Allogeneic blood transfusion is associated with well-known complications, including increased risk for infection, transfusion-associated circulatory overload, immune suppression, transfusion-related acute lung injury, transmission of infectious agents, and others.1 Furthermore, increasing demands and reduced voluntary donation often results in shortage of allogeneic blood.2 There are several proposed strategies for reducing the need for allogeneic blood transfusion, including preoperative acute normovolemic hemodilution (PANH).3,4 By reducing the red cell mass of blood loss due to surgical bleeding followed by the retransfusion of the previously withdrawn blood at the conclusion of surgery, PANH is thought to reduce the need for allogeneic blood transfusion while maintaining postoperative hemoglobin level. Meta-analyses that have addressed the effectiveness of PANH are now >10 years old,5,6 and more recent studies have suggested an inconsistent effect of this strategy.7–9 We therefore conducted a systematic review and meta-analysis to evaluate the efficacy of PANH for reducing allogeneic blood transfusion.
The Medline, Excerpta Medica Database (EMBASE), ISI Web of Knowledge, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched electronically using the following key words: “hemodilution,” “autotransfusion,” “hemorrhage,” and “blood loss.” Search strategies are found in the Appendix 1 (Supplemental Digital Content 1, http://links.lww.com/AA/B222). Potentially eligible studies were also identified through a manual search of the references and citations in the articles retrieved for full review. The searches were last updated in March 2015.
All clinical trials that used a randomized and controlled study design and assessed the reduced need for allogeneic blood transfusion benefits of PANH compared with no PANH during the perioperative period were included. Two authors initially reviewed the titles and abstracts to exclude irrelevant studies and subsequently screened the studies through a detailed review of the full-text article to determine eligibility. Controversies were resolved by consensus with a third author.
Two authors independently extracted data from the full-text article of each included study using a standardized data collection form (Table 1). The primary outcomes for the current review were the number of patients undergoing allogeneic blood transfusion, the volume of allogeneic red blood cell (RBC) transfusion, and the volume of blood loss. The secondary outcomes were adverse events (e.g., mortality, reoperation for bleeding, deep vein thrombosis, pulmonary embolus, stroke, myocardial ischemia/infarction, and renal dysfunction) and length of hospital stay. If necessary, authors were contacted to obtain further data.
Quality Assessment of Studies
A quality assessment was independently performed by 2 authors using an established tool, the Jadad scale, to assess the methodological quality of clinical trials.10 This scale included the method of randomization (2 points), double-blinding (2 points), and the description of dropouts (1 point) (Supplemental Digital Content 2, Supplemental Appendix 2, http://links.lww.com/AA/B223). Discrepancies were resolved by consensus with a third author.
All calculations were performed using STATA Software version 11.0 (StataCorp LP, College Station, TX). Dichotomous and continuous data were expressed as the relative risk (RR) and weighted mean difference (WMD) with 95% confidence intervals (CIs), respectively. We used WMD to pool the results as all included studies measured outcomes on the same scale and data with zero were excluded. Data were first pooled using a fixed-effect model. The random effects model was subsequently used when between-study heterogeneity was obvious (I2 > 50%, P ≤ 0.05). Heterogeneity was tested using the I2 statistic and the χ2 test, with values >50% and P ≤ 0.05 indicating significant heterogeneity, respectively.11 If the heterogeneity was strong, subgroup analyses and meta-regression analyses were used to identify the sources of heterogeneity. Sensitivity analyses were performed to assess the contributions of a single study to the pooled results. Publication bias was assessed using a funnel plot when the number of studies was >10.12 If bias was suspected, the meta-trim method was used to re-estimate the effect size.
Our search strategy identified 5440 potentially relevant studies. After a number of studies were excluded, 63 studies involving a total of 3819 patients were finally included in this meta-analysis (Fig. 1).7–9,13–68 The characteristics of these studies and quality scores are presented in Table 1 (see more detail in Supplemental Digital Content 3, Supplemental Table 1, http://links.lww.com/AA/B224).
Risk of Perioperative Allogeneic Blood Transfusion
Of the 63 included studies, 37 (n = 2711) compared the efficacy of PANH versus a control group to evaluate the risk of allogeneic blood transfusion during the perioperative period.7–9,13,17–19,23,25,27–30,32–37,39–41,43–46,48–50,55,58,61,63,64,66 These 37 studies found that the number of allogeneic blood transfusion was significantly reduced in the PANH group versus the control group (RR, 0.74; 95% CI, 0.63 to 0.88; P = 0.0006). These results are summarized in the forest plot in Figure 2. Moreover, our results demonstrated that the use of PANH was associated with a fewer allogeneic blood transfusion during the intraoperative (RR, 0.54; 95% CI, 0.38 to 0.78; P = 0.0009; Supplemental Digital Content 4, Supplemental Figure 1, http://links.lww.com/AA/B225) and postoperative (RR, 0.61; 95% CI, 0.43 to 0.87; P = 0.007; Supplemental Digital Content 5, Supplemental Figure 2, http://links.lww.com/AA/B226) periods.
Sensitivity analyses were performed to determine the effects of omitting a single study on the overall effect. The omission of a single study using the random method did not change the overall RR of perioperative allogeneic blood transfusion; the overall RR was changed from 0.72 (95% CI, 0.61 to 0.86; P = 0.0003) to 0.78 (95% CI, 0.67 to 0.91; P = 0.001; Supplemental Digital Content 6, Supplemental Table 2, http://links.lww.com/AA/B227).
Subgroup Analysis and Meta-Regression
Because the heterogeneity among studies was significant (I2 = 79.6%, χ2 = 151.95, P < 0.0001; Fig. 2), subgroup analyses and meta-regression were performed to identify the sources of the heterogeneity. The results of the subgroup analyses revealed that the type of surgery, the presence or absence of a transfusion protocol, and the volume of withdrawn blood could not explain the heterogeneity; thus, heterogeneity persisted in the included studies (Supplemental Digital Content 7, Supplemental Table 3, http://links.lww.com/AA/B228). We then performed further analyses using the meta-regression method. Similarly, the results of meta-regression could not identify the sources of the heterogeneity. Factors such as the type of surgery, the presence or absence of a transfusion protocol, the volume of withdrawn blood, the type of fluid for replacing the withdrawn blood, the presence or absence of other active interventions, the quality of the study, the year of publication, the sample size, and the mean age did not appear to be the source of the observed heterogeneity (Supplemental Digital Content 8, Supplemental Table 4, http://links.lww.com/AA/B229).
Publication Bias Analysis
A funnel plot of the risk of perioperative allogeneic blood transfusion revealed that 6 studies exceeded the 95% confidence limits (Supplemental Digital Content 9, Supplemental Figure 3, http://links.lww.com/AA/B230). The Egger regression asymmetry test yielded a significant publication bias (P = 0.001). To produce a more robust estimation, trim and fill tests were performed using the random effects model. Two virtual studies were filled, and the overall RR of the trim and fill method was 0.77 (95% CI, 2.57 to 8.49; P = 0.001). The overall RR was slightly higher than that of the crude meta-analysis (RR, 0.74; 95% CI, 0.63 to 0.88; P = 0.0006) but was still significant.
Units of Perioperative Allogeneic RBC Transfusion
Of the included studies, 31 (n = 1781) compared the effect of PANH versus control on the units of perioperative allogeneic RBC transfusion.8,9,16,23,25,27,28,30,33,38–47,49,50,55,60–63,65 These 31 studies revealed that the units of perioperative allogeneic RBC transfusion was significantly decreased in the PANH group compared with the control group (WMD, −0.94 units; 95% CI, −1.27 to −0.61 units; P < 0.0001). The results are presented in the forest plot in Figure 3. We further analyzed the volume of intraoperative and postoperative allogeneic RBC transfusion; the results revealed that the volume of allogeneic RBC transfusion was reduced in the PANH group versus the control group during the intraoperative period (WMD, −0.76 units; 95% CI, −1.22 to −0.30 units; P = 0.001; Supplemental Digital Content 10, Supplemental Figure 4, http://links.lww.com/AA/B231) but not in the postoperative period (WMD, −0.73 units, 95% CI, −1.63 to 0.17 units; P = 0.11; Supplemental Digital Content 11, Supplemental Figure 5, http://links.lww.com/AA/B232).
The results of the sensitivity analyses showed that omission of a single study did not change the overall WMD of the units of perioperative allogeneic RBC transfusion; the overall WMD was changed from −0.86 units (95% CI, −1.18 to −0.53 units, P < 0.0001) to −1.04 units (95% CI, −1.37 to −0.72 units, P < 0.0001; Supplemental Digital Content 12, Supplemental Table 5, http://links.lww.com/AA/B233).
Subgroup Analysis and Meta-Regression
The heterogeneity among studies with respect to the units of perioperative allogeneic RBC transfusion was strong (I2 = 95.3%, χ2 = 574.28, P < 0.0001; Fig. 3); thus, subgroup analyses and meta-regression were performed. The results of subgroup analyses revealed that the type of surgery, the presence or absence of a transfusion protocol, and the volume of withdrawn blood could not explain the heterogeneity; thus, heterogeneity persisted in the included studies (Supplemental Digital Content 13, Supplemental Table 6, http://links.lww.com/AA/B234). We then performed a meta-regression analysis. Similarly, the results of the meta-regression could not identify the sources of the heterogeneity, which indicates that the factors included in the analysis of meta-regression were not the sources of the observed heterogeneity (Supplemental Digital Content 14, Supplemental Table 7, http://links.lww.com/AA/B235).
Publication Bias Analysis
A funnel plot of the overall volume of perioperative allogeneic RBC transfusion revealed that half of the included studies (14/28) exceeded the 95% confidence limits (Supplemental Digital Content 15, Supplemental Figure 6, http://links.lww.com/AA/B236). The Egger regression asymmetry test identified a significant publication bias (P = 0.009). The included smaller studies tended to report greater benefits of PANH. Trim and fill analysis was performed, and 6 virtual studies were filled. The overall WMD of the trim and fill method was 0.30 units (95% CI, 0.21 to 0.45 units, P < 0.0001), and this overall WMD was significantly different from that of the crude meta-analysis (−0.94 units, 95% CI, −1.27 to −0.61 units, P < 0.0001). This finding raises concerns over the true efficacy of PANH in reducing the overall volume of perioperative RBC transfusion.
Volume of Perioperative Blood Loss
Eight studies (n = 317) compared the effectiveness of PANH versus a control group with respect to the overall volume of perioperative blood loss.14,21,30,40,47,62,65 These studies revealed that the overall volume of perioperative blood loss was similar in the PANH group and the control group (WMD, 21.98 mL; 95% CI, −46.90 to 90.86 mL; P = 0.53). These results are presented in the forest plot in Figure 4. Our results further revealed that the volume of blood loss was significantly reduced in the PANH group versus the control group during the postoperative period (WMD, −120.72 mL; 95% CI, −167.10 to −74.34 mL; P < 0.0001; Supplemental Digital Content 16, Supplemental Figure 8, http://links.lww.com/AA/B237) but not during the intraoperative period (WMD, −12.18 mL, 95% CI, −63.35 to 38.99 mL, P = 0.64; Supplemental Digital Content 17, Supplemental Figure 7, http://links.lww.com/AA/B238).
Sensitivity analyses revealed that omission of a single study did not change the overall WMD of the volume of perioperative blood loss; the overall WMD was changed from −6.05 mL (95% CI, −78.57 to 66.47 mL, P = 0.87) to 78.69 mL (95% CI, −26.28 to 183.65 mL, P = 0.43; Supplemental Digital Content 18, Supplemental Table 8, http://links.lww.com/AA/B239).
Subgroup Analysis and Meta-Regression
Heterogeneity among studies with respect to the overall volume of perioperative allogeneic RBC transfusion was not obvious (I2 = 31.8%, χ2 = 10.27, P = 0.174; Fig. 4). Therefore, subgroup analyses and meta-regression were not performed.
Publication Bias Analysis
Because the number of included studies was <10,12 we did not perform publication bias analysis.
The pooled RRs for the adverse events are presented in Table 2. Adverse events (e.g., mortality, reoperation for bleeding, deep vein thrombosis, pulmonary embolus, stroke, myocardial ischemia/infarction, and renal dysfunction) did not differ significantly between the PANH group and the control group. However, the risk of any infection was inclined to reduce in the PANH group versus the control group (RR, 0.64; 95% CI, 0.42 to 0.97; P = 0.037).
Length of Hospitalization
Seven studies (n = 263) compared the length of hospitalization for patients with or without PANH.17,30,37,41,61,62 The length of hospitalization was similar in the PANH group and the control group, and the pooled WMD value for the hospital length of stay is presented in Table 2.
The perioperative use of PANH is based on the principle of reducing the red cell mass of blood loss into the surgical field by euvolemic removal of the patient’s blood before surgery.19,39,69 The return of the patient’s collected blood at the conclusion of surgery should restore hemoglobin levels and augment coagulation factor and platelet concentrations, reducing bleeding and the need for allogeneic blood transfusion.70,71 In this meta-analysis of 63 randomized controlled trials (3819 patients), we showed that PANH significantly lowered the risk of allogeneic blood transfusion and the volume of allogeneic RBC transfused compared with the control group. However, blood loss, adverse events, and the length of hospitalization were comparable between these groups.
Evidence of Benefit
Although PANH is commonly used during the perioperative period, the true efficacy of PANH in reducing perioperative allogeneic blood transfusion continues to be debated. Two previous meta-analyses reported no definite benefit of PANH for reducing perioperative allogeneic blood transfusion.5,6 More recent studies have found inconsistent effects of PANH as a strategy for reducing the need for perioperative allogeneic blood transfusion compared with controls. On the basis of the current evidence, PANH appears to reduce exposure to allogeneic blood by 26% (RR, 0.74; 95% CI, 0.63 to 0.88; P = 0.0006). Furthermore, the volume of allogeneic blood transfused in the PANH groups was lower than that transfused in the control groups, by approximately 1 unit (WMD, −0.94 units; 95% CI, −1.27 to −0.61 units; P < 0.0001). Nevertheless, the results were heterogeneous across studies (I2 = 79.6%, χ2 = 151.95, P < 0.0001; I2 = 95.3%, χ2 = 574.28, P < 0.0001, respectively). In the present study, we considered a number of factors that might explain variation in the benefits of PANH. These factors included the type of surgery, the presence or absence of a transfusion protocol, the volume of withdrawn blood, the type of fluid for replacing the withdrawn blood, the presence or absence of other active interventions, the quality of the study, the year of publication, the sample size, and the mean age of the patients. However, none of the subgroup analyses or meta-regression analyses performed established a clear reason for the observed heterogeneous results (Supplemental Digital Content 7, Supplemental Digital Content 8, Supplemental Digital Content 13, Supplemental Digital Content 14, Supplemental Tables 3, 4, 6, and 7, http://links.lww.com/AA/B228, http://links.lww.com/AA/B229, http://links.lww.com/AA/B234, http://links.lww.com/AA/B235). We speculate that these analyses were hampered by the small number of trials included in some subgroups. In our analysis, 14 of 37 trials were conducted in patients undergoing cardiac surgery,8,9,18,19,23,35–37,44,45,50,61,63,64 whereas only 1 trial was conducted in patients undergoing noncardiac thoracic surgery.51 Stratification of the data by the type of surgery provided only limited information. Nevertheless, other factors also potentially contributed to the heterogeneous. Mathematical modelings have previously shown that the benefits of PANH for reducing allogeneic transfusion are dependent on the volume of intraoperative blood loss.72 Thus, PANH is effective in reducing allogeneic blood loss transfusion only when blood loss is 1 L or when it exceeds 20% of the patients’ blood volume. Furthermore, the use of a restrictive transfusion threshold may limit the clinical justification for PANH.73
Most trials that have evaluated PANH are small and likely underpowered to evaluate all end points, particularly safety and health resource utilization end points. Reliance on small trials further raises concerns about the effects of publication bias (as small positive trials are more likely to be published than small negative trials), as well as other concerns.74 Funnel plot assessment revealed some evidence of publication bias in the form of a “missing” population of small negative trials (Supplemental Digital Content 9 and Supplemental Digital Content 15, Supplemental Figures 3 and 6, http://links.lww.com/AA/B230 and http://links.lww.com/AA/B236). To produce a more robust estimation, trim and fill tests were performed, and the units of perioperative allogeneic RBC transfusion were different from those obtained in the crude meta-analysis (WMD, 0.30 units; 95% CI, 0.21 to 0.45 units; P < 0.0001 versus WMD, −0.94 units, 95% CI, −1.27 to −0.61 units; P < 0.0001). As the presence of publication bias may lead to an overestimation of benefit of PANH, the results should be evaluated with some degree of caution.
Given the heterogeneous outcomes across studies and the publication bias, this benefit of PANH that we report can only be considered an approximation.
Safety of PANH
In our analysis, there were no significant differences between the PANH group and the control group in the occurrence of adverse events such as mortality, reoperation for bleeding, deep vein thrombosis, pulmonary embolus, stroke, myocardial ischemia/infarction, renal dysfunction, and length of hospitalization, with the exception of infection (Table 2). We found that the risk of any infection tended to be lower in the PANH group versus the control group (RR, 0.64; 95% CI, 0.42 to 0.97, P = 0.037). However, the rate of adverse events presented here was small. Therefore, it is difficult to draw firm conclusions regarding the impact of PANH on important clinical outcomes.
There are some limitations of this meta-analysis. First, the source data were drawn from diverse surgical procedures and settings, leading to considerable heterogeneity, which made it difficult to compare the studies. This is confirmed by the fact that in the subgroup analyses and meta-regression, none of the investigated factors reduced the heterogeneity between studies. Second, the number of eligible trials was small; thus, statistical power was low, and results were likely biased. In the Egger regression asymmetry test, obvious publication biases were detected in the results of the risk perioperative allogeneic blood transfusion and volume of perioperative allogeneic RBC transfusion. This may lead to an overestimation of benefit of PANH. Third, most of the studies reviewed did not present data for the magnitude of hemodilution, transfusion triggers, the presence or absence of restrictive transfusion threshold, or the blood loss volume. The contribution of these factors to the marked observed heterogeneity is not explored in the present meta-analysis. Finally, the rates of adverse events were low, and the sample size of most reviewed studies was small. Thus, it is difficult to draw firm conclusions regarding the safety of PANH.
Although these results suggest that PANH is effective in reducing allogeneic blood transfusion, we identified significant heterogeneity and publication bias, which raises concerns about the true efficacy of PANH. The safety and cost-effectiveness of PANH has not been adequately addressed. Large, methodologically rigorous, controlled trials to assess the relative efficacy, safety, and cost-effectiveness of PANH in different surgical procedures are needed.
Name: Xuelong Zhou, MD.
Contribution: This author undertook the search, selection, extraction, data analysis, and wrote the initial manuscript.
Attestation: Xuelong Zhou approved the final manuscript.
Name: Chenjing Zhang, MD.
Contribution: This author undertook the search, extraction, and wrote the initial manuscript.
Attestation: Chenjing Zhang approved the final manuscript.
Name: Yin Wang, MD.
Contribution: This author undertook the search, selection, extraction, and data analysis.
Attestation: Yin Wang approved the final manuscript.
Name: Lina Yu, MD.
Contribution: This author undertook the data analysis and helped with the manuscript preparation.
Attestation: Lina Yu approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Min Yan, MD.
Contribution: This author undertook the data analysis and helped with the manuscript preparation.
Attestation: Min Yan approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript. Min Yan is the archival author.
This manuscript was handled by: Charles W. Hogue, MD.
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