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Acute Normovolemic Hemodilution Reduces Allogeneic Red Blood Cell Transfusion in Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Trials

Barile, Luigi MD*†; Fominskiy, Evgeny MD, PhD; Di Tomasso, Nora MD*; Alpìzar Castro, Ligia Elena MD§; Landoni, Giovanni MD*†; De Luca, Monica MD*; Bignami, Elena MD*; Sala, Alessandra MD; Zangrillo, Alberto MD*†; Monaco, Fabrizio MD*

Author Information
doi: 10.1213/ANE.0000000000001609

In cardiac surgery, postoperative bleeding is one of the most relevant complications and, within a national blood supply range, it accounts for 15% to 20% of total transfusion requests. Allogeneic blood transfusions are associated with a worse short- and long-term outcome.1,2 Most of the transfusions are represented by red blood cell units (RBCu), and, for each unit transfused, there is an additive risk of mortality and cardiac adverse events.3–5 Careful control of major bleeding and management of blood losses can reduce the proportion of transfused patients and the number of surgical reinterventions.6 Despite current guideline indications and despite numerous approaches to reduce bleeding and to reduce hemoglobin transfusion threshold, >50% of the patients undergoing cardiac surgery receive transfusions.7–9 This calls for different approaches, and acute normovolemic hemodilution (ANH) could be a valid alternative. However, doubts remain as to whether ANH is capable of reducing the need for allogeneic blood and for exerting a positive effect on morbidity and mortality.

ANH is performed by drawing a specific amount of blood volume from the patient, hydrating the patient to maintain isovolemia, storing patient’s blood in storing bags at room temperature with anticoagulants, and readministering it during surgery, usually after cardiopulmonary bypass (CPB) or according to the patient’s need. The beneficial effects of ANH are reduced risk of adverse reactions related to transfusion of allogeneic blood products, preservation of erythrocytes from CPB damage, enhancing coagulation with the possibility of readministering the patient’s whole blood containing clotting factors and platelets, and improved perfusion during CPB through a decrease of blood viscosity resulting in an increased tissue oxygen delivery above the critical anaerobic threshold.10,11 ANH also is a simple and low-cost procedure, with no evidence of coagulation, hemolysis, fibrinolysis, or immunological activity in the collected blood.11

Cardiac surgery can be the ideal setting for ANH.13,14 In fact, administering fresh whole blood after CPB allows prevention of the alteration induced by heparin administration, cardiotomy suction, and cellular activation during CPB, which typically results in hemolysis, platelet activation and consumption, complement activation, and stimulation of the inflammatory cascade.15–17 Furthermore, a reduction in blood viscosity during CPB seems to improve blood flow through stenotic and collateral vessels of the myocardium and counteracts the reduced blood oxygen–carrying capacity because of hemodilution.18,19

Our study is the first meta-analysis of randomized controlled trials (RCTs) conducted in adult patients undergoing any type of cardiac surgery aimed at comparing the intraoperative use of ANH versus control patients treated according to standard intraoperative care.


Search Strategies

A systematic review using PubMed/MEDLINE, Cochrane Controlled Trials Register, and EMBASE was performed by 4 trained investigators.20 Additional studies were identified by manual research of references identified from original studies. In addition, authors employed backward snowballing (scanning through references of retrieved articles and pertinent reviews) and contacted international experts. Corresponding authors were contacted for missing data. The full PubMed search strategy was developed according to Biondi-Zoccai et al21 using the following key words: ANH, intraoperative anemia, intraoperative autologous blood donation and cardiac surgery, and search strategies are found in Supplemental Digital Content 1 (Supplemental Appendix 1, updated November 2015, No language restrictions were enforced.

Study Selection

References were initially examined independently, by 4 investigators, at the title and abstract level. Divergences were resolved by consensus, and potentially relevant articles were retrieved in full formats. Inclusion criteria were as follows: human studies performed in cardiac surgery (all types of procedures), random allocation to treatment, and comparison of ANH versus standard treatment.

Figure 1.
Figure 1.:
Flow diagram of the systematic review process.

Exclusion criteria were as follows: overlapping publications, studies not conducted in adult population, and non-RCT studies. Two investigators independently assessed compliance with selection criteria and isolated the studies for final analysis (Figure 1). The authors’ judgments regarding methodological quality for each included study are described in Supplemental Digital Content 2 (Supplemental Table 1,

Data Extraction

The primary end point of this review was the number of allogeneic RBCu transfused for each patient. Secondary end points were the rate of allogeneic blood transfusion and estimated total blood loss.

Computations were performed with Stata (release 11, College Station, TX).22 This study was performed in compliance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses).23,24 Statistical heterogeneity hypothesis was tested with statistical significance set at 2-tailed 0.1 levels, whereas the extent of statistical consistency was measured with Higgins and Thompson I2. According to Higgins et al,25I2 values around 25%, 50%, and 75% were considered to represent low, moderate, and severe statistical heterogeneity, respectively. We performed sensitivity analyses by sequentially removing each study one at a time and then repeating a separate analysis for the rest of the studies. We also performed sensitivity analyses including groups of studies with a different amount of blood removed with ANH, different type of blood replacement, different type of surgery, different number of participants, the presence or absence of a transfusion protocol, different year of publication, and different amount of perioperative total blood loss. Finally, we tested the interaction between these subgroups. We reported unadjusted P values throughout the article. Study-specific risk ratio (RR) and its 95% confidence intervals (CIs) were calculated for binary outcomes, whereas continuous variables were analyzed to compute study-specific mean differences with 95% CI. Pooled data were analyzed using the inverse variance method, either with a fixed-effect model in cases of low-moderate (I2 < 50%) statistical inconsistency or with a random-effect model in case of moderate-high (I2 > 50%) statistical inconsistency.26 Publication bias was assessed by visually inspecting funnel plots of primary outcomes, by analytical appraisal based on the Begg adjusted rank correlation test and the Egger linear regression test (a 2-sided P value of .10 or less was regarded as significant).


Characteristics of the Included Studies

Table 1.
Table 1.:
Characteristics of Included Studies
Table 2.
Table 2.:
Baseline Characteristics

Twenty-nine randomized control trials for a total of 2439 patients (1252 patients in the ANH group and 1187 patients in the control group) were selected.27–55 Baseline characteristics in ANH and control group were similar in all included studies. All but 1 study included only elective patients with Herregods et al38 enrolling semiurgent coronary artery bypass graft (CABG). None of the studies mentioned the enrollment of patients with risk factors for increased risk of bleeding in cardiac surgery as per blood conservation guidelines.16 Sixteen RCTs included only CABG interventions,30,31,33,36–39,44–47,49–51,54,55 5 included combined CABG and valve operations,27,28,35,40,52 3 focused on heart valve interventions,41,48,53 1 studied CABG and aortic arch repair patients,34 and 4 took into account all types of cardiac surgery procedures.29,32,42,43 Two CABG studies focused on “off-pump” patients,46,50 2 studies did not specify if “off- or on-pump” CABG procedures were performed,35,37 whereas all other studies analyzed procedures performed with CPB. Methods used to perform ANH were different among the analyzed studies; only 1 among all RCTs analyzed 2 types of ANH methods, low- and high-volume hemodilution.29 Volume replacement was performed with colloids in the majority of studies,29–31,33,37–39,42–45,47,48,50–54 crystalloids in 3 studies,35,49,55 a combination of crystalloids and colloids in 2 studies,34,46 crystalloids and/or plasma protein fraction in 2 other cases,27,28 and albumin in 2 studies.27,32 Eight studies27–29,33,37,38,41,55 did not use specific transfusion protocols. In 2 studies, hemodilution was done after heparin infusion.36,41 Characteristics of the included studies are described in Table 1 and baseline data in Table 2.

Data Synthesis

Primary Outcome

Number of Allogeneic Red Blood Cell Units Transfused.

In the 21 studies reporting these data and including overall 1852 patients, the ANH group received fewer RBCu transfusions (mean difference = −0.79; 95% CI, −1.25 to −0.34; P = .001; I2 = 95.1%; Figure 2).

Figure 2.
Figure 2.:
Forest plot of the number of allogeneic red blood cell units transfused. ANH indicates acute normovolemic hemodilution; CI, confidence interval; SMD, mean difference.

Visual inspection of the funnel plot did not reveal asymmetry (Figure 3) and the Begg test was nonsignificant (P < .174), suggesting that studies with little precision (studies with few participants) did not give different results from studies with greater precision (studies with more participants). The Egger test (P < .074) became nonsignificant (P = .404) after the exclusion of an outlier trial (Hurpe et al29).

Figure 3.
Figure 3.:
Funnel plot of the number of allogeneic red blood cell units transfused. SMD indicates mean difference.

Sensitivity analyses showed that sequentially removing each study one at a time and then repeating a separate analysis for the rest of the studies did not change the overall mean difference of number of RBCu transfused: from a minimum of −0.76 (95% CI, −1.11 to −0.41; P < .0001) to a maximum of −0.51 (95% CI, −0.95 to −0.13; P = .01).

In exploring the reasons for heterogeneity across RCTs, we found differences between subgroups that could partially explain the observed heterogeneity, in the following categories: amount of blood removed with ANH, the type of surgery, the year of publication, and the presence or absence of a transfusion protocol. The test for differences between subgroups did not reveal variability in effect estimates within the following categories: type of blood replacement, the number of participants, and the amount of blood loss. P values for the interaction between subgroups are reported in Supplemental Digital Content 3 (Supplemental Table 2,

Secondary Outcomes

Rate of Perioperative Allogeneic Blood Transfusion.

Fewer ANH patients received allogeneic blood transfusions compared with controls, 356 of 845 (42.1%) in the ANH group versus 491 of 876 (56.1%) in controls, RR = 0.74; 95% CI, 0.62 to 0.87; P < .0001; I2 = 72.5%, with Begg test P = .940 and Egger test P = .015, in 18 studies with 1721 patients included (Supplemental Digital Content 4, Supplemental Figure 1,

Sensitivity analyses showed that sequentially removing each study one at a time and then repeating a separate analysis for the rest of the studies did not change the overall RR of patients transfused with allogeneic red blood cells: from a minimum of 0.71 (95% CI, 0.56 to 0.91; P = .005) to a maximum of 0.78 (95% CI, 0.64 to 0.94; P < .001).

Estimated Total Blood Loss.

Patients managed with ANH had less estimated total blood loss, 388 mL in ANH versus 450 mL in control, mean difference = −0.64; 95% CI, −0.97 to −0.31; P < .0001; I2 = 91.8%, with Begg test P = .013 and Egger test P = .061, according to 23 studies analyzed, which included 2043 patients (Supplemental Digital Content 5, Supplemental Figure 2,

Sensitivity analyses showed that sequentially removing each study one at a time and then repeating a separate analysis for the rest of the studies did not change the overall mean differences of total amount of blood loss: from a minimum of −92 mL (95% CI, −121.92 to −63.21), P < .00001, to a maximum of −72 mL (95% CI, −102.36 to −43.51), P < .00001.


To the best of our knowledge, the present meta-analysis, including 29 RCTs and investigating ANH use versus standard treatment in cardiac surgery, is the first performed specifically in this setting and focusing on patients’ need for allogeneic RBCu. The main identified finding is a clinically relevant reduction in RBCu transfusions in patients receiving ANH. Further findings are a decrease in the rate of patients transfused with allogeneic blood and a reduction in estimated total blood loss. These findings are of paramount importance and may have a great clinical and economic impact. Transfusions of blood products are known to be cost-intensive and to significantly increase the risk of perioperative complications, including mortality, prolonged hospitalization, and increased hospital resource utilization.56,57 In particular, cardiac and pulmonary dysfunction, neurological impairment, renal failure (50% of patients have a significant increase in serum creatinine and, among these, 5% need renal replacement therapy), and infections (nosocomial infections occur in 10%–20% of cardiac surgery patients) are increased in patients receiving transfusions and are associated with an overall worse outcome, higher in-hospital mortality, longer hospitalizations, and a higher rate of discharge to chronic care facilities.3,4 Therefore, a strategy like ANH able to minimize the exposure to blood products may reduce costs and morbidity. Moreover, as reported by Grant et al,14 cardiac surgery is the most appropriate setting in which ANH may play a relevant role because transfusion requirements remain high despite compelling evidence of many adverse effects and the advances in perioperative blood conservation techniques.6–9 Data on ANH in cardiac surgery were still greatly conflicting and inconclusive before performing this meta-analysis. As observed by Goldberg et al58 in a recent observational study on patients undergoing cardiac surgery, only 17% of patients received ANH. Although several studies have examined the role of ANH in cardiac surgery and guidelines proposed ANH as an approved practice in selected patients with adequate preoperative hemoglobin levels (class IIb, level B), to date, there have been no large randomized studies or meta-analyses that systematically review the role of this technique in the cardiac surgery field.16,59

Previous meta-analyses established a limited usefulness of ANH in terms of outcome. Bryson et al,60 in 1998, performed a systematic review and meta-analysis, regarding ANH management in cardiac and noncardiac surgery and concluded that ANH reduces the need for allogeneic red blood cell transfusions (odds ratio, 0.31; 95% CI, 0.15–0.62) in all areas, but with a less compelling evidence in cardiac surgery (odds ratio, 0.51; 95% CI, 0.26–0.99). Bryson’s meta-analysis considered only 11 RCTs performed in cardiac surgery.

Another meta-analysis performed in 2004 by Segal et al61 that compared ANH with standard of care in all surgical settings suggested a small benefit of ANH but failed to perform a specific subcategory analysis in cardiac surgery.

Recently, Zhou et al13 showed that ANH is effective in reducing allogeneic blood loss transfusion, with a significant heterogeneity and publication bias, and only when surgical blood loss is 1 L or when it exceeds 20% of the patients’ blood volume. However, the authors included in their meta-analysis a case-mixed population confirming, ultimately, the findings of previous meta-analyses. Moreover, Zhou’s meta-analysis considered only 23 RCTs in cardiac surgery.

In the present meta-analysis, to be more exhaustive and to further validate safety and reliability of ANH practice, the rate of patients transfused with allogeneic blood transfusion and the estimated total blood loss were considered.

We confirmed a significant reduction in the number of allogeneic RBCu transfused. These data are coherent with the study by Goldberg et al,58 in which a significant reduction in RBCu transfusions was observed in patients undergoing cardiac surgery in whom ANH protocol was adopted. The forest plot of RBCu transfused clearly demonstrated that, in our meta-analysis, there is strong consistency in the direction of the estimated effect among all analyzed studies, and the vast majority of our subanalyses confirmed the results of the primary analysis. Different magnitude of the effect among studies could partially explain the observed heterogeneity together with the observed differences in several subgroups: trials with different quantities of blood removed, trials published before and after the year 2000, trials with valve surgery and CABG surgery, and trials with or without a transfusion protocol.

When a great volume of blood was removed (>650 mL), there was a more pronounced reduction in RBCu transfusion, in agreement with the report of Goldberg et al.58 Recent trials show a reduced benefit from ANH probably because of reduced blood loss in modern cardiac surgery because of the widespread use in cardiac surgery of blood conservation techniques. We also found a reduction in the number of RBCu transfused in the ANH patients versus control in the subgroup of CABG surgery versus valve surgery, probably related to different tendency to bleed of these types of patients; ultimately, the use of a transfusion protocol could also influence the risk of RBCu transfusion. For the primary outcome, we noted an absence of publication bias, absence of small study effect, confirmative results from most sensitivity analyses, by sequentially removing each study one at a time, and also repeating analysis for specific groups of studies. We therefore concluded that the reason for heterogeneity was due to different magnitude in the estimated effect and by the differences between subgroups of trials.

The rate of patients transfused with allogeneic blood and the estimated total blood loss were also decreased in the ANH group, confirming the beneficial effects of ANH on clinically relevant outcomes. These findings are consistent with those reported in the study by Goldberg et al,58 in which an overall decrease in red blood cell transfusion was reported in the ANH group.

To date, this meta-analysis included the largest cardiac surgery population ever studied. Nonetheless, conclusive data are still lacking, and to obtain definitive data and demonstrate a reduction in RBCu transfusion with the use of ANH versus standard care in cardiac surgery, we will probably need a large RCT designed for a specific surgery setting (CABG or valve surgery), in which the amount of blood removed is at least 650 mL and that utilizes a precise transfusion protocol.


The following limitations of the present meta-analysis are acknowledged: only a restricted number of trials used the same hemodilution procedure and performed volume replacement with the same substance; colloids were extensively used for volume replacement in the ANH group and because they increase the risk of bleeding when compared with crystalloids, they might have worsened the coagulation, resulting in decreased ANH efficacy.62 In 2 studies, ANH was performed after heparin infusion,36,41 even though no differences in the results were found with sensitivity analyses. Heterogeneity was observed for the primary and secondary outcomes, suggesting that large, high-quality RCTs are necessary to reach more conclusive results.


This meta-analysis is the most comprehensive review regarding all RCTs on ANH published in cardiac surgery and provides an extensive evaluation of the efficacy of such technique in this setting in decreasing the number of allogeneic RBCu transfused. This is in agreement with the observed reduction in the rate of patients requiring transfusions with allogeneic blood and in the estimated total blood loss. ANH can be considered a valid technique to reduce allogeneic red blood cell transfusions in the cardiac surgery setting.


Name: Luigi Barile, MD.

Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.

Name: Evgeny Fominskiy, MD, PhD.

Contribution: This author helped collect the data, analyze the data, and prepare the manuscript.

Name: Nora Di Tomasso, MD.

Contribution: This author helped collect the data and prepare the manuscript.

Name: Ligia Elena Alpìzar Castro, MD.

Contribution: This author helped collect the data and prepare the manuscript.

Name: Giovanni Landoni, MD

Contribution: This author helped prepare the manuscript.

Name: Monica De Luca, MD.

Contribution: This author helped prepare the manuscript.

Name: Elena Bignami, MD.

Contribution: This author helped prepare the manuscript.

Name: Alessandra Sala, MD.

Contribution: This author helped prepare the manuscript.

Name: Alberto Zangrillo, MD.

Contribution: This author helped prepare the manuscript.

Name: Fabrizio Monaco, MD.

Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.

This manuscript was handled by: Roman Sniecinski, MD.


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