Complications of blood transfusions

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  • 1. TRANSFUSION PRACTICE The effect of blood transfusion on pulmonary permeability in cardiac surgery patients: a prospective multicenter cohort study _3231 82..90Alexander P Vlaar,* Alexander D. Cornet,* Jorrit J. Hofstra, Leendert Porcelijn, Albertus Beishuizen, .J. Willem Kulik, Margreeth B. Vroom, Marcus J. Schultz, A.B. Johan Groeneveld, and Nicole P Juffermans . [Correction added after online publication 11-Jul-11: The spelling of Alexander D. Cornet has been modified.] T here is a clear association between blood trans- BACKGROUND: There is an association between fusion and pulmonary complications in cardiac blood transfusion and pulmonary complications in surgery.1,2 The exact mechanism of transfusion- cardiac surgery. Mediators of increased pulmonary vas- related morbidity and mortality is not fully cular leakage after transfusion are unknown. We understood. Suggested mechanisms include increased hypothesized that factors may include antibodies or bio- risk for infections,3 hydrostatic pulmonary edema caused active lipids, which have been implicated in transfusion- by cardiac overload, or enhanced permeability of the pul- related acute lung injury. monary microvasculature caused by transfusion-related STUDY DESIGN AND METHODS: We performed a acute lung injury (TRALI).4-6 prospective cohort study in two university hospital inten- Of note, cardiac surgery was found to be a risk factor sive care units in the Netherlands. Pulmonary vascular for the development of TRALI.7,8 Therefore, mechanisms permeability was measured in cardiac surgery patients in onset of TRALI may play an important role in explaining after receiving no, restrictive (one or two transfusions), or multiple (five or more transfusions) transfusions (n = 20 per group). The pulmonary leak index (PLI), using 67 Ga-labeled transferrin, was determined within 3 hours ABBREVIATIONS: ALI = acute lung injury; CABG = coronary postoperatively. Blood products were screened for bioac- artery bypass grafting; ICU(s) = intensive care unit(s); tive lipid accumulation and the presence of antibodies. lysoPC(s) = lysophosphatidylcholine(s); MS/MS = tandem mass RESULTS: The PLI was elevated in all groups after spectrometry; PAF = platelet-activating factor; PC(s) = cardiac surgery. Transfused patients had a higher PLI phosphatidylcholine(s); PEEP = positive end-expiratory compared to nontransfused patients (33 ¥ 10-3 Ϯ pressure; PLI = pulmonary leak index. 20 ¥ 10-3 vs. 23 ¥ 10-3 Ϯ 11 ¥ 10-3/min, p < 0.01). The amount of red blood cell (RBC) products, but not of From the Department of Intensive Care Medicine, the Depart- fresh-frozen plasma or platelets, was associated with an ment of Internal Medicine, the Laboratory of Experimental increase in PLI (b, 1.6 [0.2-3.0]). Concerning causative Intensive Care and Anesthesiology (L.E.I.C.A.), and the Labora- factors in the blood product, neither the level of bioactive tory of Genetic Metabolic Diseases, Academic Medical Center; lipids nor the presence of antibodies was associated with Sanquin Diagnostic Services, Sanquin Region North West; and an increase in PLI. Patient factors such as surgery risk the Department of Intensive Care Medicine and the Institute for and time on cardiopulmonary bypass did not influence Cardiovascular Research Vrije Universiteit (ICAR-VU), VU the risk of pulmonary leakage after blood transfusion. Medical Center Amsterdam, Amsterdam, the Netherlands. CONCLUSIONS: Transfusion in cardiothoracic surgery Address reprint requests to: A.P.J. Vlaar, Laboratory of patients is associated with an increase in pulmonary Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), capillary permeability, an effect that was dose dependent Academic Medical Center, Room M0-228, Meibergdreef 9, for RBC products. The level of bioactive lipids or the Amsterdam, 1105 AZ, the Netherlands; e-mail: a.p.vlaar@ presence of HLA or HNA antibodies in the transfused amc.uva.nl. products were not associated with increased pulmonary *These authors contributed equally. capillary permeability. Received for publication February 1, 2011; revision received May 2, 2011, and accepted May 2, 2011. doi: 10.1111/j.1537-2995.2011.03231.x TRANSFUSION 2012;52:82-90.82 TRANSFUSION Volume 52, January 2012
  • 2. TRANSFUSION-RELATED PULMONARY PERMEABILITYthe frequently observed pulmonary dysfunction after car- group); or a minimum of 2 units of red blood cells (RBCs),diopulmonary bypass.9 The finding of an increased TRALI 2 units of fresh-frozen plasma (FFP), and 1 unit of plateletsincidence after cardiac surgery may be related to the “two- (PLTs) pooled from five donors (n = 20, massive transfu-hit” pathogenesis of TRALI. The “first hit” is an inflamma- sion group). Transfusions administered in the operationtory condition of the patient that primes the lung room or within the first 3 hours postoperatively wereneutrophils. In cardiac surgery, use of cardiopulmonary included. All RBCs are leukoreduced (buffy coat removedbypass as well as deflation of the lung during surgery may and the RBC suspension is filtered to remove the WBCcontribute to priming. The “second hit” is caused by count to less than 1 ¥ 106) and stored for up to 35 days. Thefactors in the blood product, resulting in neutrophil acti- hospital blood bank policy of one center holds thatvation and increased vascular permeability, with subse- cardiac surgery patients are provided with fresh RBCs onlyquent pulmonary edema. Both white blood cell (WBC) (stored <14 days) during surgery, but not while on the ICU.antibodies in the blood product that react with pulmonary RBCs were transfused to maintain the hemoglobin (Hb)neutrophils of the recipient,10-13 as well as bioactive lipids concentration higher than 5.0 mmol/L (8.7 g/dL), FFP(lysophosphatidylcholines [lysoPCs]) that accumulate and PLTs were transfused in the case of (suspected) bleed-during blood storage, have been implicated as a second ing. The volume of plasma transfused was calculated ashit.7,14-19 In line with the latter mechanism, storage time of the sum of 325 mL per unit of FFP and 250 mL per plateletblood has been associated with pulmonary complications (PLT) concentrate.in cardiac surgery,2,20,21 although not all studies have con-firmed this association.22-24 Cardiothoracic surgery and anesthesia procedures Differentiating between hydrostatic and permeability Patients were anesthetized according to local institutionalpulmonary edema is limited by the subjective interpreta- protocol, with lorazepam, etomidate, sufentanil, andtion of clinical findings.25,26 The pulmonary leak index rocuronium for induction of anesthesia and facilitation of(PLI) has been used to differentiate between hydrostatic intubation. During the surgical procedure, sufentanil wasand permeability edema.27 Also, an elevated PLI is an early used as analgesic and sevoflurane plus propofol were usedmarker of acute lung injury (ALI) in at-risk patients, yet to maintain anesthesia. Muscle relaxants were not givenbefore acute respiratory distress syndrome.28 during the surgical procedure. Steroids were given at the We hypothesized that hypoxia occurring after cardiac discretion of the cardioanesthesiologist. In all patients,surgery may be due to mild forms of TRALI not meeting cardiopulmonary bypass was performed under mild tothe TRALI criteria. To determine if there is a correlation moderate hypothermia (28-34°C), using a membrane oxy-between transfusion and pulmonary leakage, we mea- genator and a nonpulsatile blood flow. During the proce-sured the PLI in a cohort of cardiac surgery patients after dure, lungs were deflated. After the procedure, all patientsreceiving restrictive or multiple blood transfusions, as well were transferred to the ICU with mechanical ventilation.as in nontransfused controls. Known causative factors forthe onset of TRALI were determined, including bioactivelipids and HLA or HNA antibodies in the transfused blood PLIproducts. The PLI was measured within 3 hours postoperatively, as previously described.29 Transferrin was labeled in vivo, MATERIALS AND METHODS after intravenous (IV) injection of 67Ga-citrate, 4.5 MBq (physical half-life 78 hr; Mallinckrodt Diagnostica, Petten,The study was performed in the mixed medical-surgical the Netherlands). Patients were in the supine position andintensive care units (ICUs) of two university hospitals in two scintillation detection probes (Eurorad C.T.T., Stras-the Netherlands. Both ICUs are a “closed format” depart- burg, France) were positioned over the right and left lungment in which patients are under the direct care of the apices. Starting at the time of the IV injection of 67Ga,ICU team. The study was approved of by the ethical com- radioactivity was detected for 30 minutes. The 67Ga countsmittee of both hospitals. Before valvular and/or coronary are corrected for background radioactivity, physical half-artery surgery, patients of 18 years or older were asked life, spillover of 67Ga, obtained by in vitro measurement ofinformed consent for participation in the study. Exclusion 67 Ga, and expressed as cpm per lung field. At 0, 5, 8, 12, 16,criteria were off-pump surgery, emergency surgery, and 20, 25, and 30 minutes after 67Ga injection, blood samplesthe use of immunosuppressive drugs. (2-mL aliquots) were taken. Each blood sample was weighed and radioactivity was determined with a single-Design well well-counter (LKB Wallac 1480 WIZARD, PerkinIn a prospective cohort study, cardiac surgery patients Elmer, Life Science, Zaventem, Belgium), taking back-were consecutively included for analysis after they had ground, spillover of 67Ga, and decay into account. Resultsreceived no transfusion (n = 20, no transfusion group); are expressed as cpm/g. For each blood sample, a time-one or two transfusions (n = 20, restrictive transfusion matched cpm over each lung was taken. The radioactivity Volume 52, January 2012 TRANSFUSION 83
  • 3. VLAAR ET AL.ratio was calculated as (67Galung)/(67Gablood) and plotted the supernatant was stored at -80°C until further analy-against time. The PLI was calculated from the slope of sis. WBC-reactive antibodies were examined in theincrease of the radioactivity ratio divided by the intercept, plasma samples of PLT and FFP products. Samplesto correct for physical factors in radioactivity detection. were screened for HLA antibodies using a standardThe PLI represents the transport rate of 67Ga-transferrin complement-dependent cytotoxicity assay with an HLA-from the intravascular to the extravascular space of the typed donor panel (to detect complement-fixing anti-lungs and is therefore a measure of pulmonary vascular bodies to HLA Class I and II)35 and a Luminex screeningpermeability. The values for both lung fields are averaged. assay for HLA Class I and II (Tepnel Lifecode LuminexThe upper limit normal for the PLI is 14.1 ¥ 10-3/min, and Screen Deluxe, Stamford, CT). HLA Class I and II anti-the measurement error is approximately 10%.30 bodies were identified using a Luminex single antigen bead technology (Tepnel Lifecode Luminex SA).Patient data collection Lymphocyte-reactive antibodies were examined by the lymphocyte immunofluorescence test.36 WBC agglutinat-Potential risk factors for an increased PLI were scored, ing antibodies (HNA-3a) were examined by the WBCincluding alcohol abuse, smoking, myocardial infarction, agglutination technique.37 Granulocyte-reactive anti-hypertension, diabetes, vascular diseases, hematologic bodies (HNA-1a, -1b, -1c, -2a) were examined by themalignancy, solid malignancy, cerebrovascular accident, granulocyte immunofluorescence test.38 HNA-1a, -1b,and autoimmune disease. The known risk factors for ALI -2a, and -3a were typed in the granulocyte immunofluo-such as sepsis, pneumonia, and trauma were not taken rescence test.into account as the included patients were elective Lipid extraction of supernatant from stored RBC andsurgery patients and for this reason presence of such a risk PLT supernatant was performed using the method offactor was a reason to cancel surgery in these patients or Bligh and Dyer. In short, 3 mL of CHCl3 : MeOH (1:2) waschange to emergency surgery, which was an exclusion cri- added to 100 mL of sample and 100 mL of internal stan-teria. Preoperative blood values, type of surgery, operation dard solution (lysoPC 14:0, 2.5 nmol; and phosphatidyl-time, and clamp time were extracted from the electronic choline [PC] 28:0, 10 nmol). A quantity of 700 mL of HAcpatient data system. Hemodynamic monitoring was per- 0.5%, 1 mL of CHCl3, and 800 mL of HAc 0.5% wereformed by indwelling arterial and pulmonary arterial added. After each step samples were mixed vigorously forcatheters. Cardiac output was measured by triplet injec- 30 seconds. The final mixture was centrifuged for 10tion of 10 mL of saline at random during the respiratory minutes at 1892 ¥ g at room temperature. After centrifu-cycle. The pulmonary artery occlusion pressure was gation, the lower layer of CHCl3 was separated. This stepobtained after balloon inflation and wedging, from was repeated two times by adding 1 mL of CHCl3. Thegraphic recordings at end-expiration, without discontinu- separated CHCl3 layers were combined and dried (N2,ation of positive end-expiratory pressure (PEEP). All pres- 30°C). Samples were dissolved in 150 mL of CHCl3/sures were obtained after calibration and zeroing to MeOH/H2O/NH3 25% (50/45/5/0.01 vol/vol/vol/vol) foratmospheric pressure, at the time of PLI measurement. further analysis.TRALI was defined using the consensus definition of The relative concentrations of lysoPCs and PC spe-TRALI (new-onset hypoxemia or deterioration demon- cies in supernatant of RBCs and PLTs were deter-strated by a PaO2/FiO2 < 300 mmHg, within 6 hr after mined using high-performance liquid chromatographytransfusion, with bilateral pulmonary changes, in the (HPLC) tandem mass spectrometry (HPLC-MS/MS). Tenabsence of elevated left atrial pressure defined as a pul- microliters of the lipid extraction was injected on themonary arterial occlusion pressure Յ18 mmHg).31-33 HPLC-MS/MS system. Chromatographic separation wasChest radiographs were routinely taken before surgery achieved on a modular HPLC system (Surveyor, Thermoand on arrival at the ICU and assessed by two indepen- Finnigan, San Jose, CA) consisting of a cooled autosamplerdent physicians blinded to the predictor variables. When (T = 12°C), a low-flow quaternary MS pump, and analyti-interpretation differed, chest radiograph and the descrip- cal HPLC column (LichroSpher Si60, 2 ¥ 250-mm column,tion by the radiologist were reviewed to receive consensus. 5-mm particle diameter, Merck, Darmstadt, Germany).The inspiratory O2 fraction (FIO2), PEEP, and tidal volume Samples were eluted with a flow rate of 300 mL/min andwere derived from the ventilator at the time of the PLI a programmed linear gradient between Solution Bmeasurement. Lung injury score was calculated.34 Data on (chloroform : methanol, 97:3, vol/vol) and Solution Ablood group, donor sex, and storage time of the blood (methanol : water, 85:15, vol/vol); A and B contained 1products were obtained from the National Blood Bank. and 0.1 mL of 25% (vol/vol) aqueous ammonia per liter of eluent, respectively. The gradient was: T = 0 to 10 minutes,Analysis of transfused blood products 20% A to 100% A; T = 10-12 minutes, 100% A; T = 12 to 12.1Samples of the blood bags were centrifuged (1500 ¥ g minutes, 100% A to 0% A; and T = 12.1 to 17 minutes,for 10 minutes at 4°C for RBCs and at 22°C for PLTs) and equilibration with 0% A. Total run time, including the84 TRANSFUSION Volume 52, January 2012
  • 4. TRANSFUSION-RELATED PULMONARY PERMEABILITYequilibration, was 17 minutes. A splitter between the RESULTSHPLC and MS was used for the introduction of the eluentin the MS by 75 mL/min. PLI MS/MS analyses were performed on a triple quadru- The mean PLI was elevated in all cardiac surgerypole mass spectrometer (TSQ Quantum AM, Thermo patient groups. Transfusion was associated with aFinnigan, Waltham, MA) operated in the positive ion further increase in PLI compared to nontransfused con-electrospray ionization mode. The skimmer offset was set trols (33 ¥ 10-3 Ϯ 20 ¥ 10-3 vs. 23 ¥ 10-3 Ϯ 11 ¥ 10-3 min-1,at 10 V; spray voltage was 3600 V and the capillary tem- p < 0.01). The PLI did not differ between multiply trans-perature was 300°C. In the optimized MS/MS experi- fused patients and patients in the restrictive transfusionments, argon was used as collision gas at a pressure of group (33 Ϯ 24 vs. 33 Ϯ 16, NS). Patients with strongly0.07 Pa and a collision energy of 40 V. The parent ion elevated PLI (>1.5¥ the upper limit) had a nonsignificantscan of m/z 184.1 (m/z 400-m/z 1000, 1 sec) was used for decrease in PaO2/FiO2 compared to patients with a lowerthe quantization of the following precursor ions: m/z PLI (Յ1.5¥ the upper limit; 275 Ϯ 79 vs. 320 Ϯ 101, NS), as468.3 (lysoPC 14:0, internal standard), m/z 496.3 (lysoPC well as nonsignificant increase in lung injury score (1.516:0), m/z 524.3 (lysoPC 18:0/PLT-activating factor [0-3] vs. 2.0 [0-4], NS). Of the transfused patients with[PAF] 16:0), m/z 522.4 (lysoPC 18:1), m/z 482.4 (lysoPAF strongly elevated PLI (n = 27), one patient met the clinical16:0), m/z 510.4 (lysoPAF 18:0), m/z 508.4 (lysoPAF 18:1), criteria of TRALI.m/z 678.4 (PC 28:0, internal standard), m/z 758.4 (PC34:2), m/z 782.4 (PC 36:2). Patient and transfusion risk factors Patient groups did not differ in alcohol abuse, smoking,Statistical analysis myocardial infarction, hypertension, diabetes, vascularThe sample size of 60 cardiac surgery patients was cal- diseases, hematologic malignancy, solid malignancy, cere-culated as follows: a difference of 10% between the brovascular accident, and autoimmune disease (data notexperimental groups in pulmonary leakage index with a shown). Preoperative left ventricular and pulmonarystandard deviation (SD) of 10% and an alpha of 0.05 function did not differ between the groups. Patientswould result in greater than 80% power to detect modest receiving multiple transfusions were older and had aindependent increase in risk for pulmonary leakage higher Euroscore compared to nontransfused patientscaused by blood transfusion. Data were checked for dis- (Table 1, p < 0.001). Multiply transfused patients moretribution. Normal distributed data were analyzed using often had undergone a combination surgery of coronaryanalysis of variance and Dunnett posttest. Nonparamet- artery bypass grafting (CABG) and valve replacement,ric data were analyzed with Kruskal-Wallis or Mann- while the majority of the restrictive and nontransfusedWhitney U test. Categorical data were analyzed with the patients had undergone CABG. Clamp time, time on car-chi-square test. To evaluate independent causal factors diopulmonary bypass, and surgery time were longer in thefor an increase in PLI, a logistic regression analysis was multiply transfused patients compared to restrictive andperformed. The association between the amount of nontransfused patients (Table 1, p < 0.01).blood products transfused was determined in the total Blood group did not differ between groups (data notcohort (n = 60). The association between the number of shown). The multiply transfused group received a largerpositive products for antibodies and PLI as well as the amount of RBC units stored for more than 14 days com-association between lysoPC concentration and PLI were pared to the restrictive transfused group (Table 2, p < 0.01).determined in a separate model using the transfused The number of units with plasma derived from femalepatients only (n = 40). The influence of confounding donors, as well as the number of units containing antibod-and effect modification from significant patient-related ies, was higher in the multiply transfused group comparedcovariates was investigated. Confounding was defined as to the restrictive transfused group (p < 0.001 and p < 0.05,at least 10% change in the PLI coefficient as a conse- respectively). The median amount of lysoPCs per unit ofquence of adding a covariate. Effect modification was RBCs or PLTs did not differ between the two groups. Thedefined as a significant p value for the interaction term median storage time for RBCs and PLTs did not differadded to the model. Covariates without a confounding between the two groups. Univariate analysis in the totaleffect or effect modification were excluded from the cohort (n = 60) revealed that the number of RBCs, but notmodels. Subanalysis was performed on strongly elevated amount of FFP or number PLTs, was associated with anPLI (>1.5¥ the upper limit) and less elevated PLI (Յ1.5¥ increase in PLI (Table 3, p < 0.05). To investigate thethe upper limit). A p value of 0.05 or less was considered mechanism of transfusion-associated increase in PLI wesignificant. Statistical analyses were conducted with the performed a univariate analysis in the transfused patientsuse of computer software (SPSS 16, SPSS, Inc., Chicago, only (n = 40). This analysis showed no association betweenIL). the total amount, the median concentration of lysoPCs per Volume 52, January 2012 TRANSFUSION 85
  • 5. VLAAR ET AL. TABLE 1. Demographic and perioperative characteristics in transfused and nontransfused cardiac surgery patients* Transfused groups Patient characteristics Restrictive (n = 20) Massive (n = 20) Nontransfused group (n = 20) Age (years) 64 (15) 73 (6)† 64 (11) Male sex, n (%) 13 (65) 13 (65) 18 (90) Euroscore 4.3 (2.4)‡ 7.7 (3.5)† 3.6 (1.8) ASA 2.9 (0.5) 2.7 (0.7) 2.7 (0.6) Left ventricular function Poor 0 (0) 1 (5) 0 (0) Moderate 7 (35) 6 (30) 7 (35) Good 13 (65) 13 (65) 13 (65) Preoperative Hb (g/dL) 8.8 (0.8) 8.0 (1.1)‡ 8.8 (0.7) PLT count (¥109) 236 (201-273) 219 (184-288) 218 (71-256) WBC count (¥106) 7.4 (6.3-9.0) 8.5 (6.2-9.8) 6.8 (5.9-8.5) Postoperative Hb (g/dL) 5.8 (0.9) 5.4 (0.6) 6.1 (0.2)† PLT count (¥109) 134 (53) 136 (47) 158 (51) WBC count (¥106) 12.5 (5.1) 12.4 (5.5) 10.9 (4.8) Type of surgery, n (%) CABG 11 (55) 5 (25)‡ 14 (70) Valve replacement 7 (35) 4 (20) 4 (20) CABG and valve replacement 1 (5) 11 (55)‡ 1 (5) Other 1 (5) 0 (0) 1 (5) Perioperative Clamp time (min) 69 (49-104) 100 (76-136)‡ 62 (44-92) Pump time (min) 100 (80-145) 145 (107-179)‡ 102 (68-131) Total OR time (min) 311 (246-371) 340 (316-390)§ 303 (231-346) Hemodynamic variables Heart rate (beats/min) 85 (78-100) 80 (70-95) 71 (65-78) Mean arterial pressure (mmHg) 63 (47-81) 68 (29-79) 79 (68-89) PAPdia (mmHg) 15 (11-17) 14 (9-19) 13 (7-17) PAPsys (mmHg) 26 (22-32) 29 (22-33) 23 (15-29) PAOP (mmHg) 10 (8-12) 11 (7-15) 10 (8-14) CO 4.1 (3.3-5.5) 4.6 (2.5-5.2) 5.2 (4.3-6.3) CI 2.2 (1.6-3.9) 2.4 (1.5-2.8) 2.6 (2.2-2.8) CVP 7 (3-13) 8 (4-10) 9 (6-12) sVO2 63 (61-73) 59 (55-72) 69 (66-70) Respiratory variables PEEP (cmH2O) 5 (5-5) 5 (5-5) 5 (5-5) Pressure plateau (cmH2O) 10 (9-12)§ 12 (11-15) 13 (11-15) FiO2 50 (50-50) 49 (40-50) 50 (40-50) PaO2 (mmHg) 149 (115-178) 145 (94-194) 150 (112-187) PaO2/FiO2 297 (242-356) 340 (185-403) 344 (254-390) Compliance (mL/cmH2O) 84 (65-101) 102 (73-121) 72 (52-98) Chest X-ray consistent with ALI, n (%) 1 (5) 4 (20) 0 (0) Rethoracotomy, n (%) 2 (10) 4 (20) 1 (5) PLI (¥10-3/min) 33 (16)|| 33 (24)|| 23 (11) * Data are reported as mean (SD) or median (IQR) unless otherwise noted. † p < 0.001 massive transfused versus nontransfused or restrictive transfused controls. ‡ p < 0.01 massive transfused versus nontransfused or restrictive transfused controls. § p < 0.05 massive transfused versus nontransfused or restrictive transfused controls. || p < 0.05 all transfused patients versus nontransfused controls. ASA = American Society of Anesthesia classification; CO = cardiac output; CVP = central venous pressure; IQR = interquartile range; OR = operating room; PAPdia = pulmonary artery pressure diastolic; PAPsys = pulmonary artery pressure systolic.unit, the storage time of the products and the presence of (110 [82-214] hr in the restrictive transfused group andHLA or HNA antibodies, and an increase of the PLI. Addi- 175 [112-218] hr in the multiply transfused group com-tion of patient factors did not change associations. pared to 82 [58-156] hr in the nontransfused group [p < 0.01]). Patients in the multiply transfused groups had a prolonged duration of mechanical ventilationOutcome compared to the nontransfused group (14 [10-20] hr vs.Transfused patients had an increased median length 9.5 [6.3-12.8] hr, p < 0.001). No difference was found inof hospital stay compared to nontransfused patients survival or ICU stay between the groups.86 TRANSFUSION Volume 52, January 2012
  • 6. TRANSFUSION-RELATED PULMONARY PERMEABILITY TABLE 2. Transfusion descriptives and pulmonary leakage index of transfused cardiac surgery patients* Transfused groups PLI level Transfusion characteristics Restrictive (n = 20) Massive (n = 20) PLI < 1.5¥ (n = 13) PLI Ն 1.5¥ (n = 27) Number of transfusions (units) RBCs 1.1 Ϯ 0.8 5.7 Ϯ 3.8† 2.9 Ϯ 4.3 3.5 Ϯ 3.4 FFP 0.1 Ϯ 0.4 3.5 Ϯ 2.6† 2.3 Ϯ 3.0 1.6 Ϯ 2.4 PLTs 0.2 Ϯ 0.4 1.4 Ϯ 0.6† 0.8 Ϯ 0.6 0.7 Ϯ 0.8 RBCs Storage time >14 days (units) 1 (0-1) 3 (0-5)‡ 2 (0-3) 1 (0-4) Storage time (days) 15 (8-19) 15 (11-18) 15 (11-23) 15 (10-17) PLT Storage time >5 days (units) 0 (0-1) 0 (0-1) 1 (0-1)§ 0 (0-0) Storage time (days) 3 (1-6) 4 (0-7) 6 (2-7) 0 (0-4) Antibodies Number of units derived from female donors 1 (0-1) 2 (2-4.5)† 2 (0-3) 1 (1-2) Number of antibody-positive units 0 (0-1) 1 (0-2)§ 1 (0-1) 1 (0-1) Number of HLA I- or II-positive units 0 (0-0) 0 (0-1) 0 (0-1) 0 (0-1) Number of HNA-positive units 0 (0-01) 1 (0-1) 1 (0-1) 1 (0-1) Median concentration of lysoPC in RBCs LysoPC 16:0 mMol 6.8 (6.0-8.6) 7.3 (6.1-8.8) 7.0 (6.5-8.8) 7.0 (6.0-8.9) 18:0 mMol 3.5 (2.9-4.1) 3.7 (3.3-4.5) 3.8 (3.3-4.5) 3.5 (3.0-4.3) 18:1 mMol 2.0 (2.0-3.0) 2.0 (2.0-2.5) 2.0 (2.0-3.0) 2.0 (2.0-2.5) LysoPAF 16:0 mMol 0.2 (0.2-0.3) 0.3 (0.2-0.3) 0.2 (0.2-0.3) 0.3 (0.2-0.3) 18:0 mMol 0.3 (0.3-0.4) 0.4 (0.3-0.4) 0.3 (0.3-0.4) 0.4 (0.3-0.4) LysoPC 18:1/PAF 16:0 mMol 0.1 (0.1-0.2) 0.1 (0.1-0.1) 0.1 (0.1-0.1) 0.1 (0.1-0.2) Median concentration of lysoPC in PLTs LysoPC 16:0 mMol 98 (89-100) 97 (87-111) 102 (90-110) 91 (86-100) 18:0 mMol 40 (40-56) 41 (38-45) 43 (41-50) 40 (38-44) 18:1 mMol 18 (17-22) 21 (18-22) 21 (18-21) 21 (18-22) LysoPAF 16:0 mMol 2.0 (1.7-2.1) 1.8 (1.6-2.0) 1.9 (1.5-2.0) 1.7 (1.7-2.1) 18:0 mMol 2.3 (2.0-2.5) 2.3 (2.2-2.9) 2.5 (2.3-2.8) 2.3 (2.0-2.4) LysoPC 18:1/PAF 16:0 mMol 0.8 (0.7-1.0) 0.9 (0.8-1.0) 0.9 (0.8-1.0) 0.8 (0.7-0.9) * Data are presented as mean (SD) or as median (IQR). † p < 0.001. ‡ p < 0.01. § p < 0.05. DISCUSSION The finding that transfusion results in mild lung injury is in accord with a previous description of threeThis study shows that blood transfusion is associated with cases not meeting the TRALI consensus definition andincreased pulmonary vascular leakage in a cohort of who were not diagnosed as TRALI by the treating clini-cardiac surgery patients, in a dose-dependent manner for cians.39 Also, in an experimental transfusion model, weRBCs. Vascular injury after transfusion in this cohort of recently showed that transfusion of stored RBCs results incardiac surgery patients not meeting the TRALI criteria mild pulmonary inflammation, including extravasation ofwas irrespective of the presence of lysoPCs or antibodies. pulmonary neutrophils and production of proinflamma- We found in the regression analysis that blood trans- tory cytokines.40 These results indicate that pulmonaryfusion is associated with onset of pulmonary vascular leakage was dose dependent for RBCs, in line with theleakage with concomitant trend for worsening of lung suggestion that mild effects of a single transfusion mayinjury, in patients that do not meet the clinical TRALI cri- accumulate after repeated transfusions, contributing toteria. The finding of similar filling pressures and cardiac pulmonary leakage and hypoxemia after cardiac surgery.function in restricted and multiply transfused patients In accordance, observational clinical studies show that theunderlines the fact that pulmonary deterioration was not number of RBCs transfused is associated with adversedue to hydrostatic pulmonary edema. Also, operative pro- outcome.4,41cedures and time on cardiopulmonary bypass did not We found no association between the presence of HLAinfluence the association between transfusion and pul- or HNA antibodies in the transfused products and pulmo-monary leakage, in line with a previous study indicating nary leakage. Although antibodies are implicated in thean independent role for transfusion as mediator of pulmo- onset of TRALI, many antibody-containing blood productsnary dysfunction after cardiac surgery.29 fail to produce TRALI.42-44 A threshold model has been sug- Volume 52, January 2012 TRANSFUSION 87
  • 7. VLAAR ET AL. the second hit of TRALI pathogenesis.17,48 TABLE 3. Univariate analysis of transfusion-related risk factors for an Here, we found no association between increase in PLI in cardiac surgery patients* bioactive lipids in the transfused prod- Transfusion-related risk factors ucts and pulmonary vascular leakage. In Transfusion characteristics b (95% CI) p value accordance, a recent study in surgical Number of transfusions (units), n = 60 RBCs 1.6 (0.2 to 3.0) 0.03† patients showed no association between FFP 0.4 (-1.8 to 2.6) 0.7 the concentration of bioactive lipids and PLTs 1.2 (-5.9 to 8.2) 0.7 the occurrence of postoperative pulmo- RBCs (n = 40) Storage time >14 days (units) -0.9 (-3.2 to 1.3) 0.4 nary dysfunction.49 Also, we did not find Storage time (days) -0.8 (-2.1 to 0.5) 0.2 an association between storage time PLT (n = 40) and pulmonary leakage. This is in con- Storage time >5 days (units) -8.1 (-27.1 to 10.8) 0.4 Storage time (days) -1.3 (-5.1 to 2.6) 0.5 trast with experimental studies17,40,50,51 Antibodies (n = 40) and with an observational study describ- Number of female donors -0.7 (-4.7 to 3.3) 0.7 ing an association between RBC storage Number of antibody-positive units -3.8 (-15.5 to 7.9) 0.5 Number of HLA I- or II-positive units -12.0 (-36.1 to 12.0) 0.3 time and pulmonary complications,2 but Number of HNA-positive units -5.2 (-21.2 to 10.8) 0.5 not with other studies in cardiac surgery Median concentration of lysoPC in RBCs (n = 40) patients investigating the role of aged LysoPC 16:0 mMol -0.6 (-5.4 to 4.2) 0.8 RBCs.22-24 Taken together, we cannot 18:0 mMol 2.1 (-7.3 to 11.4) 0.7 rule out the fact that a larger sample 18:1 mMol 2.5 (-15.2 to 20.3) 0.8 size may have yielded an association LysoPAF 16:0 mMol 54.3 (-84.4 to 193) 0.4 between lysoPC and pulmonary leakage. 18:0 mMol 80.3 (-37.9 to 198.5) 0.2 However, in this cohort of patients, LysoPC 18:1/PAF 16:0 mMol 68 (-146.3 to 282.0) 0.5 blood transfusion was clearly associated Median concentration of lysoPC in PLTs (n = 40) LysoPC with increased PLI, while the association 16:0 mMol -0.3 (-1.0 to 0.5) 0.5 between lysoPCs and PLI was absent. 18:0 mMol -0.4 (-1.8 to 1.0) 0.5 Possibly, the RBC, and not soluble 18:1 mMol 0.6 (-2.7 to 4.0) 0.7 LysoPAF factors in the supernatant, is a key player 16:0 mMol 6.6 (-28.5 to 41.7) 0.7 in onset of lung injury, as suggested by 18:0 mMol 1.9 (-11.6 to 15.4) 0.8 recent experimental studies.40,52 LysoPC 18:1/PAF 16:0 mMol -27.1 (-90.2 to 35.8) 0.4 The design of this study has limita- * Data are presented as mean (SD) or as median (IQR). † Significant difference. tions. Sample size is small, which may have precluded positive associations. Also, although we used a regressiongested,45 in which a threshold must be overcome to induce analysis with known risk factors for transfusion and onseta TRALI reaction. Factors that determine the threshold are of ALI to correct for confounding, it is possible that factorsthe predisposition of the patient that determines priming not included in the model have contributed to PLIof the lung neutrophils and the ability of the mediators in increase. Therefore, results on causative factors in thethe transfusion to cause activation of primed neutrophils. increase in PLI should be interpreted within these limits.An explanation for the absence of increase of pulmonary We cannot exclude that antibodies or lysoPCs are caus-leakage in the presence of HLA or HNA antibodies may be ative when a larger study sample is investigated. However,twofold. First, the neutrophil-priming status of the patient given the clear association between transfusion andmay have been too low, thereby not allowing the threshold elevated PLI, the investigated factors may not be strongfor onset of lung injury to be overcome. Second, we only predictors.determined HLA or HNA antibodies in the blood products, In conclusion, transfusion in cardiothoracic surgerynot the presence of an antibody-antigen match. Third, a patients is associated with an increase in pulmonarymild increase in pulmonary permeability in cardiac capillary permeability, an effect that was dose dependentsurgery patients may be caused by other pathways than for RBC products. In this study, we found no associa-those involved in the onset of TRALI. Although recent tion between bioactive lipids or the presence of HLA orstudies suggest that exclusion of female donors for produc- HNA antibodies and increase in pulmonary capillarytion of plasma reduces pulmonary complications and permeability.TRALI,46,47 current results do not support a male-onlydonor policy with the aim to reduce pulmonary dysfunc-tion in cardiac surgery patients in general. CONFLICT OF INTEREST Bioactive lipids, which accumulate during storage ofcell-containing blood products, have been implicated in None.88 TRANSFUSION Volume 52, January 2012
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