Journal of Clinical Medicine Article The Effect of Perioperative Blood Transfusions on Microvascular Anastomoses Lidia Sanchez-Porro Gil 1, *, Xavier Leon Vintro 2 , Susana Lopez Fernandez 1 , Carmen Vega Garcia 1 , Gemma Pons Playa 1 , Manuel Fernandez Garrido 1 and Jaume Masia Ayala 1 1 Department of Plastic and Reconstructive Surgery, Hospital Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; SLopezfe@santpau.cat (S.L.F.); CVega@santpau.cat (C.V.G.); GPonsP@santpau.cat (G.P.P.); MFernandezGa@santpau.cat (M.F.G.); jmasia@santpau.cat (J.M.A.) 2 Department of Otolaryngology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; xleon@santpau.cat * Correspondence: lsanchezporro@santpau.cat or lsanchezporro@parcdesalutmar.cat Abstract: Introduction: Perioperative transfusions are associated with complications of free flaps. The purpose of the present study was to find out whether there is a significant relationship between the risk of developing complications in vascular anastomoses and the history of transfusions. Methods: We studied 372 patients retrospectively with microsurgical reconstruction between 2009 and 2017 with regards to the number of red blood cell concentrates transfused. Complications were analyzed relative to flap loss and complications in microvascular anastomoses. Results: 130 patients (34.9%)  received blood transfusions. Some 55% of them were transfused between the day of the intervention  and the first postoperative day. Ninety-six patients were reoperated on (25.7%). Of those, thirty-six Citation: Sanchez-Porro Gil, L.; Leon patients (37.5%) corresponded to anastomosis failure. The percentage of patients transfused among Vintro, X.; Lopez Fernandez, S.; Vega those who required reoperation was 55.2%. The percentage of patients transfused among those who Garcia, C.; Pons Playa, G.; Fernandez were reoperated on within the first 72 h due to an alteration in the anastomosis was 60.6%, while it Garrido, M.; Masia Ayala, J. The Effect of Perioperative Blood was 25.6% (Chi square P = 0.0001) for the rest of the patients. Conclusions: Although there is a strong Transfusions on Microvascular association between transfusion and vascular anastomosis failure, it is not possible to establish the Anastomoses. J. Clin. Med. 2021, 10, causation between the two. 1333. https://doi.org/10.3390/ jcm10061333 Keywords: microsurgery; transfusion; free flap; breast reconstruction Academic Editor: Gottfried Wechselberger 1. Introduction Received: 12 February 2021 The percentage of failures associated with the use of micro-anastomosed free flaps Accepted: 19 March 2021 in the most recently published series stands at between 1% and 9% [1–3]. In addition to Published: 23 March 2021 failure, which is understood as the partial or complete loss of the flap, the percentage of patients who suffered the appearance of complications during the perioperative period Publisher’s Note: MDPI stays neutral varied from one series to another. with regard to jurisdictional claims in Several studies have been carried out on large populations of patients treated with published maps and institutional affil- iations. micro-anastomosed free flaps that analyze the risk factors associated with the appearance of postoperative complications and the failure of the reconstructive procedure. In those studies, the factors that are significantly associated with the loss of the flap are the need for an intraoperative transfusion of three or more units and an elevated surgical time. On the other hand, the relationship to other factors such as age, sex, BMI (body max index), Copyright: © 2021 by the authors. smoking, a history of alcoholism, and the American Society of Anesthesiologist (ASA) Licensee MDPI, Basel, Switzerland. score is not so clear [4,5]. This article is an open access article During blood storage, the erythrocytes progressively undergo structural and biochem- distributed under the terms and conditions of the Creative Commons ical changes. They become less deformable and more fragile, leading to the appearance of Attribution (CC BY) license (https:// the hemolysis phenomena, the accumulation of pro-inflammatory molecules, iron, and free creativecommons.org/licenses/by/ hemoglobin (Hb) [6]. The release of free Hb leads to a reduction in nitric oxide concentra- 4.0/). tions with consequent vasoconstriction [7], the induction of a state of hypercoagulability J. Clin. Med. 2021, 10, 1333. https://doi.org/10.3390/jcm10061333 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1333 2 of 8 mediated by the adhesion of leukocytes, the increase in endothelial permeability, and the proliferation of smooth muscle after the induction of a vascular trauma [8]. It is es- timated that after one hour of transfusion, up to 30% of the transfused red blood cells have hemolyzed or been removed by the action of macrophages [9]. Moreover, there is a depletion of 2,3-diphosphoglyceride acid (2,3 DPG) and adenosine triphosphate (ATP), altering the oxygen transport capacity [10]. All these modifications justify an increase in the appearance of the thrombotic phenomena associated with giving transfusions. The main problem at the time of proposing a transfusion is to know to what extent hemoglobin (Hb) can decrease before provoking a dysfunction or severe tissue damage. Perioperative anemia contributes to an increase in morbidity and mortality. On the other hand, interventions like transfusions to correct this anemia also have adverse effects and produce complications that may increase the risk to patients. The benefit obtained with transfusions has a cost associated with the risk of bacterial or viral infections caused by the transfusion, immunological reactions including anaphylaxis and hemolysis, and disorders in the regulation of the immune system that could favor the appearance of infectious complications in the postoperative period [11]. From studies developed in hemodynamically stable patients without active blood loss admitted to critical care units, a transfusion threshold or trigger of 70 g/L has been established as reasonable to avoid the harmful effects of anemia [11,12]. It remains to be determined what the ideal Hb or hematocrit level is for patients treated with a micro-anastomosed free flap. Different studies have experimentally evaluated, in animal and human models, the effect of perioperative hematocrit on the microvascular success rate. They came up with contradictory results [5,13–16]. The effect of anemia on microvascular reconstruction is controversial. Some studies have suggested a benefit in normovolemic hemodilution based on the theory that the decrease in viscosity increases arterial flow and perfusion at the tissue level [15,16]. Other studies argue that basal anemia is a variable intrinsically related to the patient’s physiological state, but that it does not appear as a predictor of outcomes in patients treated with a micro-anastomosed free flap [17,18]. The main objective of the present study was to find out whether there is a significant relationship between the risk of developing complications in vascular anastomoses and the history of transfusion in reconstructions with micro-anastomosed free flaps. 2. Patients and Methods The study included 372 patients with a history of microsurgical reconstruction in the Plastic Surgery service of the Hospital de la Santa Creu and Sant Pau between 2009 and 2017. Patients who had undergone a second microsurgical reconstruction were excluded from the study. The number of red blood cell concentrates transfused was counted from seven days before the intervention until the fourth postoperative day. Likewise, the data referring to the preoperative and postoperative hemoglobin (Hb) values were collected. The decision to transfuse the patient was made at the discretion of the anesthesiologist or surgeon in accordance with the protocol of the Hospital de la Santa Creu i Sant Pau. Transfusion is called for if Hb <70 g/L. However, if Hb is <80 g/L, transfusion is required in patients with difficulties adapting to anemia, those older than 65 years of age, and patients with a history of cardiovascular and/or pulmonary disease. 2.1. Parameters Evaluated Clinical data on age, sex, BMI, vascular history, and preoperative and postoperative hemoglobin values were obtained from each patient. The transfusion requirements and the existence of reoperation and reason were studied: hematoma, anastomosis failure, or flap necrosis. The operative time was also studied. Complications have been classified as partial or total loss of the flap, wound dehiscence, fistula, or infection. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 8 flap necrosis. The operative time was also studied. Complications have been classified as J. Clin. Med. 2021, 10, 1333 partial or total loss of the flap, wound dehiscence, fistula, or infection. 3 of 8 2.2. Statistical Analysis A descriptive study was made of the characteristics of the patients, the results ob- 2.2. Statistical tained, Analysis variables potentially related to the results. Depending on the and the prognostic conditionsA descriptive studythe of application, wascomparison made of thebetween characteristics of the variables qualitative patients, the wasresults doneobtained, using theand the prognostic Chi-Square Test orvariables Fisher’s potentially related exact test. The to the results. relationship Depending between on the continuous conditions and qual- of application, the comparison between qualitative variables was done using itative variables was evaluated using the Student’s t-Test for independent samples for the the Chi-Square Test or Fisher’s evaluation exact test.dependent of dichotomous The relationship between variables continuous and with the ANOVA and qualitative variables test in the case of dependent variables with more than two categories. We classified patients based on trans- of was evaluated using the Student’s t-Test for independent samples for the evaluation dichotomous fusion requirementsdependent variables by recursive and with partitioning the ANOVA analysis (CHAID test in the case method), of dependent considering the variables failure of thewith more than anastomosis as atwo categories. dependent We classified patients based on transfusion variable. requirements by recursive partitioning analysis (CHAID method), considering the failure of the anastomosis as a dependent variable. 3. Results 3.1.3.Overall Results Results OfOverall 3.1. the 373 patients included in the study, 51% underwent reconstruction of the Results breast, 22% reconstruction of the head Of the 373 patients included andstudy, in the neck, 51% 20% underwent reconstruction of the lower reconstruction ofextrem- the breast, ity,22% andreconstruction the rest of the patients corresponded to a miscellany of several specialties. of the head and neck, 20% reconstruction of the lower extremity, As for and thethe flaps rest of the patients corresponded to a miscellany of several specialties. As for thethe made, 97% corresponded to perforator flaps, 8% to osteocutaneous flaps, and flaps restmade, to non-perforating 97% correspondedflaps. to perforator flaps, 8% to osteocutaneous flaps, and the rest to Ninety-six patients non-perforating flaps.were reoperated on (25.7%). Of those, 45 (46.8%) corresponded to anastomosis failure, Ninety-six 19 (19.8%) patients weretoreoperated hematomaon evacuation (25.7%). Ofwith no evidence those, 45 (46.8%)ofcorresponded anastomosis to failure, anastomosis failure, 19 (19.8%) to hematoma evacuation with no evidence ofdifferences and 32 (33.3%) to debridement of partial flap. There were no significant anastomosis in terms failure,ofand reoperation 32 (33.3%)intoterms of the type debridement of flapflap. of partial or the surgical There wereindication. Most no significant of the differences reinterventions, for revision in terms of reoperation inofterms the anastomosis of the type ofor flap hematoma evacuation, or the surgical occurred indication. during Most of the thereinterventions, first 72 h postoperatively for revision (Figure of the 1). anastomosis or hematoma evacuation, occurred during the first 72 h postoperatively (Figure 1). Figure Figure 1. Interval 1. Interval between between the the dayday of the of the surgery surgery andand reoperation. reoperation. There was a partial loss in 31 (8.3%) flaps even though they maintained their recon- There was a partial loss in 31 (8.3%) flaps even though they maintained their recon- structive purpose. In 24 (6.4%) instances, there was a total loss of the flap. Although a structive purpose. In 24 (6.4%) instances, there was a total loss of the flap. Although a lower percentage of loss was observed in breast reconstructions, there were no significant lower percentage of loss was observed in breast reconstructions, there were no significant differences as regards the surgical indication or the type of flap. differences as regards the surgical indication or the type of flap. Of the 45 patients on whom revision of the anastomosis was performed, in 9 cases we Of the 45 patients on whom revision of the anastomosis was performed, in 9 cases performed a flap removal due to necrosis and in 36 patients we performed an anastomosis we performed a flap removal due to necrosis and in 36 patients we performed an anasto- revision. Of the 36 patients on whom revision of the anastomosis was performed, there mosis revision. Of the 36 patients on whom revision of the anastomosis was performed, was a complete rescue of the flap in 14 (38.9%), partial flap loss in 8 (22.2%) without there being an alteration in the reconstructive purpose, and a total loss of the flap in 14 (38.9%). This means that repair of the anastomosis succeeded in 61.1% of the instances. there was a complete rescue of the flap in 14 (38.9%), partial flap loss in 8 (22.2%) without there being an alteration in the reconstructive purpose, and a total loss of the flap in 14 J. Clin. Med. 2021, 10, 1333 4 of 8 (38.9%). This means that repair of the anastomosis succeeded in 61.1% of the instances. 3.2. Transfusion Requirements 3.2.ATransfusion total of 130 Requirements patients (34.9%) received blood transfusions. The highest density of transfusions occurred during (34.9%) A total of 130 patients the dayreceived of the intervention (intraoperative blood transfusions. or immediate The highest density of postoperative) transfusions occurred during the day of the intervention (intraoperative orcells and the first postoperative day. A total of 394 packed red blood were immediate transfused. Someand postoperative) 55%theof first thempostoperative were transfusedday.between A total ofthe 394day of thered packed intervention blood cellsand were thetransfused. first postoperative Some 55%day. There of them were were significant transfused differences between the dayin of thethe transfusion intervention require- and the ments relative to patient first postoperative day.gender, There wereit being more frequent significant in male differences in thepatients (p = 0.001). transfusion There requirements were also differences relative regarding to patient gender, the ASA it being score more of the patients. frequent There were in male patients (p =no0.001). significant There differences in terms of age or BMI. were also differences regarding the ASA score of the patients. There were no significant The average differences Hb ofofthe in terms agepatients or BMI.who did not receive a transfusion was 136 g/L, while the average of thoseHb The average who didpatients of the receive who a transfusion was 128 did not receive g/L (Figurewas a transfusion 2). 136 There was g/L, a while significant the averagerelationship between of those who preoperative did receive Hb levels a transfusion and128 was theg/L probability of receiving (Figure 2). There was aa blood transfusion significant (p = 0.0001). relationship between preoperative Hb levels and the probability of receiving a blood transfusion (p = 0.0001). Figure Figure 2. Preoperative 2. Preoperative hemoglobin hemoglobin values values (g/L)(g/L) in relation in relation to the to the number number of transfused of transfused blood blood con- concentrates centrates (0–4). (0–4). 3.3. Relationship between Transfusion and Complications 3.3. Relationship between Transfusion and Complications The percentage of patients transfused among those who required reoperation was The percentage of patients transfused among those who required reoperation was 55.2%, while it was 27% for patients who did not require reoperation (Table 1). The 55.2%, while of percentage it was 27%transfused patients for patients who those among did not whorequire reoperationon were reoperated (Table in the1). The first 72 per- h due centage of patients to an alteration intransfused among the anastomosis wasthose who 60.6%, wereitreoperated while on=in0.0001) was 25.6% (p the first for72theh rest dueof to the an alteration in the2). patients (Table anastomosis Of the totalwas of 3360.6%, while patients it was 25.6% in whom (p = 0.0001)was the anastomosis for reviewed the rest of during the patients (Table 2). Of the total of 33 patients in whom the anastomosis was reviewed the first 72 h after surgery, 15 (45.5%) had either undergone a prior transfusion or during one onthethe first 72 hday same after ofsurgery, 15 (45.5%) the revision. had either Transfusions wereundergone a prior not required transfusion in 16 (48.5%) cases or one on the same day of the revision. Transfusions were not required in 16 (48.5%) and transfusions were made after doing the revision of the anastomosis in 2 patients (6%) cases and transfusions (Table 3). were made after doing the revision of the anastomosis in 2 patients (6%) (Table 3). Table 1. Relationship between blood transfusion and reoperated patients. Blood Transfusion Total No Yes No 200 (72.2%) 77 (27.8%) 277 (100.0%) Reoperation Yes 43 (44.8%) 53 (55.2%) 96 (100.0%) Total 243 (65.1%) 130 (34.9%) 37 3(100.0%) J. Clin. Med. 2021, 10, 1333 5 of 8 Table 2. Relationship between reoperations due to anastomosis failure and blood transfusion during the first 48 h. Blood Transfusion in the First 48 h Total No Yes No 253 (74.4%) 87 (25.6%) 340 (100.0%) Anastomosis failure Yes 13 (39.4%) 20 (60.6%) 33 (100.0%) Total 266 (71.3%) 107 (28.7%) 373 (100.0%) Table 3. Relationship between the day of the first transfusion and the day of the anastomosis revision. First Transfusion Total No Day Zero Day One Day Two Day zero 2 (6.1%) 0 (0%) 0 (0%) 0 (0%) 2 (6.1%) Anastomosis Day one 9 (27.3%) 2 (6.1%) 8 (24.2%) 2 (6.1%) 21 (63.6%) revision Day two 2 (6.1%) 0 (0%) 3 (9.1%) 1 (3.0%) 6 (18.2%) Day three 3 (9.1%) 0 (0%) 1 (3.0%) 0 (0%) 4 (12.1%) Total 16 (48.5%) 2 (6.1%) 12 (36.4%) 3 (9.1%) 33 (100.0%) Complete flap loss occurred 24 times (6.4%). Of the patients who suffered flap necrosis, 75% had received a transfusion, while the percentage was 32.1% for patients in whom there was no flap necrosis (Table 4). Table 4. Relationship between transfusion and flap loss. Transfusion Total No Yes No 237 (67.9%) 112 (32.1%) 349 (100%) Flap loss Yes 6 (25.0%) 18 (75.0%) 24 (100%) Total 243 (65.1%) 130 (34.9%) 373 (100%) The preoperative Hb of patients with flap loss was 125.5 g/L. The Hb of the patients who did not suffer loss of the flap was 134 g/L (p = 0.012). There was a significant relationship between the minimum perioperative Hb value and flap failure (90 g/L) and non-failure of the flap (98.4 g/L) (p = 0,012). In a multivariate analysis, the transfused patients had a 6.28 times higher risk (CI 2.91–13.55) of requiring a surgical revision related to the vascular permeability of the micro-anastomosed flap. For each transfused concentrate, the risk of requiring a surgical reoperation due to problems with the permeability of the anastomosis increased 1.39 times (CI 1.20–1.61). No relationship was established between the preoperative Hb and surgical reoperation related to vascular permeability. According to the results of a recursive partition analysis (CHAID method), three categories of patients were defined according to the transfusion needs. We considered failure at the anastomosis level as a dependent variable (Figure 3). The percentage of patients who required surgical reoperation as a consequence of a failure in the anastomosis was 4.9% for patients without transfusion (n = 243), 20.4% for patients with a transfusion of 1–3 concentrates, and 37.8% for patients with a transfusion of 4 or more concentrates. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 6 of 8 J. Clin. Med. 2021, 10, 1333 6 of 8 Recursingpartitioning Figure 3.3.Recursing Figure partitioning analysis analysis (RPA) (RPA) was was used used to create to create a regression a regression tree tree according according to reoperation to reoperation rates rates and and transfusion. transfusion. 3.4.Duration 3.4. DurationofofSurgery Surgery Theaverage The average duration duration of of surgery surgery was was9.10 9.10hh(standard (standarddeviation deviation2.3 2.3h,h, range 3.5–18 range h). 3.5–18 h). The reconstructive procedures at the level of the head and neck were those that had aa The reconstructive procedures at the level of the head and neck were those that had longer average duration (10.46 h, SD: 2.24 h), while the breast reconstructions were those longer average duration (10.46 h, SD: 2.24 h), while the breast reconstructions were those that had shorter average duration (8.52 h SD: 2 h) that had shorter average duration (8.52 h SD: 2 h) A relationship between the duration of surgery and the use of transfusions (ANOVA A relationship between the duration of surgery and the use of transfusions (ANOVA p = 0.0001) could be seen. Patients who had not received transfusions had a mean surgery p = 0.0001) could be seen. Patients who had not received transfusions had a mean surgery duration of 8.69 h while the average duration was 10.5 h in patients with four or more duration of 8.69 h while the average duration was 10.5 h in patients with four or more transfused concentrates. transfused concentrates. 4. Discussion 4. Discussion The main conclusion of the results is the existence of a significant relationship between The main conclusion the appearance of postoperativeof thecomplications results is the after existence of a significant performing relationship a microsurgical be- reconstruc- tween the appearance of postoperative complications after tion and the practice of transfusing. The percentage of patients transfused among those performing a microsurgical reconstruction and the practice who required reoperation of transfusing. was 55.2%, while it was The27% percentage for patients of who patients did nottransfused require among those who required reoperation was 55.2%, while it reoperation (Table 1). If only those reinterventions performed as a result of problems was 27% for patients whoatdid the not require level reoperation (Table of the anastomosis 1). If only are considered, those 60.6% of reinterventions the patients had performed a history ofas a result of perioperative problems transfusion at the (p =level of the 0.0001). anastomosis Equally, are considered, a significant relationship 60.6%aroseof the patients between thehad a history performance of perioperative transfusion (p = 0.0001). Equally, a significant of transfusions and complete flap loss and the consequent reconstructive failure. relationship arose betweenThe the performance of transfusions and complete flap loss and percentage of patients transfused among those in whom there was complete flap loss was the consequent reconstructive failure. The percentage 75%, while this percentage of patients went downtransfused to 32.1% among (p =those 0.0001)in whom for thethere rest of was thecomplete patients. flap The loss wasof75%, totality thesewhile this indicates findings percentage thatwenttheredown to 32.1% (p between is a relationship = 0.0001)transfusion for the restand of the patients. TheThe complications. totality majorityof these findings of authors indicates coincide that there in pointing outis how a relationship transfusion between during transfusion and complications. the perioperative The majority period of microsurgery withoffree authors coincide in flaps increases thepointing out how risk of medical or transfusion during the perioperative surgical complications and increasesperiod of microsurgery the duration of the hospitalwithstay free and flapstheincreases percentage the risk of medical of failure of theor surgical complications reconstructive procedure and increases the duration of the hospital stay [4,5,17–24]. and the percentage From the results of failure obtained, of the we reconstructive know that there procedure [4,5,17–24]. is a relationship between transfusion and From problems associated the results with the obtained, wepermeability know that there of micro-anastomoses. is a relationship betweenHowever, we cannot transfusion determine and problems to what degree associated thisthe with relationship permeability is due to the transfusion itself, of micro-anastomoses. to thewe However, reasons can- why not the transfusion determine to whatwas degreeperformed (like the is this relationship appearance due to the of anemia) or transfusion if the itself, to need the rea-for transfusion is the consequence of the alterations caused by sons why the transfusion was performed (like the appearance of anemia) or if the need for the micro-anastomosis. To define the chronological relationship between the existence transfusion is the consequence of the alterations caused by the micro-anastomosis. To de-of problems at the level of the vascular fine anastomosis and the chronological the performance relationship between of thetransfusions, existence ofthe sequence problems between at the level giving of the a transfusion vascular and surgical anastomosis and the revision of the microvascular performance of transfusions,anastomosis the sequence was analyzed. between giving Of athe 33 patients transfusion and insurgical whom arevision revisionofofthethe anastomosis anastomosis microvascular was performed, was either analyzed. a previous Of the transfusion 33 patients inhad whom beenaperformed revision ofor it anastomosis the had been done wasonperformed, the same day on which either the revision a previous trans- fusion had been performed or it had been done on the same day on which thethe was carried out in 45.5% of the cases. It is a figure that is slightly higher than 34.9% revision of patients that received some type of perioperative transfusion. In any case, we cannot J. Clin. Med. 2021, 10, 1333 7 of 8 guarantee that the realization of transfusions, especially those carried out on the same day as the surgical revision of the anastomosis, was before or after the complication for which the reoperation was carried out. Therefore, no type of causal relationship between transfusing and the appearance of complications can definitively be established. Reconstructive failure, defined as the complete loss of the flap, affected 6.4% of the patients included in our series. This percentage is in the range of those previously reported in various studies, which calculated the percentage of necrosis or removal of the flap at between 2% and 9% [4,5,13,17,18,25]. As noted above, most authors have found a correlation between the occurrence of postoperative complications or reconstructive failure and the giving of transfusions during the perioperative period [4,5,17–22,24]. Other variables related to transfusion that have demonstrated an ability to influence the appearance of postoperative complications are the number of transfused concentrates [18] and the period of storage of blood prior to transfusion [23]. There are no studies in the literature that have been designed in such a way as to determine whether the appearance of complications is the reason for the transfusion being indicated, or if it is the transfusion itself that is related to the appearance of complications, especially in what refers to the permeability of the anastomoses. It is evident, for ethical reasons, that it is not possible to carry out randomized transfusion clinical trials regardless of their requirements in patients undergoing reconstructive surgery with free flaps. The only way to evaluate the causal relationship between transfusion and the appearance of problems with the permeability of vascular micro-anastomoses would be to carry out a prospective study with the ability to determine the chronological sequence between the permeability of anastomoses and giving transfusions. 5. Conclusions Although there is a strong association between transfusion and vascular anastomosis failure, it is not possible to establish the causation between the two. Given the existing strong association, it would be convenient to avoid perioperative transfusion. The priority for microsurgeons should be to further minimize blood loss in the operating room and improve the management of perioperative anemia. To clarify the sequential relationship between transfusion and failure of anastomoses, it would be necessary to design a new, highly detailed prospective study. Author Contributions: Conceptualization, X.L.V. and L.S.-P.G.; methodology, X.L.V.; software, X.L.V. Validation, S.L.F.; formal analysis, X.L.V.; investigation, L.S.-P.G.; Resources, C.V.G.; data curation, X.L.V.; writing-original draft preparation, L.S.-P.G.; writing-review and editing, J.M.A.; visualization, M.F.G.; supervision, C.V.G. and G.P.P. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Ethical review and approval were waived for this study because the study was limited to observing events in the clinical history retrospectively without exercising any type of act or action on the patients involved. Informed Consent Statement: The study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Because of the retrospective nature of the study, no formal consent was required. Data Availability Statement: The statistical study was carried out with the SPSS 17.0 program. Conflicts of Interest: The authors declare no conflict of interest. References 1. Suominen, S.; Asko-Seljavaara, S. Free Flap Failures. Microsurgery 1995, 16, 396–399. [CrossRef] [PubMed] 2. Rao, S.S.; Parikh, P.M.; Goldstein, J.A.; Nahabedian, M.Y. Unilateral Failures in Bilateral Microvascular Breast Reconstruction. Plast. Reconstr. Surg. 2010, 126, 17–25. [CrossRef] [PubMed] J. Clin. Med. 2021, 10, 1333 8 of 8 3. Shestak, K.C.; Jones, N.F. Microsurgical Free-tissue Transfer in the Elderly Patient. Plast. Reconstr. Surg. 1991, 88, 259–263. [CrossRef] [PubMed] 4. Wong, A.K.; Joanna Nguyen, T.; Peric, M.; Shahabi, A.; Vidar, E.N.; Hwang, B.H.; Leilabadi, S.N.; Chan, L.S.; Urata, M.M. Analysis of Risk Factors Associated with Microvascular Free Flap Failure Using a Multi-institutional Database. Microsurgery 2015, 35, 6–12. [CrossRef] [PubMed] 5. Sanati-Mehrizy, P.; Massenburg, B.B.; Rozehnal, J.M.; Ingargiola, M.J.; Hernandez Rosa, J.; Taub, P.J. Risk Factors Leading to Free Flap Failure: Analysis From the National Surgical Quality Improvement Program Database. J. Craniofac. Surg. 2016, 27, 1956–1964. [CrossRef] 6. Almac, E.; Ince, C. The Impact of Storage on Red Cell Function in Blood Transfusion. Best Pract. Res. Clin. Anaesthesiol. 2007, 21, 195–208. [CrossRef] [PubMed] 7. Jia, L.; Bonaventura, C.; Bonaventura, J.; Stamler, J.S. S-nitrosohaemoglobin: A Dynamic Activity of Blood Involved in Vascular Control. Nature 1996, 380, 221–226. [CrossRef] 8. Vamvakas, E.C.; Carven, J.H. Length of Storage of Transfused Red Cells and Postoperative Morbidity in Patients Undergoing Coronary Artery Bypass Graft Surgery. Transfusion 2000, 40, 101–109. [CrossRef] 9. Luten, M.; Roerdinkholder-Stoelwinder, B.; Schaap, N.P.; de Grip, W.J.; Bos, H.J.; Bosman, G.J. Survival of Red Blood Cells after Transfusion: A Comparison between Red Cells Concentrates of Different Storage Periods. Transfusion 2008, 48, 1478–1485. [CrossRef] 10. Valeri, C.R.; Collins, F.B. The Physiologic Effect of Transfusing Preserved Red Cells with Low 2,3-diphosphoglycerate and High Affinity for Oxygen. Vox Sang. 1971, 20, 397–403. [CrossRef] 11. Hebert, P.C.; Wells, G.; Blajchman, M.A.; Marshall, J.; Martin, C.; Pagliarello, G.; Tweeddale, M.; Schweitzer, I.; Yetisir, E. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N. Engl. J. Med. 1999, 340, 409–417. [CrossRef] [PubMed] 12. Raghavan, M.; Marik, P.E. Anemia, Allogenic Blood Transfusion, and Immunomodulation in the Critically Ill. Chest 2005, 127, 295–307. [CrossRef] 13. Hill, J.B.; Patel, A.; Del Corral, G.A.; Sexton, K.W.; Ehrenfeld, J.M.; Guillamondegui, O.D.; Shack, R.B. Preoperative Anemia Predicts Thrombosis and Free Flap Failure in Microvascular Reconstruction. Ann. Plast. Surg. 2012, 69, 364–367. [CrossRef] 14. Velanovich, V.; Smith, D.J., Jr.; Robson, M.C.; Heggers, J.P. The Effect of Hemoglobin and Hematocrit Levels on Free Flap Survival. Am. Surg. 1988, 54, 659–663. [PubMed] 15. Desyatnikova, S.; Winslow, C.; Cohen, J.I.; Wax, M.K. Effect of Anemia on the Fasciocutaneous Flap Survival in a Rat Model. Laryngoscope 2001, 111, 572–575. [CrossRef] 16. Alperstein, J.B.; Levine, H.L.; Tucker, H.M. The Relationship of Hematocrit Levels to Skin Flap Survival Length in the Pig. Otolaryngol. Head Neck Surg. 1981, 89, 750–752. [CrossRef] 17. Mlodinow, A.S.; Ver Halen, J.P.; Rambachan, A.; Gaido, J.; Kim, J.Y. Anemia is not a Predictor of Free Flap Failure: A Review of NSQIP Data. Microsurgery 2013, 33, 432–438. [CrossRef] [PubMed] 18. Rossmiller, S.R.; Cannady, S.B.; Ghanem, T.A.; Wax, M.K. Transfusion Criteria in Free Flap Surgery. Otolaryngol. Head Neck Surg. 2010, 142, 359–364. [CrossRef] [PubMed] 19. Kim, B.D.; Ver Halen, J.P.; Mlodinow, A.S.; Kim, J.Y. Intraoperative Transfusion of Packed Red Blood Cells in Microvascular Free Tissue Transfer Patients: Assessment of 30-day Morbidity Using the NSQIP Dataset. J. Reconstr. Microsurg. 2014, 30, 103–114. [CrossRef] [PubMed] 20. Appleton, S.E.; Ngan, A.; Kent, B.; Morris, S.F. Risk Factors Influencing Transfusion Rates in DIEP Flap Breast Reconstruction. Plast. Reconstr. Surg. 2011, 127, 1773–1782. [CrossRef] 21. Lymperopoulos, N.S.; Sofos, S.; Constantinides, J.; Koshy, O.; Graham, K. Blood Loss and Transfusion Rates in DIEP Flap Breast Reconstruction. Introducing a New Predictor. J. Plast. Reconstr. Aesthet. Surg. 2013, 66, 1659–1664. [CrossRef] [PubMed] 22. Fischer, J.P.; Nelson, J.A.; Sieber, B.; Stransky, C.; Kovach, S.J.; Serletti, J.M.; Wu, L.C. Transfusions in Autologous Breast Reconstructions: An Analysis of Risk Factors, Complications, and Cost. Ann. Plast. Surg. 2014, 72, 566–571. [CrossRef] 23. Lee, H.K.; Kim, D.H.; Jin, U.S.; Jeon, Y.T.; Hwang, J.W.; Park, H.P. 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. Microsurgery 2014, 34, 434–438. [CrossRef] [PubMed] 24. Leon, X.; Quer, M.; Luz Maestre, M.; Burgues, J.; Muniz, E.; Madoz, P. Blood Transfusions in Laryngeal Cancer: Effect on Prognosis. Head Neck 1996, 18, 218–224. [CrossRef] 25. Rosado, P.; Cheng, H.T.; Wu, C.M.; Wei, F.C. Influence of Diabetes Mellitus on Postoperative Complications and Failure in Head and Neck Free Flap Reconstruction: A Systematic Review and Meta-analysis. Head Neck 2015, 37, 615–618. [CrossRef]