EFFECT OF PERIOPERATIVE TRANSFUSION OF OLD RED BLOOD CELLS ON POSTOPERATIVE COMPLICATIONS AFTER FREE MUSCLE SPARING TRANSVERSE RECTUS ABDOMINIS MYOCUTANEOUS FLAP SURGERY FOR BREAST RECONSTRUCTION HYE-KYOUNG LEE, M.D.,1 DONG-HO KIM, M.D.,1 UNG-SIK JIN, M.D.,2 YOUNG-TAE JEON, M.D., Ph.D.,3 JUNG-WON HWANG, M.D., Ph.D.,3 and HEE-PYOUNG PARK, M.D., Ph.D.1*

Background: Transfusion with old red blood cells (RBCs) was associated with adverse clinical outcomes. The effect of perioperative transfusion of old RBCs on postoperative complications after free muscle sparing transverse rectus abdominis myocutaneous (TRAM) flap surgery was retrospectively investigated. Methods: Two hundred sixty-one patients undergoing breast reconstruction were assigned to two groups: no transfusion and transfusion groups. Transfused patients were further divided according to the RBC storage duration (fresh, 14 days; old, >14 days). Postoperative complications such as vascular thrombosis, hematoma, and flap congestion were noted. Results: Patients who received old blood (n 5 34), compared with those received fresh blood (n 5 40) or no transfusion (n 5 187), had a higher incidence of postoperative complications (44.1% vs. 20.0% or 12.8%, P < 0.05). Conclusions: Perioperative transfusion of old C 2014 Wiley RBCs can be associated with an increase in postoperative complications after free muscle sparing TRAM flap surgery. V Periodicals, Inc. Microsurgery 34:434–438, 2014.

It is widely accepted that stored red blood cells (RBCs) undergo several changes, collectively referred to as a “storage lesion.” These changes, including loss of deformability, morphological alterations, and depletion of adenosine triphosphate and 2,3-diphosphoglycerate, decrease the oxygen-transporting capacity of RBCs and impair RBC passage through the capillaries.1,2 Previous studies in trauma and critically ill patients and in patients who underwent cardiac surgery have reported adverse clinical outcomes, such as increased length of hospital stay, postoperative infections, multiple organ failure, thrombosis, and mortality, after transfusions using old blood.3–5 Various flaps including the transverse rectus abdominis myocutaneous (TRAM) flap, deep inferior epigastric perforators (DIEP) flap, superior gluteal artery perforator flap, and superficial inferior epigastric artery flap have been used for breast reconstruction after mastectomy.6–9 1 Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea 2 Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea 3 Department of Anaesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea *Correspondence to: Hee-Pyoung Park, M.D., Department of Anaesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected] Received 8 October 2013; Revision accepted 6 February 2014; Accepted 14 February 2014 Published online 28 February 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/micr.22240

Ó 2014 Wiley Periodicals, Inc.

Among the flaps, microsurgical breast reconstruction with the DIEP and TRAM flaps has been commonly and safely used in even patients with comorbidity because they are associated with low postoperative complication rates, excellent aesthetic outcome, and high patient satisfaction.10 Especially, the muscle-sparing TRAM free flap has less morbidity on the donor site than the classic TRAM flap and less harvesting time than the DIEP flap.11 Prevention of complications such as vascular thrombosis or hematoma formation, which can result in flap failure,12 and adequate oxygen supply to the transferred tissue13 are critical for the success of microsurgical breast reconstruction using free flap. The preservation of optimal homeostasis during surgery is important for preventing these complications and providing adequate oxygen supply to the transferred tissue. Maintaining adequate hemoglobin levels during the intraoperative and postoperative periods is of particular importance. The oxygen content in arterial blood is determined by the amount of hemoglobin and a reduction in arterial oxygen resulting from anemia is directly associated with flap failure.14 A review of the literature indicated that the transfusion rate in TRAM flap patients is 6–95%.15–17 Recent studies showed that transfusion is associated with adverse clinical outcomes in free flap surgery.18–20 However, no study has investigated the effect of transfusing old blood on postoperative complications following TRAM flap surgery. The present study assessed the effect of perioperative blood transfusion on postoperative complications

Old Blood and Postoperative Complications after TRAM Surgery

following TRAM flap surgery, particularly when the transfused RBCs had been stored longer than 2 weeks. PATIENTS AND METHODS

Institutional ethical approval was obtained from Seoul National University Hospital prior to conducting this retrospective study. A total 261 consecutive patients who underwent free muscle sparing TRAM flap surgery for unilateral breast reconstruction under general anesthesia between January 2009 and December 2012 were enrolled. All operations were performed by two expert surgeons, and their surgical techniques were similar. In brief, all free TRAM flaps were elevated with muscle sparing technique. The thoracodorsal or internal mammary vessels were used as the recipient vessels. After the appropriate recipient vessel site was prepared, the deep inferior epigastric vessels were divided near their attachment to the external iliac vessels. The flap was then passed up to the chest site where end-to-end anastomoses were performed. After completing the anastomoses, the low molecular weight heparin (1250 U) was intravenously infused. Patients were divided into groups according to whether or not they had received RBC transfusions. The transfusion group was defined as those having received at least one RBC unit from the intraoperative period to postoperative day 1. Nontransfused patients received no blood products during that period. The RBC transfusion group was further divided according to the duration of the RBC storage; fresh blood was defined as a storage duration 14 days and old blood was defined as a storage duration of >14 days. These criteria were used in a previous study.3 The selection of fresh or old blood was exclusively dependent on a decision of a clerk working in blood bank in our hospital. Neither an anesthesiologist nor a plastic surgeon participated in the selection of transfused bloods. In this study, two transfused patients had mixed transfusion (one unit: old RBC, one unit: fresh RBC). They were considered as fresh blood group because the storage duration of old blood in them was 14.3 days each, and the transfused volume (320 mL) of old blood was smaller than the volume (400 mL) of fresh blood. In patients who required reoperation due to postoperative surgical complications on postoperative day 1, if they received blood transfusion before reoperation, they were considered to be the transfusion group; however, if they received blood transfusion during and after reoperation, they were considered to be the nontransfusion group. The decision to administer a blood transfusion was made by an anesthesiologist during surgery or by a senior plastic surgery resident postoperatively. A particular

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Table 1. Comparison of Demographic Data in Patients Receiving Non-Blood Transfusion, Fresh Blood Transfusion, and Old Blood Transfusion Non-blood transfusion (n5187)

Fresh blood transfusion (n540)

Old blood transfusion (n534)

Age (year) 46.7 6 7.2 46.5 6 6.8 47.2 6 6.7 Body mass 22.8 6 2.6 22.2 6 2.0 21.7 6 2.2 index (kg m22) Chemotherapy (n/%) 36 (19.3%) 5 (12.5%) 3 (8.8%) Radiation therapy (n/%) 18 (9.6%) 3 (7.5%) 1 (2.9%) Smoking (n/%) 7 (3.7%) 0 (0.0%) 2 (5.9%) Duration of 520.2 6 63.4 553.9 6 97.4 542.4 6 95.0 surgery (min) Hemoglobin (g dL21) Preoperative 13.2 6 0.9 12.7 6 1.4 12.4 6 1.5 At the end of 10.9 6 1.1 10.0 6 1.3 9.8 6 1.2 anastomosis Immediate 10.3 6 1.0 9.3 6 1.4 9.3 6 1.1 postoperative Hospital stay (days) 11.3 6 3.5 11.9 6 2.7 14.0 6 5.1

protocol for blood transfusion in TRAM flap surgery was not used. Generally, blood transfusion was indicated when the hemoglobin level was 14 days was associated with a significant increase in the risk for postoperative complications and long duration of hospital stay after breast reconstruction using free TRAM flap surgery. In our study, the postoperative complication rate after TRAM flap surgery was 18%, which is consistent with previous studies in which complication rates of 7.6–40% were reported after free flap surgery.14,21–24 In the present study, of patients with postoperative complications, 62% showed vascular thrombosis or poor perfusion to the flap tissue. This study is the first to reveal a harmful effect of old blood transfusion on postoperative complications in TRAM flap surgery for breast reconstruction. We offer two possible explanations for the association between transfusion of old blood and vascular thrombosis or poor perfusion after the flap surgery. First, mechanical changes that occur during storage may reduce the ability of RBCs to circulate through the microcirculatory bed, resulting in decreased microvascular flow and local hypoxia, which may contribute to vessel thrombosis. Moreover, the release of free hemoglobin and microparticles by hemolysis during storage may reduce

Old Blood and Postoperative Complications after TRAM Surgery

nitric oxide bioavailability, which may result in reduced microvascular flow. Alternatively, biomechanical changes in the RBCs and/or white blood cells (WBCs) during storage may impair the coagulation system, leading to vessel thrombosis. A previous study showed that, echinocytic RBCs generated during storage adhered to the vascular endothelium.25 Stadler et al.26 found that the fragmentation of RBCs during storage provided a thrombogenic surface for platelets, causing platelet activation and platelet-derived procoagulant activity. Increased level of adenosine diphosphate during long blood storage induces platelet aggregation, which may result in reduced microvascular flap perfusion.27 RBC concentrate contains WBCs, cytokines, and other bioactive substances generated by WBCs.28 In an in vitro study, Luk et al.29 reported that non-WBC-reduced RBC units stored for 28 days demonstrated a greater degree of adherence to endothelial cells than did RBCs stored for 1 or 15 days. The authors suggested that WBCs and/or proinflammatory cytokines, which are released by WBCs during storage, act directly on RBCs or endothelial cells, leading to altered adhesion properties. A recent experimental study demonstrated that interleukin-6, a proinflammatory cytokine, mediated thrombocytosis, exaggerated platelet aggregation, and enhanced thrombus development in a model of experimental colitis.30 Transfusion per se is associated with adverse clinical outcomes in free flap surgery. A recent study revealed a strong association of the presence of postoperative complications related to flap with transfusion in DIEP flap breast reconstruction.20 In that study, long surgical time and increased flap weight were identified as predictors of significant blood loss. A large-scaled study investigating complications following breast reconstruction using TRAM and latissimus dorsi flaps or implant demonstrated that intraoperative transfusion was an independent risk factor for major surgical and medical complications.18 In contrast, another recent study showed that intraoperative RBC transfusion caused an increase in overall and medical postoperative complications, but it was not associated with postoperative surgical complications such as flap loss in various free flap surgeries.19 In this study, preoperative hemoglobin level was significantly lower in the transfusion group than the nontransfusion group. A literature review showed inconsistent results concerning the effect of preoperative anemia on postoperative flap failure. A recent study using the National Surgical Quality Improvement Program demonstrated that preoperative anemia did not predict flap failure after free flap reconstructive surgery.31 By contrast, another recent report showed that preoperative anemia was directly related to vascular thrombosis and free flap failure in microvascular reconstruction, and especially, patients with preoperative hematocrit level less than 30% had more chance of flap failure.14 Ting

437

et al.32 also reported that patients with preoperative anemia could be at high risk of flap failure in DIEP flap surgery for breast reconstruction. In free flap surgery, optimal patient management for maintaining blood flow through the anastomoses during surgery and the postoperative period has a significant impact on patient outcome. Scholz et al.33 found a beneficial effect of dobutamine infused after completion of the microvascular anastomoses on blood flow in the anastomosed arteries of free tissue flaps in head and neck reconstructive surgery. Another study using laser doppler flowmetry showed that norepinephrine may take an advantage over epinephrine, dopexamine, and dobutamine in preserving flap blood flow after head and neck cancer resection and free flap reconstruction.34 The total amount of fluid infused intra and postoperatively is associated with development of postoperative complications after TRAM flap surgery.21,35,36 Previous studies showed that persistent positive-balance fluid management after TRAM flap surgery caused hemodilution and relative anemia, and the authors suggested that tissue oedema and pressure on the microcirculation may directly affect tissue survival.21,35 Another study demonstrated that perioperative fluid overload was linked to thrombus formation at the anastomosis, a major postoperative complication, in the free TRAM flap.36 However, no guidelines for transfusion, fluid balance, and the choice of vasopressor are currently in place for the management of optimal perfusion to anastomosed tissue after microsurgical breast reconstruction procedures. The present study has several limitations. First, it was a retrospective study with a small sample size from a singlereferral medical center. In this study, data were collected in only patients undergoing muscle-sparing TRAM flap surgery, which may limit the ability to generalize our results to other free flap surgery for breast reconstruction because surgical technique, postoperative complication rate, and perioperative transfusion rate are different. Surgical factors such as inadequate bleeding control and narrowing of the anastomosis site were not considered in our study; however, all surgeries were performed by two skilled surgeons, and the patency of vessel anastomosis was checked using Doppler ultrasonography following anastomosis and prior to final skin closure. Finally, our study focused on postoperative complications occurred during hospital admission. Long-term complications after hospital discharge, such as fat necrosis, delayed wound infection, and delayed wound breakdown, were not analyzed. CONCLUSIONS

The transfusion of stored RBCs may increase postoperative complications and the duration of hospital stay after free TRAM flap surgery. This effect may be more significant with a blood storage age 14 days. A largeMicrosurgery DOI 10.1002/micr

438

Lee et al.

scaled prospective randomized trial should be required to definitely confirm the association of transfused old blood with increased postoperative complications in patients undergoing different free flap surgeries.

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