Review Article

Transfusion Triggers for Guiding RBC Transfusion for Cardiovascular Surgery: A Systematic Review and Meta-Analysis* Gerard F. Curley, MB, MSc, PhD, FCARCSI1; Nadine Shehata, MD, MSc, FRCPC2; C. David Mazer, MD, FRCPC1; Gregory M. T. Hare, MD, PhD, FRCPC3; Jan O. Friedrich, MD, MSc, DPhil, FRCPC4 Objective: Restrictive red cell transfusion is recommended to minimize risk associated with exposure to allogeneic blood. However, perioperative anemia is an independent risk factor for adverse outcomes after cardiovascular surgery. The purpose of this systematic review and meta-analysis is to determine whether peri-

*See also p. 2647. 1 Departments of Anesthesia and Critical Care, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada. 2 Departments of Medicine and Laboratory Medicine and Pathobiology (Mount Sinai Hospital), Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada. 3 Department of Anesthesia, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada. 4 Departments of Critical Care and Medicine, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants 301852 and 232416 from the Canadian Institutes for Health Research. Dr. Curley received grant support from the International Anesthesia Research Society (Mentored Research Award) and the University of Toronto (Department of Anesthesia Clinician Scientist Transition Award). Dr. Shehata is employed by Canadian Blood Services and received grant support from the Canadian Institute for Health Research, Canadian Blood Services, and Health Canada for Transfusion Triggers in Cardiac Surgery. Dr. Mazer received support for article research from the Canadian Institutes for Health Research and consulted for Astra Zeneca, Cuibist, and Medicines Company. His institution received grant support from the Canadian Institutes for Health Research, University of Toronto, Fresenius Kabi, NovoNordisk, Cubist, CSL Behring, Boehringer Ingelheim, and the Medicines Company and consulted for Fresenius Kabi. Drs. Mazer and Hare hold Merit Awards from the University of Toronto, Department of Anesthesia. Dr. Friedrich is supported by a Clinician Scientist Award from the Canadian Institutes of Health Research. Address requests for reprints to: C. David Mazer, MD, FRCPC, Department of Anesthesia, Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada. E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000548

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operative restrictive transfusion thresholds are associated with inferior clinical outcomes in randomized trials of cardiovascular surgery patients. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from inception to October 2013; reference lists of published guidelines, reviews, and associated articles, as well as conference proceedings. No language restrictions were applied. Study Selection: We included controlled trials in which adult patients undergoing cardiac or vascular surgery were randomized to different transfusion thresholds, described as a hemoglobin or hematocrit level below which RBCs were transfused. Data Extraction: Two authors independently extracted data from included trials. We pooled risk ratios of dichotomous outcomes and mean differences of continuous outcomes across trials using random-effects models. Data Synthesis: Seven studies (enrolling 1,262 participants) met inclusion criteria with restrictive and liberal transfusion thresholds most commonly differing by a hemoglobin of 1 g/dL or hematocrit of 6–7%, resulting in decreased transfusions by 0.71 units of RBCs (95% CI, 0.31–1.09, p = 0.0002) without an associated change in adverse events: mortality (risk ratio, 1.12; 95% CI, 0.65–1.95; p = 0.60), myocardial infarction (risk ratio, 0.94; 95% CI, 0.30–2.99; p = 0.92), stroke (risk ratio, 1.15; 95% CI, 0.57–2.32; p = 0.70), acute renal failure (risk ratio, 0.98; 95% CI, 0.64–1.49; p = 0.91), infections (risk ratio, 1.23; 95% CI, 0.85–1.78; p = 0.27), or length of stay. There was no betweentrial heterogeneity for any pooled analysis. Including four pediatric trials (456 participants) and 10 trials utilizing only intraoperative acute normovolemic hemodilution (872 participants) did not substantially change the results except that unlike the transfusion threshold trials, the hemodilution trials did not reduce the proportion of patients transfused (interaction p = 0.01). Conclusions: Further randomized controlled trials are necessary to determine the optimal transfusion strategy for patients undergoing cardiovascular surgery. (Crit Care Med 2014; 42:2611–2624) www.ccmjournal.org

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METHODS

A

sound physiologic basis exists for the use of RBCs to improve oxygen delivery to tissues in situations of hemorrhage and anemia (1), and clinical reports (2, 3) of survival benefit support transfusion in certain clinical situations. Although RBCs can increase oxygen delivery, a concomitant increase in tissue oxygenation or oxygen utilization is not a necessary consequence (4). In addition, risks are associated with blood transfusions, including transmission of microorganisms; transfusion-related immunomodulation, which may increase the risk of infections; transfusion-related acute lung injury or transfusion-associated circulatory overload; and human errors (wrong blood in tube, incorrect patient identification, etc.), which can cause hemolytic transfusion reactions (5). Cardiac or vascular surgery is associated with a high rate of allogeneic blood transfusion, varying from less than 10% to more than 90% (1, 6). The rationale for perioperative RBC transfusion is based on the observation that anemia is an independent risk factor for morbidity and mortality after cardiovascular operations (2). However, transfusions have been associated with high rates of morbidity and mortality in critically ill patients (7), and some recent studies have shown worse outcomes, including increased rates of renal failure and infection, as well as respiratory, cardiac, and neurologic complications, in transfused patients compared with nontransfused patients after cardiac surgery (8, 9). Despite the large number of published clinical studies that have attempted to determine the optimal hemoglobin concentration at which to transfuse cardiac or vascular surgical patients, no clear consensus has emerged to guide clinical practice. Retrospective analyses have demonstrated increased morbidity and mortality near preoperative hemoglobin values less than 120 g/L (10, 11) and at intraoperative hemoglobin values ranging from 50 to 80 g/L (12, 13). Habib et al (13) reported a retrospective analysis of 5,000 consecutive cardiac operations in which stroke, myocardial infarction (MI), low cardiac output, cardiac arrest, renal failure, prolonged ventilation, pulmonary edema, reoperation due to bleeding, sepsis, and multiple organ failure were all significantly increased in patients with hematocrit below 22%. However, the use of allogeneic transfusion to treat low hemoglobin concentrations or to prevent hemodilutional anemia during cardiopulmonary bypass multiplied the risks of renal dysfunction 2- to 3.5-fold (14), and patients undergoing cardiovascular surgery with postoperative hematocrit values of 34% (hemoglobin concentrations of 110 g/L) or higher appear to have increased morbidity (15), including an increased risk of MI (15). Because there is a wide range of hemoglobin concentrations for transfusion, and because both anemia and transfusions are each independently associated with morbidity and mortality, a systematic review was conducted to determine the effects of restrictive transfusion (transfusion of RBC at lower hemoglobin concentrations), compared with liberal transfusion (transfusion

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The predefined review protocol was registered at the PROSPERO international prospective register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42013005788. Study Identification Three databases (Cochrane Central Register of Controlled Trials [CENTRAL] The Cochrane Library 2013, Issue 1; MEDLINE [Ovid] 1950 to February Week 4 2013; and EMBASE [Ovid] 1980 to 2013 February Week 4) were searched for articles from 1950 to February 2013. We did not restrict our search for trials by date, language, or publication status. We also searched the reference lists of relevant reviews, published articles, available online conference proceedings (Annual Meetings of the American Society of Anesthesiologists, Canadian Anesthesiologists Society, European Society of Anesthesiology, American Society for Hematology, European Hematology Association, Society for Critical Care Medicine, Society of Cardiovascular Anesthesiologists, and European Society for Cardiovascular Anaesthesiologists), and practice guidelines (American Society of Anesthesiologists, National Institute for Clinical Excellence, and Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists), as well as the reference lists of all included trials for further studies. We searched for ongoing or completed trials on trial registration websites (World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov). The full search criteria can be found in the online supplement (Supplemental Digital Content 1, http://links.lww.com/CCM/B27). Eligibility Criteria To be included in this systematic review, the following four inclusion criteria had to be met: 1) study design: randomized controlled trial (RCT); 2) patient population: patients undergoing cardiac or vascular surgery; 3) intervention: transfusion threshold or strategy whereby in the restrictive transfusion group, patients received RBCs at a lower hemoglobin concentration or hematocrit level, compared with liberal transfusion, where patients receive blood at a higher hemoglobin concentration or hematocrit; and 4) outcomes: the primary outcome of interest was all-cause mortality; secondary outcomes included stroke, MI, acute renal failure, infections (pneumonia, wound infections, and sepsis), arrhythmias, bleeding, ICU, and hospital length of stay. We also evaluated the frequency of RBC transfusions and the number of units transfused. We used definitions for morbidity events as provided by the authors in each trial. Studies were excluded if the effect of transfusion strategy could not be elicited due to multiple interventions or if none of our a priori outcomes was reported. For our primary analysis, we pooled data only from randomized trials enrolling adult cardiac or vascular surgery patients that compared more restrictive to liberal transfusion thresholds. To be more inclusive, we planned sensitivity analyses that also included randomized trials December 2014 • Volume 42 • Number 12

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utilizing only intraoperative acute normovolemic hemodilution (ANH) since such trials could have produced comparable separation in hemoglobin levels and transfusions, as well as trials enrolling pediatric patients, as separate subgroups. Study Selection and Data Collection Two reviewers (G.F.C., J.O.F.) independently screened citations to select trials that met inclusion criteria and abstracted data using a structured data extraction form. Disagreements were resolved by consensus. The two reviewers independently extracted study characteristics and outcomes, including study design, methodology, the transfusion thresholds and protocols, the type of surgery, patient characteristics, and outcomes. Risk of Bias Assessment The methodological quality of individual studies was assessed in duplicate using the Cochrane Collaboration’s tool for assessing risk of bias as described in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (16). We assessed the following domains for each study: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential sources of bias. A description of the study’s performance in the aforementioned categories and our overall judgment of the risk of bias for each entry is as follows: “low,” “unclear” (indicating unclear or unknown risk of bias), and “high” risk of bias (16).

Data Synthesis We combined data from all studies to estimate the pooled risk ratio (RR) and associated 95% CIs for the binary outcomes of mortality, MI, stroke, acute renal failure, infections, arrhythmias, and transfusion. We used the pooled mean difference with 95% CIs to estimate the effect on the continuous outcomes of units of blood transfused, blood loss, and ICU and hospital length of stay. Medians and interquartile ranges (17) and ranges (18) were converted to means and sds using previously published methods where necessary. Pooled RRs and mean differences were estimated by the inverse variance approach using the random-effects model of DerSimonian and Laird (19) to estimate variances. When only one group had no events, then one-half was added to each cell to allow estimation of the RR. The presence of heterogeneity was tested by a weighted inverse variance chi-square test and quantified using I2 which is the percentage of total between-study variability due to heterogeneity rather than chance (20). Substantial heterogeneity is considered to exist when I2 is more than 50%. For the chi-square test, we used a p value of less than 0.10 to indicate the presence of statistically significant heterogeneity. All analyses were conducted using Review Manager software (­Version 5.2, The Cochrane Collaboration, Oxford, UK). We considered p value of less than 0.05 to be statistically significant for pooled results. We examined funnel plots for evidence of publication bias. The authors of one trial were contacted because they reported composite outcomes and were able to provide the individual components for some of the composite outcomes (21). Subgroup and Sensitivity Analysis Anticipating significant heterogeneity in our primary outcome, we defined, a priori, subgroup analyses to examine possible causes of heterogeneity: 1) by targeted transfusion threshold (difference < 20 g/L vs difference ≥ 20 g/L); 2) by concealed allocation (yes vs unclear or no), 3) by trials in which anemia was induced by ANH during cardiopulmonary bypass by the removal and subsequent retransfusion of autologous blood versus transfusion threshold, and 4) by adult versus pediatric trials. Differences between pooled RRs between subgroups were evaluated using  z tests.

RESULTS

Figure 1. Flow diagram indicates the number of studies identified, screened and assessed for eligibility, and included in the meta-analysis.

Characteristics of Included and Excluded Studies The literature search identified 1,265 studies. Of these 1,229

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Table 1.

Characteristics of Included Studies

Trial

Funding

Methodological Quality

Intervention/Comparison

 Johnson et al (39)

Governmental

AC, unclear; blinding, no; ITT, yes; follow-up, 97% (38/39); sample size not calculated a priori

Postoperative hematocrit target of 32% in liberal group vs 25% in restrictive group

 Bush et al (38)

Not reported

AC, yes; blinding, no; ITT, yes, follow-up, 100%; sample size not calculated a priori

Intra- and postoperative hemoglobin target of ≥ 9 g/dL in the restrictive group or 10 g/dL in the liberal group

 Bracey et al (37)

Not reported

AC, no; blinding, no; ITT yes; follow-up, not reported; sample size not calculated a priori

Postoperative hemoglobin target of 8 g/dL in the restrictive group vs 9 g/dL in the liberal group

 Slight et al (42) and  Slight et al (57)

None

AC, unclear; blinding, no; ITT, yes; follow-up, 89% (86/97); sample size calculated a priori

Intra- and postoperative transfusion strategy based on a red cell volume calculation in the restrictive group (resulting in a hemoglobin target of 7.2–8.5 g/dLa) vs a hemoglobin target of 8–9 g/dL in the liberal groupb

 Hajjar et al (21)

None

AC, yes; blinding, outcome assessors only; ITT, yes; follow-up, 98% (502/512); sample size calculated a priori

Intra- and postoperative hematocrit target of 24% in the restrictive group and 30% in the liberal group

 Karkouti et al (40)

Private not for profit

AC, yes; blinding, no; ITT, yes; follow-up, 83% (60/72); sample size calculated a priori

Preoperative transfusion with 2 units of erythrocytes (liberal group) or standard of care (restrictive group)

 Shehata et al (41)

Private not for profit

AC, yes; blinding, no; ITT, yes; follow-up, 100%; sample size calculated a priori

Intraoperative hemoglobin target of 7 g/dL and postoperatively target of 7.5 g/dL in the restrictive group; intraoperative target of 9.5 g/dL and postoperative target of 10 g/dL in the liberal group

Transfusion threshold RCTs

Normovolemic hemodilution RCTs  Spahn et al (50)

Governmental

AC, not reported; blinding, no; ITT, Intraoperative hemodilution with isovolemic yes; follow-up, not reported; replacement of 12 mL/kg blood with sample size not calculated a 6% hydroxyethyl starch vs control (no priori hemodilution)

 Kahraman et al (45)

Not reported

AC, unclear; blinding, no; ITT, yes; follow-up, 100%; sample size not calculated a priori

Intraoperative hemodilution with two intervention groups with isovolemic replacement of 5–8 mL/kg following removal of 1 unit, vs 12–15 mL/kg following removal of 2 units of autologous blood, vs control (no hemodilution)

 Casati et al (43)

Private not for profit

AC, unclear; blinding, no; ITT, yes; follow-up, 100%; sample size calculated a priori

5–8 mL/kg of whole blood withdrawn after induction of anesthesia in the acute normovolemic hemodilution group, reinfused after surgery, vs standard care in the control group

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Participants

38 patients undergoing elective myocardial revascularization, who donated 3 units of autologous blood preoperatively

Actual Hemoglobin/ Hematocrit (Mean/Median)

Not reported

Outcomes

Mortality, MI, stroke, arrhythmia, transfusions, blood loss, ICU stay, hospital stay

99 patients undergoing elective aortic or Restrictive hemoglobin, infrainguinal arterial reconstructions 9.8 ± 1.3 g/dL; liberal hemoglobin, 11.0 ± 1.2 g/dL

30-day mortality, MI, transfusions, ICU stay, hospital stay

428 patients undergoing first time elective myocardial revascularization

Not reported

Hospital mortality, MI, stroke, acute renal failure (creatinine > 2.5 mg/dL or urine output < 400 mL/24 hr or RRT), arrhythmia, transfusions, ICU stay, hospital stay, pneumonia, serious infections

86 patients undergoing elective cardiac surgery

Not reported

Hospital mortality, MI, stroke, need for dialysis, arrhythmia, ICU stay, hospital stay, chest, and/or wound infection

502 patients undergoing elective myocardial revascularization or valve repair

Restrictive hemoglobin, 9.1 g/dL (95% CI, 9–9.2); liberal hemoglobin, 10.5 g/dL (95% CI, 10.4–10.6)

30-day mortality, composite endpoint of all-cause mortality and severe morbidity (cardiogenic shock, acute respiratory distress syndrome, or acute renal failure [defined as need for RRT]), respiratory, cardiac (separate arrhythmia rates obtained from authors), neurologic (separate stroke rates obtained from authors), and infectious complications, dialysis (or hemofiltration), ICU stay, hospital stay, transfusions

60 anemic patients undergoing myocardial revascularization and/or valve repair

Restrictive hemoglobin, 10.8 g/dL (10.3–11.7); liberal hemoglobin, 12.6 g/dL (12.2–13.3)

Mortality, MI, acute renal failure (estimated glomerular filtration rate decrease by 25%), dialysis, arrhythmia, transfusions, blood loss, infections

50 high-risk patients (Cardiac Anesthesia Risk Score 3 or 4, or age > 80) undergoing myocardial revascularization and/or valve repair

Restrictive hemoglobin, 9.1 g/dL; liberal hemoglobin, 10.7 g/dL

Hospital mortality, MI, stroke, acute renal failure (creatinine rise by 50%), transfusions

90 chronically β-blocked patients undergoing elective first time myocardial revascularization

Restrictive hemoglobin, 9.9 ± 0.1 g/dL; liberal hemoglobin, 12.5 ± 0.2 g/dL

Hospital mortality, MI, transfusions

42 patients with normal cardiac function Not reported undergoing elective myocardial revascularization (results of two intervention groups combined)

Mortality, MI, acute renal failure (undefined criteria), transfusions, blood loss, ICU stay, hospital stay

204 patients with normal cardiac function presenting for myocardial revascularization, valve surgery, or aortic root surgery

Mortality, MI, stroke, acute renal failure (creatinine doubling), transfusions, blood loss, ICU stay, hospital stay

Restrictive hematocrit, 22.5% (21–27); liberal hematocrit, 24% (22–28.5)

(Continued)

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Table 1.

(Continued) Characteristics of Included Studies

Trial

Funding

Methodological Quality

Intervention/Comparison

 Höhn et al (44)

Governmental

AC, unclear; blinding, no; ITT, Blood withdrawn to reach a hematocrit of 28%, yes; follow-up, 96% (77/80); and replaced with hydroxyethyl starch, vs sample size calculated a priori standard care in the control group

 McGill et al (49)

Governmental

AC, yes; blinding, postoperative only; ITT, yes; follow-up, 98% (252/256); sample size calculated a priori

10 mL/kg of whole blood withdrawn after induction of anesthesia and replaced with modified gelatin and intraoperative cell salvage, vs intraoperative cell salvage only

 Licker et al (46)

Institutional department funds

AC, yes; blinding, postoperative only; ITT, yes; follow-up, 95% (80/84); sample size calculated a priori

Blood withdrawn to reach a hematocrit of 28%, and replaced with hydroxyethyl starch, vs standard care in the control group

 Wolowczyk et al (52) and Wolowczyk et al (58)

Not reported

AC, unclear; blinding, no; ITT, yes; follow-up, 94% (34/36); sample size not calculated a priori

15 g/kg of blood withdrawn after induction of anesthesia, and simultaneously replaced with a similar volume of hydroxyethyl starch

 von Heymann et al (51) and Berger et al (59)

Hospital

AC, unclear; blinding, no; ITT, yes; follow-up, 95% (54/57); sample size not calculated a priori

Intraoperative hematocrit target of 20% in the restrictive group and 25% in the liberal group

 Licker et al (47)

Institutional department funds

AC, yes; blinding, postoperative Blood withdrawn to reach a hematocrit of 28%, only; ITT, yes; follow-up, 93% and replaced with hydroxyethyl starch in a ratio (40/43); sample size calculated of 1.15:1, vs standard care in the control group a priori

 Mathew et al (48)

Governmental

AC, yes; blinding, postoperative only; ITT, yes; follow-up, 94% (101/108); sample size calculated a priori

 Jonas et al [55]

Governmental

AC, not reported; blinding, Intraoperative hemodilution to a hematocrit of physicians and outcome 20% in the restrictive group and 30% in the assessment; ITT, yes; follow-up, liberal group 97% (147/152); sample size not calculated a priori

 Newburger et al (56)

Governmental

AC, not reported; blinding, Intraoperative hemodilution to a hematocrit of physicians and outcome 25% in the restrictive group and 35% in the assessment; ITT, yes; follow-up, liberal group 98% (124/126), sample size not calculated a priori

 Willems et al (54)

Governmental

AC, yes; blinding, no; ITT, yes; follow-up, 98%; sample size calculated a priori

Postoperative hemoglobin target of 70 g/L in the restrictive group, and 95 g/L in the liberal group

 Cholette et al (53)

Private not for profit

AC, not reported; blinding, no; ITT, yes; follow-up, 97% (60/62); sample size calculated a priori

Postoperative (48 hr) hemoglobin target of 90 g/L in the restrictive group and 130 g/L in the liberal group

Blood withdrawn and replaced with 500–1,000 mL hetastarch to reach a hematocrit of 15% (profound hemodilution), vs maintenance of hematocrit of 27% (moderate hemodilution) via packed red cells added to cardiac pulmonary bypass prime

Pediatric RCTs

RCT = randomized controlled trial, AC = allocation concealment, ITT = intention to treat analysis, MI = myocardial infarction, RRT = renal replacement therapy. a Gender and weight based. b 8 g/dL for first 4 hr postoperative then 9 g/dL. c Cardiac surgery subgroup out of a total of 648 randomized patients (60).

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Participants

Actual Hemoglobin/ Hematocrit (Mean/Median)

Outcomes

77 patients with normal cardiac function and no high risk of ischemic complications undergoing open heart surgery

Restrictive hematocrit, 27.9% ± 2.7%; liberal hematocrit, 36.9% ± 3.6%

Hospital mortality, arrhythmias, transfusions, blood loss, ICU stay, hospital stay

168 patients undergoing elective myocardial revascularization (third control group [84 patients] with no intraoperative cell salvage excluded)

Not reported

Hospital mortality, MI, stroke, acute renal failure (undefined criteria), arrhythmias, transfusions, blood loss, ICU stay, hospital stay, infections

80 patients with normal cardiac function and no major comorbidities undergoing myocardial revascularization

Restrictive hematocrit, 28% (95% CI, 27–29); liberal hematocrit, 39% (95% CI, 37–43)

Hospital mortality, MI, stroke, acute renal failure (creatinine 120% of baseline), arrhythmias, transfusions, blood loss, ICU stay, hospital stay

34 patients with normal or mildly impaired cardiac function undergoing elective open abdominal aortic aneurysm repair

Restrictive hemoglobin, 9.4 g/dL (range, 7.0–12.1); liberal hemoglobin, 13.8 g/dL (12.1–15.6)

Mortality, MI, acute renal failure (undefined criteria), transfusions, blood loss

54 patients undergoing elective myocardial revascularization

Not reported

ICU mortality, MI, stroke, acute renal failure (RRT, continuous loop diuretics, or creatinine > 2 mg/dL), ICU stay, transfusions, blood loss

40 patients with severe aortic stenosis, with mild left ventricular dysfunction only and absence of significant coexisting diseases, undergoing aortic valve replacement

Restrictive hemoglobin, 9.0 ± 0.9 g/dL; liberal hemoglobin, 13.9 ± 1.1 g/dL

Hospital mortality, MI, stroke, acute renal failure (creatinine 120% of baseline), arrhythmias, transfusions, blood loss, ICU stay, hospital stay

108 patients older than 65 undergoing myocardial revascularization

Restrictive 18% ± 1.7%; liberal 26.9% ± 2.8%

Mortality at 6 wk, stroke, acute renal failure (creatinine > 2 mg/dL), transfusions

147 infants < 9 mo of age undergoing cardiac surgery for correction of congenital heart defects

Restrictive hematocrit, 21.5% ± 2.9%; liberal hematocrit, 27.8% ± 3.2%

124 infants < 9 mo of age undergoing cardiac surgery for correction of congenital heart defects

Restrictive hematocrit, 24.8% ± 3.1%; Liberal hematocrit, 32.6% ± 3.5%

Mortality, ICU stay, hospital stay, transfusions

Mortality (time not specified), stroke, acute renal failure (creatinine > 1.5 mg/dL), arrhythmias, ICU stay, hospital stay

125 childrenc undergoing cardiac surgery Restrictive hemoglobin, or catheterization for correction of 9.1% ± 13 g/dL; liberal congenital heart disease hemoglobin, 11.2% ± 14 g/dL

28-day mortality, ICU stay, infections

60 infants and children with variations of single ventricle physiology presenting for cavopulmonary connection

Mortality, transfusions, ICU stay, hospital stay

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Restrictive hemoglobin, 11.1 ± 1.3 g/dL; liberal hemoglobin, 13.9 ± 0.5 g/dL

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were excluded from further assessment at title and abstract screening, and 36 studies underwent full-text screening (Fig. 1). Excluded Studies. Two trials were not randomized comparisons of different transfusion thresholds (22, 23) and one trial was subsequently retracted by the journal (24). Twelve studies did not report on our outcomes of interest (25–36). Description of Included Studies. We included 21 full-text articles for review. Seven studies were randomized trials of different transfusion thresholds (21, 37–42). Ten trials used only ANH (43–52), whereas four trials involved pediatric patients, two comparing different postoperative transfusion thresholds (53, 54) and two using only ANH (55, 56). Table 1 describes the patient population, the trial interventions, and outcomes. Of the seven included transfusion threshold trials, two studies enrolled patients undergoing elective myocardial revascularization only (37, 39), four recruited patients who had myocardial revascularization and/or valve repair or replacement (21, 40–42), and one study was of vascular

surgery patients (38). Six studies excluded patients with significant comorbidities, including severe left ventricular dysfunction and renal dysfunction (21, 37–40, 42). One study included patients who were high risk only (41), whereas another study recruited patients with preoperative anemia only (40). A range of transfusion triggers was used, from 70 to 90 g/L in the restrictive group or a hematocrit of 24–25%, and from 80 to 100 g/L in the liberal group or a hematocrit of 30–32%. Four studies used intra- and postoperative thresholds (21, 38, 41, 42), two studies used postoperative thresholds only (37, 39), and one study used preoperative transfusion only (40). One study used autologous predonated blood almost exclusively (39). Further details on the ANH and pediatric studies are contained in Table 1. Quality Assessment and Risk of Bias. The quality of the included studies as assessed by Grades of Recommendation, Assessment, Development and Evaluation criteria (58) was low for each of the primary outcomes (Table S1, Supplemental Digital Content 2, http://links.lww. com/CCM/B28; and Table S2, Supplemental Digital Content 5, http://links.lww.com/ CCM/B31). Randomization was clearly concealed in four of seven trials (21, 38, 40, 41) that used central randomization, not concealed in one trial that used hospital record numbers to allocate patients (37), and unspecified in two trials (39, 42). Intention to treat analysis was performed in all seven. No trials blinded patients or caregivers, but one trial blinded outcome assessments (21). A summary of the methodological quality for each included trial is discussed in the online supplement (Supplemental Digital Content 1, http://links.lww.com/ CCM/B27) and shown in Figures S1 and S2 (Supplemental Digital Content 3, http://links.lww. com/CCM/B29) and Table S1 (Supplemental Digital Content 2, http://links.lww.com/CCM/B28).

Figure 2. Forest plot showing the effect of liberal and restrictive transfusion thresholds on mortality at hospital discharge (Bracey et al [37], Slight et al [42], Shehata et al [41], Spahn et al [50], Höhn et al [44], McGill et al [49], and Licker et al [46, 47]), ICU discharge (von Heymann et al [51]), 28 d (Willems et al [54]), 30 d (Bush et al [38] and Hajjar et al [21]), 6 wk (Mathew et al [48]), or not specified but followed to at least hospital discharge (Johnson et al [39], Karkouti et al [40], Kahraman et al [45], Casati et al [43], Wolowczyk et al [52], Cholette et al [53], Jonas et al [55], and Newburger et al [56]). Transfusion threshold randomized controlled trials (RCTs) versus normovolemic hemodilution RCTs, interaction p = 0.31; pediatric versus all adult (transfusion threshold RCTs plus normovolemic hemodilution RCTs), interaction p = 0.80.

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Quantitative Analysis Mortality. A restrictive or liberal transfusion strategy had no statistically significant effect on hospital mortality when the data from seven trials were pooled (RR, 1.12; 95% CI, 0.65–1.95; p = 0.68; test for heterogeneity p = 0.60; I2 = 0%) (Fig. 2). One study (21) contributed 35.9% of

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Figure 4. Forest plot showing the effect of liberal and restrictive transfusion thresholds on stroke (includes both cerebrovascular accident (CVA) and transient ischemic attack (TIA) for Licker et al [46, 47], and CVA, TIA, or paralysis for Bracey et al [37]). Transfusion threshold randomized controlled trials (RCTs) versus normovolemic hemodilution RCTs, interaction p = 0.72.

the weight in the meta-analysis of this outcome. The funnel plot showed no evidence of asymmetry (Fig. S3, Supplemental Digital Content 4, http://links. lww.com/CCM/B30). Myocardial Infarction. Six trials reported on rate of MI. The use of a restrictive transfusion threshold did not significantly impact adversely on the rates of MI (RR, 0.94; 95% CI, 0.3–2.99; test for heterogeneity p = 0.87; I2 = 0%) (Fig. 3). Stroke. Five trials reported on the frequency of stroke. There was no significant impact of transfusion threshold on the risk of stroke (RR, 1.15; 95% CI, 0.57–2.32; test for heterogeneity p = 0.51, I2 = 0%) (Fig. 4). Acute Renal Failure. Five trials reported on acute renal failure and/or need for renal replacement therapy. There was no significant difference between transfusion strategies (RR, 0.98; 95% CI, 0.64–1.49) (Fig. 5). Transfusions and Blood Loss. Overall units of blood transfused was lower in the restrictive group (weighted mean difference, –0.71; 95% CI, –1.09 to –0.33; p = 0.0002; test for heterogeneity p = 0.11; I2 = 47%) (Fig. 6). Data on the frequency of transfusions were available from all seven trials (Fig. S5, Supplemental Digital Content 7, http://links.lww. com/CCM/B33) As expected, the implementation of a restrictive transfusion trigger reduced the risk of receiving a red cell transfusion by a relative 25% (RR, 0.75; 95% CI, 0.61–0.92). Heterogeneity between these trials was statistically significant (chi-square = 50; df = 6; p < 0.00001; I2 = 88%). Other Outcomes. A number of other potentially relevant clinical outcomes were reported in individual trials, including infections (Fig. 7), arrhythmias

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Figure 3. Forest plot showing the effect of liberal and restrictive transfusion thresholds on myocardial infarction. Transfusion threshold randomized controlled trials (RCTs) versus normovolemic hemodilution RCTs, interaction p = 0.96.

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(Fig. S4, Supplemental Digital Content 6, http://links.lww. com/CCM/B32), blood loss (Fig. S6, Supplemental Digital Content 8, http://links.lww. com/CCM/B34), and lengths of stay (Fig. S7, Supplemental Digital Content 9, http://links.lww. com/CCM/B35; and Fig. S8, Supplemental Digital Content 10, http://links.lww.com/CCM/ B36). There were no statistically significant differences between restrictive and liberal transfusion strategies for any of these outcomes.

Figure 5. Forest plot showing the effect of liberal and restrictive transfusion thresholds on acute renal failure and/or dialysis (dialysis events only for Slight et al [42] and Hajjar et al [21]). Transfusion threshold randomized controlled trials (RCTs) versus normovolemic RCTs, interaction p = 0.72. Including only dialysis events (Karkouti et al [40]: 1/31 vs 1/29 and Shehata et al [41]: 0/25 vs 1/25) gives risk ratio 0.70 (95% CI, 0.34–1.45, p = 0.33, I2 = 0%) for the transfusion threshold RCT group of trials.

Subgroup and Sensitivity Analyses ANH. We compared trials that used the technique of ANH with trials that used transfusion triggers only. Interestingly, the normovolemic hemodilution trials did not reduce the proportion of patients who were transfused: RR = 1.03, 95% CI = 0.84–1.27, with no heterogeneity (Fig. S4, Supplemental Digital Content 6, http://links.lww.com/CCM/

Figure 6. Forest plot showing the effect of liberal and restrictive transfusion thresholds on units of blood transfused. RCT = randomized controlled trial.

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showed similar rates of death (RR, 1.26; 95% CI, 0.72–2.21) to those that did not (RR, 0.73; 95% CI, 0.36–1.49), although these trends were in opposite directions (p value for the difference between groups, p = 0.24) (Fig. S10, Supplemental Digital Content 12, http:// links.lww.com/CCM/B38).

DISCUSSION In this systematic review and meta-analysis of randomized trials of transfusion thresholds for guiding RBC transfusion during cardiovascular surgery, restrictive transfusion compared with liberal transfusion strategies resulted in decreased rates of RBC transfusion. Although significant practice Figure 7. Forest plot showing the effect of liberal and restrictive transfusion thresholds on infections (pneuvariability exists (6), restricmonia, sepsis, and wound infections; for Shehata et al [41], we assumed that the four patients with pneumonia tive strategies form the basis of were different than the three patients with sepsis; for Slight et al [42], we combined 12, 2, 1 vs 11, 3, 1 patients many blood management proin restrictive and liberal groups with pneumonia, superficial, and deep wound infections, respectively, assuming these occurred in different patients). Interaction p = 0.18 for adult transfusion threshold randomized controlled grams and can result in signifitrials (RCTs) versus adult normovolemic hemodilution RCTs and p = 0.73 for pediatric RCTs versus all adult RCT. cant institutional cost savings (62), reduced patient exposure B32), in contrast to the transfusion threshold trials (interaction to adverse events secondary to transfusion (63), and reduced p = 0.01). Other primary or secondary outcomes did not differ demand on the blood supply (64). However, this meta-analysis based on whether anemia was induced by ANH or occurred by did not conclusively establish the safety of restrictive transfusion strategies in patients undergoing cardiovascular surgery. The other means perioperatively (Figs. 2–5 and 7). Pediatric Studies. We compared pediatric and adult trials. In subgroups examined exhibited similar trends, and inclusion of trials using only intraoperative normovolemic hemodilution or the two transfusion threshold pediatric trials, the proportion of patients transfused was decreased more than in the transfusion pediatric patients did not materially change any of the results. Blood transfusion has been implicated as a major mechanism threshold adult trials (interaction p = 0.01) (Fig. S4, Supplemenof harm after cardiac surgery, based largely on observational tal Digital Content 6, http://links.lww.com/CCM/B32). Based on limited data, ICU and hospital stays were increased by about 1 day studies that demonstrated an independent association between blood transfusion and mortality (65–67). However, some studin pediatric patients who were randomized to restrictive transfusion thresholds or normovolemic hemodilution (Fig. S7, Supple- ies provide evidence suggesting that transfusion might not be mental Digital Content 9, http://links.lww.com/CCM/B35; and deleterious in acutely ill patients (68). Two recent observational Fig. S8, Supplemental Digital Content 10, http://links.lww.com/ studies (69, 70) suggested that transfusion is not independently associated with mortality in cardiac surgery and that the extent CCM/B36), but only the increased hospital length of stay was difor severity of bleeding may be more prognostically important ferent than hospital length of stay data in the adult patients (inter(70). This is supported by other observational studies that sugaction p = 0.0004). All other outcomes were similar between the gest that anemia impacts adversely on outcomes during cardiac groups. Hemoglobin Threshold. Subgroup analyses showed similar or vascular surgery (10–13). This meta-analysis attempts to address whether RBCs are rates of death in trials targeting hemoglobin thresholds that harmful, as significantly more blood was transfused in the differed by 20 g/L or greater (1.13; 95% CI, 0.64–2.00; p = 0.67) as those with a narrower threshold difference (< 20 g/L) (RR, liberal arms (Fig. 6). The results of observational studies that assessed the adjusted risks associated with blood transfusion 0.88; 95% CI, 0.43–1.77; p = 0.71; p value for the difference (65–67) suggest that marked increases in both mortality and between groups, p = 0.58) (Fig. S9, Supplemental Digital Conmorbidity would be expected in the liberal arms of these RCTs. tent 11, http://links.lww.com/CCM/B37). Allocation Concealment. We compared trials that used Based on the studies included in this meta-analysis, this does not appear to be the case. One could argue that these studies allocation concealment with trials that did not or trials in which this was unclear. Trials that used allocation concealment are underpowered for this endpoint, as death, as well as other Critical Care Medicine

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clinical outcomes, was infrequent. However, there was also no difference in ICU length of stay or severity of postoperative organ dysfunctions. The largest study randomly assigned 502 patients to liberal and restrictive thresholds (21). Mortality was not significantly different between the groups although the noninferiority margins were large (8%). In addition, no difference was found in the rate of acute respiratory failure, acute renal failure, or length of ICU and hospital stays. The results of this meta-analysis, therefore, do not demonstrate a causal relationship underlying the association between blood transfusion and mortality and morbidity. In this systematic review, patients allocated to a lower hemoglobin concentration threshold experienced numerically more adverse events, including death, stroke, and infections. The trend toward increased mortality in the restrictive transfusion strategy group during cardiac surgery has been observed previously. The Transfusion Requirements in Critical Care trial raised concerns about the applicability of restrictive transfusion triggers in patients with acute coronary syndromes (71). A subsequent subgroup analysis of patients with cardiovascular disease showed a trend toward increased survival in the liberal transfusion group, but transfusion also resulted in a statistically significant increase in pulmonary edema and multiple organ system dysfunction (72). In support of this, Wu et al (73) published an analysis based on Medicare administrative data that showed an improvement in survival for patients older than 65 years treated for acute MI if they received blood transfusions when their admission hematocrit was less than 30. More recently, a prospective, randomized trial (74) (conservative vs liberal red cell transfusion in acute MI study) found a higher prevalence of heart failure with liberal transfusion strategies after MI. No significant differences occurred in the prevalence of in-hospital mortality or recurrent MI. This is in contrast, however, to a pilot study of 110 patients with acute coronary syndrome or unstable angina who were randomized to a liberal or restrictive transfusion strategy (75). Patients transfused using a restrictive strategy had more than twice the rate of death, MI, or unscheduled revascularization in the first 30 days of care compared with those transfused using a liberal strategy. The inconsistent results among these two small clinical trials, together with the results from this meta-analysis, further support equipoise on this issue and underscore the need for more definitive trials in patients with cardiovascular disease. In addition, ICU and hospital stay were increased by about 1 day in pediatric patients who were randomized to restrictive transfusion thresholds or normovolemic hemodilution. This is consistent with the finding that lower hematocrit levels are associated with worse psychomotor developmental index scores and a tendency for higher lactate levels in neonates in two trails of ANH, whereas higher hematocrit levels were not associated with adverse events or outcomes (76). A separate adult trial reported greater neurocognitive impairment among older patients receiving extreme hemodilution (48). This is clearly a concern for restrictive transfusion strategies in these vulnerable populations. It is interesting to note that in The Erythropoietin NeuroProtective Effect: Assessment in Coronary Artery Bypass Graft Surgery trial, in which patients were given erythropoietin 2622

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preoperatively, there were slightly lower rates of neurocognitive dysfunction at 2 months postoperatively among those individuals given the study drug compared with placebo (77). These data highlight the importance of neurocognitive dysfunction as a relevant outcome after transfusion threshold studies. Strengths of our review include methods to minimize bias, including a comprehensive literature search, duplicate data abstraction, and consideration of a broad range of important clinical outcomes. However, our review also has limitations, in particular the limited data in this area. We were only able to identify a small number of trials, 19 cardiac surgical and only two vascular trials, and these were primarily single centre each enrolling a small number of patients and using variable timing for the interventions (preoperative, intraoperative, and/or postoperative), with variable transfusion thresholds in both the intervention and control groups, variable patient populations (e.g., cardiac with or without valvular surgery, vascular surgery), and variable outcome measure definitions. For example, the criteria for reporting acute renal failure/dialysis were variable (Table 1), which could have introduced bias into the reported prevalence. In addition, the short duration of follow-up (mainly in-hospital only) could potentially have resulted in underreporting of adverse outcomes after surgery. A more homogenous group, such as patients undergoing coronary revascularization only, might have demonstrated a higher risk of harm from restrictive transfusion strategies. However, the small number of trials limited our ability to conduct meaningful subgroup analyses. The trials were also of variable quality, with only four of seven reporting concealed allocation, and only one reporting blinding of outcome assessors. Given the limited data, we tried to be more inclusive by also including trials using only intraoperative normovolemic hemodilution and enrolling pediatric patients; however, this resulted in only a small increase in total events with a risk of further increasing clinical heterogeneity. Despite the high degree of clinical heterogeneity, there was surprisingly no statistical heterogeneity for the pooled mortality or morbidity analyses; however, the small number of trials may have resulted in an underestimation of heterogeneity, the tests of which have low statistical power. In conclusion, the results of this systematic review and meta-analysis demonstrate that the RCT-level data testing different perioperative transfusion thresholds in cardiac and vascular surgery are extremely limited. Consequently, adequately powered trials are needed to assess the appropriate transfusion thresholds in this patient population.

ACKNOWLEDGMENTS We thank Drs. Ludhmila Hajjar and Jean-Louis Vincent for providing the individual components for some of the composite outcomes reported in their trial (21).

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