Purpose: Restrictive red blood cell transfusion strategies remain controversial in patients undergoing cardiac surgery. We performed a meta-analysis to assess the prognostic benefits of restrictive red blood cell transfusion strategies in patients undergoing cardiac surgery. Methods: We identified randomized clinical trials through the 9th of December 2017 that investigated a restrictive red blood cell transfusion strategy versus a liberal transfusion strategy in patients undergoing cardiac surgery. Individual patient data from each study were collected. Meta-analyses were performed for the primary and secondary outcomes. The risk of bias was assessed using the Cochrane Risk of Bias Tool. A trial sequential analysis (TSA)-adjusted random-effects model was used to pool the results from the included studies for the primary outcomes. Results: Seven trials involving a total of 8886 patients were included. The TSA evaluations suggested that this meta-analysis could draw firm negative results, and the data were sufficient. There was no evidence that the risk of 30-day mortality differed between the patients assigned to a restrictive blood cell transfusion strategy and a liberal transfusion strategy (odds ratio (OR) 0.98; 95% confidence interval (CI) 0.77 to 1.24; p = 0.87). Furthermore, the study suggested that the restrictive transfusion strategy was not associated with significant increases in pulmonary morbidity (OR 1.09; 95% CI 0.88 to 1.34; p = 0.44), postoperative infection (OR 1.11; 95% CI 0.95 to 1.3; p = 0.58), acute kidney injury (OR 1.03; 95% CI 0.92 to 1.14; p = 0.71), acute myocardial infarction (OR 1.01; 95% CI 0.80 to 1.27; p = 0.78), or cerebrovascular accidents (OR 0.97; 95% CI 0.72 to 1.30; p = 0.66). Conclusions: Our meta-analysis demonstrates that the restrictive red blood cell transfusion strategy was not inferior to the liberal strategy with respect to 30-day mortality, pulmonary morbidity, postoperative infection, cerebrovascular accidents, acute kidney injury, or acute myocardial infarction, and fewer red blood cells were transfused. Keywords: Restrictive transfusion strategy, Liberal transfusion strategy, Cardiac surgery, Prognosis, Meta-analyses * Correspondence: email@example.com Department of Cardiology, Northern Jiangsu People’s Hospital; Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou 225001, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Critical Care (2018) 22:142 Page 2 of 9 Background full texts of the articles were then reviewed independ- Anemia is common after cardiac surgery and is associ- ently in accordance with the inclusion and exclusion ated with significant increases in morbidity and mortal- criteria. Any discrepancies were resolved by reaching a ity [1–3]. Red blood cell (RBC) transfusions can be consensus regarding the inclusion or exclusion of a trial lifesaving in patients with severe anemia and the purpose by discussion with a third reviewer. of perioperative RBC transfusion is to improve oxygen delivery in patients with anemia . More than 50% of Data extraction and management patients receive a postoperative transfusion, which uses Two reviewers independently extracted the data using a a substantial proportion of blood supplies . standardized data extraction protocol. Any disagree- However, RBC transfusion has been associated with ments between the two reviewers were resolved by high rates of mortality and morbidity in critically ill discussion. Information, including trial characteristics, patients . It is associated with infection, acute lung in- included authors, year of publication, country of origin, jury, acute kidney injury, and death . The infectious study design, sample size, the inclusion and exclusion and non-infectious risks associated with transfusion criteria, the methods of statistical adjustment, transfu- support restrictive transfusion practices in several sion strategies, and study results, was extracted from the clinical settings . Whether the restrictive approach to included studies. preoperative RBC transfusion in cardiac surgery safely achieves outcomes similar to those achieved by means of more liberal approaches remains unclear. Trial sequential analysis Recent studies have demonstrated that a restrictive We conducted a trial sequential analysis (TSA) to pre- strategy for RBC transfusion is not inferior to a liberal vent the risk of increases in random error by repeated strategy with respect to death and other outcomes in updates according to the method we described previ- patients undergoing cardiac surgery [9, 10]. The aim of ously . A TSA-adjusted random-effects model was this meta-analysis is to assess the effects of restrictive used to pool the results from the included studies for compared to liberal RBC transfusion on the prognoses the primary outcomes. A two-sided TSA was performed of adult patients undergoing cardiac surgery. to maintain a risk of 5% for type I error and a power of 80%. Additionally, an estimated function was used to Methods calculate the required information size. Eligibility criteria We included trials with the following features: Statistical analysis 1. Types of studies: Randomized controlled clinical trials Review Manager (version 5.3) was used for the 2. Population: Patients undergoing cardiac surgery meta-analysis. For each of the included studies, we cal- 3. Intervention: Patients receiving restrictive RBC culated the odds ratio (OR) with 95% confidence inter- transfusion vals (CIs) for dichotomous outcomes. The heterogeneity 4. The following outcomes were included: a) primary among studies was calculated with the Mantel-Haenszel outcome, 30-day mortality; b) secondary outcomes, chi-square test and the I test. The statistical heterogen- pulmonary morbidity (including acute respiratory eity of the data was quantified. Obvious heterogeneity distress syndrome, acute lung injury, delayed extu- was defined as p < 0.05 using the Mantel-Haenszel bation), postoperative infection (including deep chi-square test or an I > 50%. Furthermore, the funnel sternal wound infection, leg wound infection, sepsis, plot technique was used to assess the publication bias. etc.), cerebrovascular accident, acute kidney injury (including all stages, acute kidney injury requiring renal replacement treatment), and myocardial Results infarction. Study location and selection Our search strategy identified a total of 6765 titles and Search strategy and study selection abstracts. After screening the abstracts and title, 4535 We searched the Medline, Elsevier, Embase, Cochrane publications were left after duplicates were removed. (Central), Web of Science, and ClinicalTrials.gov Among them, 4431 publications were non-relevant, databases from inception to December 9, 2017 for stud- which were therefore excluded. The remaining 104 pub- ies investigating the perioperative use of restrictive RBC lications were retrieved for an eligibility assessment; 97 transfusion in patients undergoing cardiac surgery. Two publications were deemed ineligible and were therefore reviewers independently reviewed all abstracts and titles excluded. Seven studies with a total of 8886 patients and excluded trials that were obviously irrelevant. The were included in the final analysis [9, 10, 12–16] (Fig. 1). Chen et al. Critical Care (2018) 22:142 Page 3 of 9 Fig. 1 Flow diagram of the identified trials. RCT randomized controlled trial Characteristics of the trials patients. The cumulative z-curve did not cross the con- We included seven trials that compared restrictive RBC ventional boundary for benefit or the trial sequential transfusion with controls in patients undergoing cardiac sur- monitoring boundary for benefit but did cross the esti- gery. The characteristics of the included trials are presented mated information size boundary (Fig. 3). The TSA eval- in Table 1. Four trials included only low-risk surgical patients uations suggested that this meta-analysis could draw who were undergoing elective cardiac surgery and excluded firm negative results, and the data were sufficient. patients who were at the highest risk of requiring RBC transfusion [10, 12, 13, 15]. The other three trials included Mortality patients who were at the highest risk of requiring RBC trans- The effect of restrictive RBC transfusion on 30-day mor- fusion [9, 14, 16]. Patients allocated to the restrictive RBC tality rates was estimated from seven trials that included transfusion group were infused with fewer RBCs compared a total of 8886 patients. A total of 139 deaths occurred to patients in the liberal-threshold group. The median num- among 4440 patients who were allocated to the restrict- ber of cell salvage and allogeneic RBC units transfused per ive RBC transfusion group compared with 142 deaths patient ranged from one to three in the four studies [9, 12– among the 4446 patients allocated to the control group. 14]. RBC transfusion rates reported in three trials ranged No evidence of publication bias was detected after a fun- from 44 to 75% [10, 13, 15]. The other trial did not report nel plot analysis (Fig. 4), and the heterogeneity was de- the units of RBC transfusion or transfusion rate . The re- termined to be non-significant (p = 0.36, I = 9). There sults of random sequence generation are shown in Fig. 2. was no evidence that the risk of 30-day mortality dif- fered between the patients assigned to the restrictive Trial sequential analysis RBC transfusion and control groups (OR 0.98; 95% CI A TSA sensitivity analysis including all trials revealed 0.77 to 1.24; p = 0.87; Fig. 5). that the diversity-adjusted information size was 8886 Chen et al. Critical Care (2018) 22:142 Page 4 of 9 Table 1 Characteristics of included studies Study N Age Strategy of blood transfusion Units of RBC transfusion or transfusion rate Restrictive Control Setting Restrictive Control Restrictive Control Triggered Hb Observed Hb Triggered Hb Observed Hb Bracey et al.1999  428 61 ± 11 62 ± 11 Elective CABG Hb < 8 g/dl 9.1 g/dl Hb < 9 g/dl 9.7 g/dl 0.9 ± 1.5 1.4 ± 1.8 Murphy et al. 2007  321 NS NS Elective or urgent cardiac surgery Hb < 7 g/dl NS Hb < 8 g/dl NS NS NS Hajjar et al. 2010  502 58.6 ± 12.5 60.7 ± 12.5 Elective cardiac surgery Hct < 24% 9.6 g/dl Hct < 30% 10.7 g/dl 0 (0–2) 2 (1–3) Shehata et al. 2012  50 67.2 ± 11.2 68.8 ± 9.2 Cardiac surgery with CARE score of 3 or 4 Hb < 7.5 g/dl 9.1 g/dl Hb < 10 g/dl 10.7 g/dl 11 (44) 17 (68) Murphy et al. 2015  2003 69.9(63.1 –76.0) 70.8(64.1–76.7) Elective or urgent cardiac surgery Hb < 7.5 g/dl 9.0 g/dl Hb < 9 g/dl 9.8 g/dl 1 (0–2) 2 (1–3) Koch et al. 2017  717 59 ± 15 60 ± 13 Elective CABG or HVR Hct < 24% 28% Hct < 28% 30% 195 (54) 265 (75) Mazer et al. 2017  4860 72 ± 10 72 ± 10 Cardiac surgery with a EuroSCORE I of 6 or more Hb < 7.5 g/dl Hb < 8.5 g/dl Hb < 9.5 g/dl 10.5 g/dl? 2 (1–4) 3 (2–5) CABG coronary artery bypass grafting, Hb hemoglobin, Hct hemotocrit, HVR heart valve replacement, NS normal saline Chen et al. Critical Care (2018) 22:142 Page 5 of 9 cardiac surgery remains to be defined. Our meta-analysis demonstrated that the OR for 30-day mortality did not favor a restrictive transfusion strategy or a liberal trans- fusion strategy in randomized controlled trials of adult patients undergoing cardiac surgery. Furthermore, a re- strictive RBC transfusion strategy was not inferior to a liberal strategy with respect to pulmonary morbidity, postoperative infection, cerebrovascular accident, acute kidney injury, or acute myocardial infarction, and fewer RBCs were transfused. Some studies have suggested that the transfusion of RBCs is associated with many harmful effects, such as infection, acute lung injury, acute kidney injury, pro- longed hospital stays, and increased mortality and hos- pital costs [7, 17]. A restrictive threshold for transfusion is likely to be favored because it requires the use of fewer units of RBCs [18, 19]. Considering the known risks of RBC transfusions and the observational studies linking transfusion with increased adverse complications , clinicians have been adopting restrictive RBC trans- fusion strategies in cardiac surgery . However, re- strictive RBC transfusion strategies remain controversial in patients undergoing cardiac surgery . Patients undergoing cardiac surgery have a lower cardiovascular reserve and restrictive RBC transfusion may increase the risk of anemia-induced tissue hypoxia . Our meta-analysis provides evidence that restrictive transfu- sion is not associated with the risk of adverse outcomes such as infection, acute kidney injury, and pulmonary morbidity. However, the definitions of those secondary outcomes differed between studies. For instance, the KDIGO criteria were adopted to diagnose acute kidney injury in TRICS 3 trial , but Hajjar et al. applied the RIFLE classification , and some others employed Fig. 2 Risk of bias summary. Review of the authors’ judgements dialysis-dependent or 50% or greater increase in serum about each risk of bias item for each included study. Red indicates creatinine [15, 16]. Nonetheless, this meta-analysis sug- high risk, green indicates low risk, blank indicates unclear gests that restrictive transfusion strategies are as safe as liberal strategies in patients undergoing cardiac surgery. Secondary outcomes Observational studies of adult patients undergoing car- Five studies (3658) reported pulmonary morbidity as an diac surgery have shown strong associations between outcome. The results revealed that there was no signifi- RBC transfusion and high mortality [24, 25]. In the cant reduction in the risk of pulmonary morbidity with Transfusion Indication Threshold Reduction (TITRe2) restrictive RBC transfusion (p = 0.42, Table 2). Further- clinical trial, 90-day mortality was higher with restrictive more, the study suggested that the restrictive transfusion postoperative RBC transfusion than with a liberal strategy was not associated with significant increases in threshold . A meta-analysis of there randomized pulmonary morbidity, postoperative infection, acute kid- controlled trails reported that the odds for mortality fa- ney injury, acute myocardial infarction, or cerebrovascu- vored a liberal RBC transfusion strategy rather than a re- lar accidents (Table 2, Additional files 1, 2, 3, 4, and 5). strictive RBC transfusion strategy, but the difference between strategies was not statistically significant . Discussion However, the recently published TITRe3 trial did not Restrictive RBC transfusion strategies remain controver- provide evidence supporting this. The study showed that sial in patients undergoing cardiac surgery [3, 7]. Thus, in patients undergoing cardiac surgery who were at the effect of restrictive versus liberal transfusion strat- moderate to high risk for death, a restrictive RBC trans- egies on clinical outcomes in patients undergoing fusion strategy was noninferior to a liberal strategy with Chen et al. Critical Care (2018) 22:142 Page 6 of 9 Fig. 3 Trial sequential analysis for mortality in the randomized controlled trials with a two-sided boundary and an incidence of 2.78% in the control arm and an incidence of 1.42% in the treatment arm respect to the composite outcome of death from any cause strategy was not inferior to the liberal strategy with re- . Similar to the TRICS 3 trial, our meta-analysis demon- spect to 30-day mortality. strated that a restrictive RBC transfusion strategy is not There are some procedures and techniques to reduce inferior to a liberal strategy with respect to 30-day mortal- RBC transfusion in patients undergoing cardiac surgery ity. To avoid the risk of random error increase due to re- . In 2010, the World Health Organization encour- peated updates, a sensitivity analysis of the TSA was aged all member countries to implement patient blood performed. The TSA evaluations suggested that this management (PBM) programs employing multiple com- meta-analysis could draw firm negative results, and the bined strategies to increase and preserve autologous data were sufficient. Thus, the restrictive RBC transfusion erythrocyte volume to restrict RBC transfusions . Fig. 4 Funnel plot of the mortality demonstrating that no publication bias existed Chen et al. Critical Care (2018) 22:142 Page 7 of 9 Fig. 5 Effect of restrictive red blood cell transfusion on postoperative mortality in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials PBM programs included preoperative optimization of duration treatment increase red cell mass and reduce allo- hemoglobin levels, blood-sparing techniques, and geneic blood transfusions . Erythropoietin adminis- standardization of transfusion practice [28, 29]. Since tered before cardiac surgery seems effective in reducing then the PBM program has been adopted to minimize the need for RBCs without increasing adverse events, blood loss in patients undergoing cardiac surgeries . hence reducing transfusion requirements [37, 38]; how- Gross et al.  reported that implementing meticulous ever, it is still controversial . Recently Urena et al.  surgical techniques, a goal-directed coagulation algo- showed that combined erythropoietin and iron therapy rithm, and a more restrictive transfusion threshold in failed to reduce RBC transfusion in anemic patients combination resulted in an obvious decrease in RBC undergoing cardiac surgery. transfusions and lower total direct costs. Despite the This meta-analysis has several limitations. First, the benefits of PBM, many barriers limit translation of PBM hemoglobin thresholds of the restrictive RBC transfusion guidelines into clinical practice worldwide, particularly strategies varied between the trials. Thus, the appropri- in the absence of interdisciplinary commitment, lack of ate threshold remains to be defined and could vary for resources, and general concerns. Strategies for overcom- different patients. Second, the types of cardiac surgery ing the obstacles include the use of bundles of care and differed among the included studies and patients under- specifically designed measures on the basis of local con- going different types of cardiac surgery may have differ- ditions . ent tolerances to restrictive transfusion strategies. Several pharmacologic agents have been used to de- crease intraoperative blood loss, which is helpful to reduce RBC transfusion. Antifbrinolytic agents, including tranex- Conclusions amic acid and epsilon aminocaproic acid, have been ex- The available evidence from our updated meta-analysis tensively studied, and they decrease hemostatic activation, suggests that the OR for 30-day mortality did not favor a reduce bleeding, and decrease allogeneic RBC transfusions restrictive or liberal transfusion strategy in randomized [33, 34]. Furthermore hemostatic treatment with fibrino- controlled trials of adult patients undergoing cardiac gen concentrate in patients undergoing aortic surgery surgery. Our meta-analysis is the best available evidence significantly reduced allogeneic blood transfusion . In that restrictive RBC transfusion is as effective and safe addition, several erythropoietin dosing regimens and as liberal transfusion strategies in adult cardiac surgery, Table 2 Effects of red blood cell transfusion by outcome Number of studies Number of patients Fixed effects Odds ratio Fixed effects p value I (%) Heterogeneity p value (95% CI) Mortality 7 8886 0.98 (0.77–1.24) 0.87 9 0.36 Pulmonary morbidity 5 3658 1.09 (0.88–1.34) 0.42 0 0.44 AKI 6 8355 1.03 (0.92–1.14) 0.65 0 0.71 AMI 4 7302 1.01 (0.80–1.27) 0.95 0 0.78 Infectious morbidity 6 8444 1.11 (0.95–1.3) 0.19 0 0.58 Cerebrovascular accident 6 8528 0.97 (0.72–1.30) 0.84 0 0.66 AKI acute kidney injury, AMI acute myocardial infarction Chen et al. Critical Care (2018) 22:142 Page 8 of 9 although the appropriate threshold remains to be de- Consent for publication All authors have agreed to the publication of this manuscript. fined and could vary for different patients. Competing interests Additional files The authors declare that they have no competing interests. Additional file 1: Effect of restrictive red blood cell transfusion on pulmonary morbidity. Forest plot of adult patients undergoing cardiac Publisher’sNote surgery. Pulmonary morbidity includes acute respiratory distress Springer Nature remains neutral with regard to jurisdictional claims in syndrome, acute lung injury, delayed extubation. ARDS and ALI are published maps and institutional affiliations. according to the Berlin definition. Delayed extubation defined by inability to extubate the patients within 24 h after the completion of the surgical Author details procedure. (PNG 5 kb) Department of Critical Care Medicine, Northern Jiangsu People’s Hospital; Additional file 2: Effect of restrictive red blood cell transfusion on Clinical Medical College, Yangzhou University, 98 Nantong West Road, postoperative acute kidney injury (AKI). Forest plot of adult patients Yangzhou 225001, People’s Republic of China. Department of Cardiology, undergoing cardiac surgery. AKI is defined according to the KDIGO or Northern Jiangsu People’s Hospital; Clinical Medical College, Yangzhou RIFLE criteria or as dialysis-dependent or 50% or greater increase in serum University, 98 Nantong West Road, Yangzhou 225001, People’s Republic of creatinine. (PNG 6 kb) China. Additional file 3: Effect of restrictive red blood cell transfusion on Received: 1 January 2018 Accepted: 10 May 2018 postoperative infections. Forest plot in adult patients undergoing cardiac surgery. 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