clear, but several hypotheses have been proposed. First, the antibodymediated model proposed that the reaction is secondary to antibodies in donor plasma against antigens present on the recipient’s leucocytes. The HLA antibodies may be directed against either HLA class I or HLA class II or infusion of donor leucocytes into a recipient. The antigen-antibody interaction causes complement activation, resulting in the

pulmonary sequestration and activation of neutrophils, endothelial cell damage and a consequent capillary leak syndrome in the lung leading to TRALI.2)5)13)16)

The biologically active mediator model proposes that TRALI is the result of two events. The first event is the clinical condition of the patient, resulting in pulmonary endothelial activation and neutrophil sequestration, and the second one is the transfusion of biologically active mediators including lipids, and anti granulocyte antibodies that activate adherent neutrophils leading to endothelial damage, capillary leak and TRALI.1)23)24)

Kopko et al.10) proposed combined model postulating that TRALI occurred in patients when the pulmonary vascular bed was primed by transfusion followed by the activation of primed neutrophils by either biologically active mediators or by anti granulocyte antibodies leading to pulmonary vascular endothelial damage and TRALI.

The management of TRALI is conservative, because TRALI is a self-limiting disease and carries better prognosis than most of the usual causes of acute lung injury in most instances. Popovsky et al.16) reported that the pulmonary infiltrates resolved rapidly in 81% of patients within four

days with a mortality of 6%. Transfusion of the suspected blood product should be immediately ceased when TRALI is likely to occur.15)

Respiratory support is dictated by the clinical feature. For mild cases, supplemental oxygen and supportive care may be sufficient. In severe cases, mechanical ventilatory support is useful, but optimal method of ventilation is unknown.

Diuretics are not recommended, as the pulmonary edema is not due to fluid overload. In addition, corticosteroids have no demonstrable role in the management of TRALI1.15)16) The

best outcomes are obtained in cases where the diagnosis is made early, and treatment instituted promptly. Limiting the amount of blood product transfusion can reduce the incidence of TRALI.16)

In the present study, all patients with TRALI required mechanical ventilatory support. Because the best method of ventilation is unclear, patients in this study were treated by using the usual setting of small volume, high frequency rate, optimizing positive end-expiratory pressure and fraction of inspired oxygen, and allowing permissive hypercapnia.

Although rapid diagnosis is the most important in patients with TRALI, the pathophysiology and etiology of TRALI are not well known yet.

Rana et al.17) reported that although any blood component can cause TRALI, plasma-rich units are more likely to induce this disease. Silliman et al.23) noted that the platelet age of TRALI cases was a statistically significant risk factor compared with that in controls. They also found that patients who had hematologic malignancies and were undergoing induction chemotherapy and those with cardiac disease requiring coronary artery bypass surgery are also at particular risk.23) Since 1971, multiple previous pregnancies in the donor variable have been considered a risk factor for inducing TRALI.25) Multiparity is associated with an increased frequency of antibodies, and then these antibodies could induce TRALI. Recently, Sanchez et al.21) noted that the number of whole blood units transfused was the factor that emerged as a clear predictor for TRALI. They also reported that spine surgery is associated with the development of TRALI.21)

In the present study, total amount of transfused blood components exceeding 1,200cc was associated with the development of TRALI. This finding explains the antigenantibody

mechanism of TRALI that all plasma-containing blood products, not just whole blood, would be a risk factor.

The chance of antigen-antibody reaction acquisition can be increased when massive transfusion was required during the operation or perioperative period. Another risk factor was Fisher grade III & IV, through which unexplained mechanisms. Although clinical grade manifested by higher Hunt-Hess grade or lower GCS score were not associated with TRALI, previous reports have

shown that development of pulmonary edema after SAH is associated with worse neurologic status.7)

Our study includes some limitations. One is the small number of cohorts obtained in a single institute in a tertiary care center. This limitation does not permit firm conclusions about any other risk factors and may not easily generalize our results. Another limitaion is the lack of specific information of blood components; storage time of blood components, donor age, donor sex, and donor parity. These variables were related with the development of TRALI, and

so future studies should involve these values. Despite these caveats, this study at least showed that real situation of TRALI in neurosurgical practice.

Conclusions

TRALI is a rare complication and is associated with Fisher grad III, IV and total amount of transfused blood components exceeding 1200cc. But, the exact cause and mechanism of TRALI is still unknown, and therefore practicular attention should be paid on to these high-risk patients when conducting volume replacement. In near future, randomized, prospective, multicenter studies are needed to determine the etiologies and management of TRALI in patients with aneurysmal SAH.

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