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ECONOMICS, EDUCATION, AND HEALTH SYSTEMS RESEARCH

Perioperative Blood Transfusions and Delayed Wound Healing After Hip Replacement Surgery: Effects on Duration of Hospitalization

Eric W. G. Weber, MD^*, Robert Slappendel, MD, PhD, Martin H. Prins, MD, PhD, Dick B. van der Schaaf, MD, Marcel E. Durieux, MD, PhD^*||, and Danja Strümper, MD^*¶

Departments of *Anesthesiology and Clinical Epidemiology, University Hospital Maastricht, Maastricht, The Netherlands; Departments of Anesthesiology and Orthopedic Surgery, St. Maartens Hospital, Nijmegen, The Netherlands; ||Department of Anesthesiology, University of Virginia, Charlottesville, Virginia; and ¶Department of Anesthesiology, University Hospital Münster, Münster, Germany

Address correspondence and reprint requests to Eric W. G. Weber, MD, University Hospital Maastricht, PO Box 5800, NL-6202 AZ Maastricht, The Netherlands. Address e-mail to eweber{at}knmg.nl.

	Abstract

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Patients who receive allogeneic blood transfusions after orthopedic surgery have a longer duration of hospitalization, and this cannot be explained by a more frequent incidence of infections in transfused patients. To determine whether transfusion of allogeneic blood interferes with wound healing and therefore increases the duration of hospitalization, we performed an observational study in 444 consecutive patients scheduled for elective primary hip surgery. Transfusion, wound, and infection variables were collected at five time points during treatment. Of the 444 consecutive patients studied, 92 received blood transfusions during their perioperative course. Thirty-one percent of transfused patients developed wound-healing disturbances versus 18% of the nontransfused group (P < 0.05); allogeneic blood transfusion was the only significant predictor for development of minor wound-healing disturbances. Duration of hospitalization was prolonged in transfused patients (12.3 versus 9.8 days) and could be predicted by 4 significant variables: requirement for blood transfusion (adds 2.7 ± 0.5 days), presence of wound-healing disturbances (adds 1.3 ± 0.5 days), duration of surgery (adds 0.2 ± 0.1 days/10 min), and patient's age (adds 0.9 ± 0.2 days/10 yr). These data suggest that allogeneic blood transfusion is associated with an increased incidence of wound-healing disturbances and that prevention of allogeneic blood transfusion may be relevant in limiting the duration of admission after elective orthopedic surgery.

	Introduction

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Perioperative blood loss is still a major problem in elective orthopedic surgery. Allogeneic blood transfusion is the standard approach to treat potentially detrimental decreases in hemoglobin (Hb) concentration. However, allogeneic blood transfusion is associated with various adverse events, including febrile reactions induced by leukoagglutinins and transmission of infectious diseases (1,2). Moreover, allogeneic blood transfusion has an immunomodulatory effect, which is thought to increase the frequency of postoperative infections (3–6).

Nonetheless, the clinical observation that patients who receive any allogeneic blood transfusion after major orthopedic surgery stay in the hospital significantly longer is undisputed (7). Because postoperative infections are relatively rare (1%–3%) and because the role of allogeneic blood transfusion is not yet established (8), other factors are likely to be responsible for the prolonged hospital stay. A host of other factors (age, length of surgery, use of implants, and so on) might influence the incidence of postoperative infections as well, and, in addition, the end-point of frank wound infection may not be appropriate. Less severe types of wound-healing disturbances could occur after transfusion and lead to subsequent complications or prolonged hospitalization. To address these issues, we undertook this prospective observational study. In 444 patients who underwent elective total hip arthroplasty, we studied (among other variables) the frequency of allogeneic blood transfusion, wound-healing disturbances, superficial and deep wound infections, and length of hospital admission.

	Methods

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We performed an observational study in 444 consecutive patients hospitalized to undergo total hip replacement in the St. Maartens Hospital, Nijmegen, The Netherlands, from October 29, 1998, to October 27, 1999. The hospital's IRB approved the study, and all patients gave written informed consent after having received information and an explanation of the study. Inclusion criteria included planned elective primary total hip arthroplasty, at least 18 yr of age, living in The Netherlands, or otherwise available for follow-up for at least 6 wk postsurgery. Exclusion criteria were any infection of any body system at screening, as determined by symptoms or erythrocyte sedimentation rate (ESR) >20 mm (unless known to be preexistent); any blood transfusion received within 6 wk before surgery; and any other operation within 6 wk before surgery. Patients who donated autologous blood before surgery were excluded from the study. Five patients refused to participate.

During admission, patients received standard care according to hospital protocol. Transfusions of packed red blood cells were administered according to the following transfusion triggers: Hb <8.1 g/dL (5.0 mmol/L) during surgery and until 4 h postsurgery and Hb <8.9 g/dL (5.5 mmol/L) more than 4 h postsurgery. For subjects with cardiovascular disease, all transfusion triggers were increased by 0.8 g/dL (0.5 mmol/L). Packed red blood cells were supplied by the local blood bank and consisted of buffy coat-depleted red cells, mean volume 320 mL, Hb 17.8 g/dL, hematocrit 0.58, and leukocytes 0.4 x 10⁹/L.

All patients were treated equally according to standard protocol by using active body warming and so on. Therefore, fraction of inspired oxygen, body temperature, and so on were comparable between groups. Furthermore, because of the length of the study period, the group of surgeons was very limited, and their distribution was comparable between groups.

Data were collected at five time points during treatment: 1) last week before surgery (screening), 2) on the day of surgery (postoperative day [POD] 0), 3) 1 day after surgery (POD 1), 4) 4 days after surgery (POD 4), and 5) at discharge. At all these time points, we recorded vital signs, any signs of infection present, and other relevant variables. In addition, the following data were collected at specific time points. At screening, informed consent, medical history, physical examination, use of antibiotics, and transfusion information over the past 3 mo (including pretransfusion Hb, volume and type of product transfused, and routine clinical laboratory tests, including at least Hb, ESR, white blood cell count and differential, serum prealbumin, and C-reactive protein) were collected. At POD 0, all routine clinical postoperative assessments, name of the surgeon, and Hb level were collected. At POD 1, blood loss, transfusion data (including units and type of blood products given and Hb before transfusion), any blood-saving techniques used, and medications used were collected. At POD 4, serum prealbumin and pretransfusion Hb (only if transfused) were collected. At discharge, blood loss, transfusion data (number of units and type of blood products), and length of hospitalization were collected.

In addition, during and after surgery until discharge, all relevant medical events were documented in a checkbox database, including infections, wound leakage, superficial wound disturbances, and hematomas. Wounds were examined daily by orthopedic surgeons, who were trained to the assessment protocol but not blinded to the transfusion. Wound and urinary tract infections were defined by the presence of a positive culture. Classification of infection as "deep" required joint involvement. Wound-healing disturbance was defined by erythematous inflammation of >1 cm, wound fluid discharge, purulent suture, wound dehiscence, blister, or any degree of wound necrosis. Moreover, certain events were recorded at any moment during the follow-up period: postoperative infections, withdrawal from the study (including the reason for withdrawal), and death (including cause of death).

Descriptive statistics were used when appropriate. The occurrence of wound disturbances in relation to receiving blood transfusion and other potentially related factors were calculated with logistic regression analysis. For this purpose, use of transfusion and gentamycin cement were coded as binary variables (yes or no); other factors were handled as continuous variables.

First the effect of each variable was calculated with univariate analysis. Then, by using stepwise conditional backward and forward selection of variables, multivariate analysis was performed. The effect of variables on the duration of hospitalization was calculated with linear regression analysis. For this purpose, the duration of hospitalization was log-normalized. A similar univariate and multivariate analysis approach was used.

	Results

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Of the 444 consecutive patients studied, 92 received blood transfusions during their perioperative course (Table 1). Comorbidities and drugs, which were included in the model but did not reach significance, are listed in Table 2. There were significant differences between groups in sex distribution, height, weight, preoperative Hb, ESR and prealbumin levels, operation duration, perioperative blood loss, total blood loss, and duration of hospitalization. Of these, the differences in preoperative ESR, prealbumin levels, and length were considered to be so small as to be clinically insignificant. As expected, there were no significant differences in the rate of positive wound cultures or the incidence of deep infection (1% in each group). Nonetheless, the clear trend for an increased incidence of positive cultures (2.0% in the nontransfused group versus 3.3% in the transfused group) suggested that a more detailed analysis of wound-healing disturbances would be warranted.

Comparing the incidence of wound disturbances between groups, we found a clear difference: 31% of the transfused group developed a wound disturbance versus 18% of the nontransfused group (P < 0.05; Fig. 1). To determine whether the amount of perioperative blood loss affected this relationship, we divided the group into 3 subgroups: blood loss of 0–700 mL, 701–1000 mL, or >1000 mL. For each of these subgroups, we observed essentially the same proportion in the incidence of wound disturbances as was found for the groups as a whole (Fig. 1). However, because the study was not powered for this analysis, the correlation between transfusions and wound disturbances did not reach significance in these subgroups.

View larger version (28K): [in this window] [in a new window]   Figure 1. Percentages of wound-healing disturbances in transfused and nontransfused patients. Patients were divided into 3 subgroups: perioperative blood loss of 0–700 mL (Group I), 701–1000 mL (Group II), or more than 1000 mL (Group III). *P < 0.05.

As a group, transfused patients stayed in the hospital significantly longer than nontransfused patients (9.8 versus 12.3 days; P < 0.001). In addition, the differences in hospitalization duration suggest a potential major economic effect. However, many factors can affect this important but broad outcome measure. We therefore determined whether the duration of hospitalization was affected by the amount of perioperative blood loss per se. As indicated in Figure 2, when the patients were subdivided by amount of perioperative blood loss, we observed 1) that duration of hospitalization was essentially unaffected by blood loss and 2) that a similar difference in hospitalization duration between transfused and nontransfused patients was maintained among the subgroups. Indeed, although the study was not powered to detect significant differences in this subanalysis, the difference between transfused and nontransfused patients did reach significance in patients who lost more than 700 mL of blood perioperatively.

View larger version (35K): [in this window] [in a new window]   Figure 2. Length of hospital admission in transfused versus nontransfused patients, divided into subgroups according to perioperative blood loss volume: 0–700 mL (Group I), 701–1000 mL (Group II), or more than 1000 mL (Group III). *P < 0.05.

To analyze the effects of other factors, such as sex, height, weight, and preoperative Hb, more formally, we performed univariate and multivariate analysis across these factors and determined which of the variables best predicts the development of postoperative wound-healing disturbances (Table 3). With univariate analysis, blood transfusion was clearly the main factor associated (odds ratio, 2.1) with wound-healing disturbances. With stepwise modeling using multivariate analysis, blood transfusion appeared to be the only statistically significant variable in this model.

We developed a regression model to predict duration of hospital stay from the factors analyzed in this study. Duration of stay could be predicted by four significant variables (Table 4): requirement for blood transfusion, presence of wound disturbances, duration of operation, and patient age. Whereas each 10 additional years of age adds 0.9 ± 0.16 days to hospital stay and each 10 min of additional operation duration adds 0.2 ± 0.08 days to hospital stay, the effects of wound disturbance and transfusion are much more pronounced. The presence of wound disturbances adds 1.25 ± 0.45 days, and the requirement for transfusion adds 2.71 ± 0.47 days to hospital duration.

	Discussion

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The deleterious clinical effects of perioperative allogeneic blood transfusion in elective orthopedic surgery are well established (7,9,10). However, the precise impact and mechanisms of these effects are much less clear. Allogeneic blood transfusion may increase postoperative infections through immunomodulation. To test this hypothesis, numerous observational studies have investigated rates of cancer recurrence (4,5) and postoperative infections in patients who had received perioperative allogeneic blood transfusion (3–6). These studies, however, have produced conflicting results. Controlled trials on this subject have also not resolved the issue (11–18). Because the bulk of these studies involve patients undergoing gastrointestinal surgery, the role of allogeneic blood transfusion in the development of adverse effects is even more unclear in elective orthopedic surgery patients.

In this prospective observational study, we found that allogeneic blood transfusion is associated with prolonged hospital admission. We found that this prolonged admission is not a straightforward consequence of an increased postoperative infection rate. Deep infections (which have frequent morbidity) (19) occurred at similar rates in both transfused and nontransfused patients. Other infections tended to be increased in the transfused group, but this did not reach statistical significance. The requirement for blood transfusion was not the only difference between the two study groups, and some of these other significant factors may also have been responsible in part for the increased incidence of wound disturbances. However, many of the factors that showed significant differences between transfused and nontransfused patients can be logically linked to red cell loss and, thereby, to transfusion requirement. For example, male sex, greater height and weight, and a higher preoperative Hb (>8 mmol/L) are all associated with a larger red cell mass, and these patients will therefore tolerate more red cell loss before transfusion triggers are reached. Similarly, a longer operation and larger blood loss are logically correlated with transfusion incidence. However, allogeneic blood transfusion was the sole significant predictor of the development of wound-healing disturbances, and together these two factors were the main predictors of prolonged hospitalization (Fig. 1). No significant influence on wound-healing disturbance and hospitalization was found, either by univariate or multivariate analysis, of age, sex, height, weight, operation duration, blood loss, or the use of gentamycin cement.

Because this was an observational study, the mechanism by which wound-healing disturbances and length of hospital stay are related was not studied in detail. A direct effect of tissue hypoxia as a consequence of decreased Hb seems unlikely. The effect (both on wound disturbances and on hospital admission duration) was evenly distributed among three subgroups with varying volumes of blood loss (Fig. 1). Frank anemia can delay wound healing in experimental animals (20,21), but this did not play a role in our patient series. It is conceivable that subclinical bacterial infection is responsible for disturbed wound healing, but then one would expect to find a concomitantly increased body temperature. An alternative explanation might be that allogeneic blood transfusion induces a small but significant delay in wound healing. Experimental studies have shown that the immunomodulatory effects of allogeneic blood transfusion (22) might lead to a decrease in proangiogenic factors that are essential for wound healing, such as interleukin 8 (23).

Although the nature of the observed wound disturbances remains unclear and warrants further investigation, our data demonstrate an association of allogeneic blood transfusion and duration of hospitalization after elective orthopedic surgery. If this is indeed the case, it amplifies the importance of measures to prevent perioperative blood loss, cell-saving techniques, and methods to enhance preoperative Hb (such as erythropoietin) (24).

	Footnotes

 
Accepted for publication October 29, 2004.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999