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REVIEW PAPERS

Intraoperative Red Blood Cell Transfusion Decision-making

A Systematic Review of Guidelines

Baker, Laura MD∗,†; Park, Lily MD; Gilbert, Richard MD; Ahn, Hilalion MD; Martel, Andre MD; Lenet, Tori MD∗,†; Davis, Alexandra MSc; McIsaac, Daniel I. MD, FRCPC†,§; Tinmouth, Alan MD, FRCPC†,¶,||; Fergusson, Dean A. PhD∗,†,¶,||; Martel, Guillaume MD, FRCSC, FACS∗,†

Author Information
doi: 10.1097/SLA.0000000000004710

Abstract

Red blood cell (RBC) transfusion is one of the commonest medical interventions worldwide. In the United States alone, 11 million units of RBCs are administered annually,1 of which over one quarter is given to surgical patients.2,3 During surgery, RBC transfusions are potentially life-saving when clinically indicated, but they can also at times be administered inappropriately and be associated with harm.4 Their short-term risks are well-described but remain relatively uncommon,5 when compared with the immediate risk of end-organ ischemia with under-transfusion.6 Among others, early risks include transfusion-related acute lung injury7 in 0.1%–8% of patients, and transfusion-associated circulatory overload8 in 3.5%–5% of patients, which have become the leading causes of transfusion-related mortality. In contrast, long-term risks are incompletely understood and are the subject of debate in the literature due to confounding by indication in observational research.9–11 Nevertheless, the risk of over-transfusion during surgery is of great concern to surgeons and patients alike,12 in light of reports of transfusion associated immunomodulation,13 postoperative complications,9 and possibly worse cancer-specific outcomes.9–11 Finally, surgical over-transfusion is also of concern to healthcare administrators, given the cost of blood and its limited supply.14–16

There is evidence in the literature of significant variation in transfusion practice in patients undergoing surgery, both in the intraoperative and postoperative settings. Risk-adjusted variation in RBC transfusion has been identified prominently in cardiac surgery,17 and in major noncardiac surgery.18–20 Although a certain degree of variation is expected based on casemix, wide variation that cannot be explained by disease severity or patient preference likely reflects unwarranted variation in clinical care.21–23

To address the observed variation in intraoperative transfusion, one must first dissect and understand intraoperative transfusion decision-making. The latter is a complex and dynamic process that relies upon anesthesiologist judgement and is informed by multiple clinical parameters, and nonclinical intangibles (availability heuristics, peer influence, clinical personality, and confidence about knowledge).24 This process has traditionally been taught using an apprenticeship model, relying upon a backbone of limited but evolving evidence.

Clinical practice guidelines (CPGs) exist to support clinicians in making evidence-based medical decisions. Prominent CPGs exist to strengthen transfusion decision-making,25,26 but these focus primarily on the nonsurgical setting, such as the emergency department, intensive care unit, and medical wards. Their generalizability to the surgical patient, defined as a patient undergoing a procedural intervention under general anesthesia, is arguably limited. A surgical patient is at risk of acute and rapid blood loss, whereby transfusion triggers or hemoglobin concentrations at which a transfusion is indicated may not always apply.5 In the nonsurgical patient, hemodynamic instability can be a reflection of anemia and is utilized to guide the need for transfusion following acute blood loss. However, in surgical patients, variations in hemodynamic changes may result from several concurrent and competing factors, such as potent pharmacologic agents, patient positioning, mechanical ventilation, neuraxial analgesia, surgical manipulation, abdominal insufflation, and surgical blood loss.27 Finally, it is noteworthy that end-organ ischemia – a commonly cited transfusion indication – cannot be easily assessed during surgery.28

A recent systematic review reported on the quality of evidence-based RBC and plasma transfusion guidelines.29 It identified 26 guidelines reporting on RBC transfusions, of which 4 were targeted to anesthesiologists or surgeons. More importantly, this review did not examine recommendations guiding RBC transfusion in the operative setting, and no such work has previously been published.

In the context of significant unexplained provider- and institutional-level variation in intraoperative RBC transfusion, it is hypothesized that existing intraoperative transfusion CPGs may reflect the observed variation. Thus, the objective of this work was to carry out a comprehensive and systematic examination of CPGs pertaining to intraoperative RBC transfusions, in terms of indications and decision-making.

METHODS

A systematic review of CPGs reporting on indications for intraoperative RBC transfusion was performed using the Preferred Reporting Items for Systematic Review and Meta-analysis statement.30,31 The Preferred Reporting Items for Systematic Review and Meta-analysis protocol checklist is presented in Supplemental Table 1, http://links.lww.com/SLA/C845. The protocol for this systematic review was registered with PROSPERO (CRD42018111487) and published.32

Eligibility Criteria

All CPGs providing recommendations on the transfusion of allogeneic RBCs in the intraoperative setting were considered for inclusion. We defined CPG according to the Institute of Medicine definition.33 Specifically, these were recommendations aimed at health care providers intended to improve patient care and were based on systematic review of the evidence.

Guidelines that did not explicitly state that recommendations were indicated for surgical patients in the intraoperative setting were excluded. The intraoperative period referred to the period of time during which patients were under the care of an anesthesiologist, during a surgical intervention. Recommendations pertaining to the “perioperative period” or “surgical patient” without explicit reference to the intraoperative period were excluded. If multiple editions from the same guideline were identified, the most recent CPG was included.

Information Sources and Search Strategy

A Peer Reviewed Electronic Search Strategy was devised by medical librarians with expertise in systematic reviews. The following databases were searched from inception to January 18, 2019: Ovid MEDLINE (including In-Process and Epub Ahead of Print), Ovid EMBASE, and CINHAL. The search strategy included a combination of MeSH terms and search terms such as “red blood cell transfusion,” “guideline,” and “operative.” The comprehensive search strategy for MEDLINE is presented in Supplemental Table 2, http://links.lww.com/SLA/C846. There were no date or language restrictions. Additionally, the following guideline databases were manually searched in duplicate: the National Institute for Health and Care Excellence, the Canadian Medical Association Infobase, the G-I-N International Guideline Library, the New Zealand Guidelines Group, The World Health Organization, and the Scottish Intercollegiate Guidelines Network. A manual search of the first 200 hits on Google Scholar was performed on January 10, 2019, using the following search terms: “intraoperative,” “guidelines,” and “red blood cell transfusions.” Finally, the references of eligible guidelines were manually reviewed for any relevant missing citations.

Study Records

Retrieved citations were screened using Covidence (Melbourne, Australia). Guidelines identified from guideline databases were recorded separately in an Excel spread sheet (Microsoft Corporation, Redmond, WA). Title and abstract screening was performed in duplicate by 2 independent reviewers. Articles advanced to full-text screening were reviewed in duplicate for eligibility. Any disagreements regarding relevancy were resolved by the 2 senior authors. Reasons for study exclusion were documented (Fig. 1).

FIGURE 1
FIGURE 1:
PRISMA flow diagram. PRISMA indicates Preferred Reporting Items for Systematic Review and Meta-analysis.

Data Items

The following characteristics were extracted independently by 2 reviewers: publication details (authors, year of publication, journal, etc), surgical population that is targeted by the intraoperative transfusion guidelines, patient variables taken into consideration in determining the appropriateness of transfusion (eg, hemodynamics, blood loss, evidence of cardiac ischemia, etc), the evidence cited to support specific recommendations, and grading of recommendations. Where appropriate, transfusion triggers were defined as a hemoglobin/hematocrit at which a transfusion is indicated, whereas a transfusion target referred to the minimum level a patient's hemoglobin/hematocrit should be maintained at. Data extraction forms were developed and piloted independently by 2 reviewers on a set of 5 randomly selected guidelines. Modifications were made as necessary. Discrepancies were resolved by consensus.

Data Synthesis

A descriptive summary of identified guidelines and their associated recommendations was synthesized and tabulated.

The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was applied independently by 4 reviewers to assess the quality of included guidelines.34–36 AGREE II consists of 25 items pertaining to key quality and reported domains for CPGs, graded using a 7-point Likert scale. For a given item, any scores differing by more than 2 points were discussed amongst all 4 reviewers, as previously reported.37,38 Following discussion, evaluators were given the opportunity to amend or keep their original score. Domain scores were reported separately using both the median and scaled domain scores, as recommended by the AGREE II consortium. The scaled domain scores were calculated as follows: [(obtained score – minimum possible score) / (maximum possible score – minimum possible score)] × 100. The minimum possible score was calculated as: (number of questions) × (number of reviewers) × 1. The maximum possible score was calculated as: (number of questions) × (number of reviewers) × 7.

Finally, a subgroup qualitative examination of guidelines targeted towards indications for RBC transfusion in patients undergoing cardiac surgery was planned a priori, owing to the very different blood management procedures used with cardiopulmonary bypass (CPB).

RESULTS

Selected Guidelines

The search identified 974 unique records (Fig. 1). Following screening, 10 guidelines met our eligibility criteria.39–48 The majority of included guidelines were produced by speciality societies (n = 7).39,41–43,45,46,48 The remainder were from government affiliated organizations (n = 2)44,47 and academic experts (n = 1)40 (Table 1). Of the guidelines created by speciality societies, the majority were produced by 1 organization (n = 5),39,42,43,46,48 with two41,45 created by collaborative efforts by 2 speciality societies. Five guidelines were produced with representatives from a single country (United States n = 3,43,46,48 France n = 1,44 Scotland n = 1,47), 1 with North American representation,40 and 4 with greater than 2 continents represented.39,41,42,45

TABLE 1 - Characteristics of Included Guidelines
Guideline Language Journal Location (Countries) Development Group (Type) Medical Specialities Involved Target Population: Patient/Procedure No. of Individuals No. of Institutions
Bennet, 201840 English Annals of Surgery North America (2) N/A (I) Anesthesiology, critical care, hematology, surgery Liver resection 11 6
Cholette, 201841 English Pediatric Critical Care Medicine International (8) SCCM, WFPICCS (S) Pediatrics Cardiac surgery in pediatric heart disease 38 29
Kozek-Langenecker, 201742 English European Journal of Anaesthesiology International (14) ESA (S) Anesthesiology, surgery Severe perioperative bleeding 25 23
Apfelbaum, 201543 English Anesthesiology United States ASA (S) Anesthesiology, pathology NR 10 10
Lienhart, 201444 French N/A France HAS (G) Anesthesiology, geriatrics, gastroenterology, hematology, medical genetics, neonatology, pediatrics NR 26 NR
Ferraris, 201145 English The Annals of Thoracic Surgery International (3) STS, SCA (S) Anesthesiology, pathology, surgery Cardiovascular surgery 19 17
Moll, 201139 English European Journal of Vascular and Endovascular Surgery International (6) ESVS (S) Surgery AAA repair 13
Belfort, 201046 English American Journal of Obstetrics and Gynecology United States SMFM (S) Obstetrician-gynecology Placenta accreta 13 NR
Tansey, 200147 English NA Scotland SIGN (G) Anesthesiology, general practitioner, hematology, surgery Elective surgery 18 NR
Audet, 199248 English Annals of Internal Medicine United States ACP (S) Cardiology, general medicine Elective surgery 6 NR
AAA indicates abdominal aortic aneurysm; ACP, American College of Physicians; ASA, American Society of Anesthesiologists; ESA, European Society of Anesthesiologists; ESVS, European Society for Vascular Surgery; G, government; HAS, Haute Autorité de Santé (France); I, independent experts; ICEBP, The International Consortium for Evidence Based Perfusion; IF, impact factor; N/A, not applicable; No., number; NR, not reported; S, speciality society; SCA, Society of Cardiovascular Anesthesia; SCC, Society of Critical Care Anesthesia; SCCM, Society of Critical Care Medicine; SIGN, Scottish Intercollegiate Guidelines Network; SMFM, Society for Maternal-Fetal Medicine; SOAP, Society for Obstetric Anesthesia and Perinatology; STS, The society of thoracic surgeons; WFPICCS, World Federation of Pediatric Intensive and Critical Care Society.

Anesthesiologists contributed at least in part to the development of 60% (n = 6)40,42–45,47 of included guidelines, and the remainder were created under the provision of a single medical subspecialty (internists, pediatricians, and obstetrician and gynecologists) (Table 1). Forty percent (n = 4) of guidelines included medical professionals from both surgery and anesthesia in their development group.40,42,45,47

Target Populations

Of the 10 guidelines identified, 5 focused on the perioperative management of patients undergoing surgery in general (Fig. 2).42–44,47,48 They included transfusion recommendations pertaining to both the intraoperative and postoperative periods. The remaining 5 guidelines were focused around the management of a specific clinical condition (ie, management of abdominal aortic aneurysms,39 children with acquired or congenital heart disease41) or surgical procedure (ie, hepatectomy40). All identified guidelines included a minimum of 1 recommendation dedicated to approach or indication(s) for RBC transfusion in the intraoperative period. Intraoperative recommendations were included under the following subheadings: “intraoperative” (n = 4),40,41,46,47 “under general anesthesia” (n = 2),44,48 “intraoperative during active bleeding” (n = 1),42 “perioperative” (n = 1),39 “intraoperative and postoperative” (n = 1),43 and “during cardio-pulmonary bypass” (n = 1).41 None of the included guidelines were dedicated exclusively to the intraoperative period.

FIGURE 2
FIGURE 2:
Included clinical practice guidelines.

Indications for Transfusion

A summary of transfusion decision-making factors is provided in Table 2. A summary of recommendations from included guidelines is presented in Table 3.

TABLE 2 - Summary of Intraoperative Transfusion Considerations and Recommendations
Variable Recommendation Clinical Practice Guideline
Hemoglobin (g/dL)
 Trigger <6.0 to ≤7.5 without increased risk end-organ ischemia or NOS 40, 44, 45,47
<7.0 to <10.0 with increased risk end-organ ischemia 44, 45
 Target 7.0–9.0 42
 Other Restrictive transfusion strategy may be safe, decision to transfuse between 6.0–10.0 is multifactorial 43
Transfusion contraindicated >8.5§ to >10.0 40, 43, 45, 47
Hematocrit concentration
 Trigger <30% 39
Instrument used to measure hemoglobin concentration No recommendations provided regarding acceptability of point of care testing (example: HemoCue vs i-STAT) versus lab testing
Timing/frequency of hemoglobin testing Repeated measurement, timing unspecified 42
Blood loss
 Trigger ≥1500 mL 40
Monitor surgical field, drains, sponges, suction canister 39, 42, 43, 45–47
Hemodynamics Recommend monitoring BP and HR 41, 43, 47, 48
End organ perfusion ST changes 40
O2 sat, ECG, echocardiogram, urine output, cerebral oximetry and near infrared spectroscopy, arterial blood gas, mixed venous oxygen saturation 41–46
Transfusion strategy One at a time 43, 47, 48
Early blood product replacement recommended 46
This was defined differently in different guidelines. Definitions included history of coronary artery disease, angina, heart failure, cardiovascular, or peripheral vascular disease.
One guideline provided recommendations on transfusion trigger not condition on past medical history (1).
Recommended target during active bleeding.
§Without major indication (major blood loss, ST segment changes) transfusion for hemoglobin ≥9.5 g/dL is inappropriate, and transfusion for hemoglobin ≥8.5 g/dL requires strong justification.
In the context of ongoing bleeding.BP indicates blood pressure, CAD, coronary artery disease, ECG, electrocardiogram, HR, heart rate, NOS, not otherwise specified, O2 sat, oxygen saturation.

TABLE 3 - Summary of Recommendations From Included Guidelines. Transfusion Directives Highlighted in Bold
Guideline Hemoglobin (g/dL) or Hematocrit (%) Blood Loss Hemodynamics and End-organ Perfusion Other Evidence Level
Bennet, 201840 Hgb ≤7.5 ≥1500 mL ST changes Level 1, 2, 3
Cholette, 201841 Considering Hgb concentration Consider overall clinical context Level 2, 3
Kozek-Langenecker, 201742 Target Hgb 7.0–9.0, with repeated measurements Recommend using other parameters to monitor dynamics of blood loss Measure lactate, base deficit for tissue perfusion. Measure CO (dynamic), CO2 gap and CV O2 saturation Level 1
Apfelbaum, 201543 The determination of whether Hgb concentration between 6.0 to 10.0 justify or require red blood cell transfusion should be based on potential or actual ongoing bleeding, intravascular volume status, signs of organ ischemia, and adequacy of cardiopulmonary reserve; monitor Hgb/Hct if anemia suspected based on estimated blood loss and clinical signs Monitor using visual assessment of surgical field, including extent of microvascular bleeding, surgical sponges, clot size and shape, and volume in suction canister. Monitor for perfusion using BP, HR, O2 saturation and ECG. Additional monitoring may include echocardiogram, urine output, cerebral monitoring, NIRS, ABG and mixed venous O2 saturation Transfuse 1 unit at a time Level 1, 2, 3
Lienhart, 201444 Hgb <7.0 w/o CAD, Hgb <8.0 with CAD, Hgb <10.0 with angina, HF or beta-blocked Recommend evaluating O2 saturation Level 1, 2, 3
Ferraris, 201145 Hgb <6.0 in pts on CPB with moderate hypothermia, Hgb <7.0 in pts on CPB at risk of end organ ischemia Massive or acute blood loss should be taken into consideration Laboratory and clinical parameters should be taken into consideration (SVO2, EEG or echocardiographic evidence of MI) With Hgb >6.0 while on CPB, it is reasonable to transfuse based on clinical situation, and this should be considered the most important component of the decision making process. Level 2, 3
Moll, 201139 Hct <30% and ongoing blood loss Monitor NR
Belfort, 201046 Recommend monitoring Hgb and Hct Monitor abdominal/vaginal blood loss Recommend early blood product replacement NR
Tansey, 200147 Hgb <7.0 no cardiovascular disease, Hgb <9.0 with cardiovascular Surgical and anticipated post-op blood loss should be considered Consider hemodynamics No indication thresholds should differ during intraoperative period (compared to non-operative period). The use of intraoperative transfusion must reflect the ongoing rate of surgical blood loss, continued hemodynamic instability and anticipated post-operative bleeding; transfuse 1 unit at a time Level 2, 3
Audet, 199248 Transfusion indicated in patients at risk of MI/cerebral ischemia with vital signs instability, independent of hemoglobin Transfuse 1 unit at a time Level 1, 2, 3
See Supplementary Digital Content Tables 4a and 4b, http://links.lww.com/SLA/C848 for details. Please note that level 1 evidence refers primarily to clinical trials involving nonsurgical patients and trials conducted in the postoperative setting.ABG indicates arterial blood gas, CAD, coronary artery disease, CO, cardiac output, CPB, cardiopulmonary bypass, CV, central venous, ECG, electrocardiogram, EEG, electroencephalogram, Hct, hematocrit, Hgb, hemoglobin, HR, heart rate, MI, myocardial infarction, NIRS, near infrared spectroscopy, NR, not reported, SVO2, Central venous oxygen saturation.

Hemoglobin or Hematocrit Concentration

Six guidelines provide trigger or target hemoglobin or hematocrit concentrations to guide RBC transfusion.39,40,42,44,45,47 Recommended transfusion triggers range from 6.0 g/dL to 10.0 g/dL, depending on clinical context and patients’ pre-existing medical conditions. Three guidelines provide recommendations irrespective of patients’ medical comorbidities. They include: transfusion triggers of 7.5 g/dL,40 a hematocrit of 30%39 or targeting a hemoglobin between 7.0 g/dL to 9.0 g/dL.42 Three guidelines provide recommendations tailored to patients’ medical history.44,45,47 Specifically, The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists recommend a transfusion trigger of 6.0 g/dL in patients on CPB with moderate hypothermia and 7.0 g/dL in those at risk of critical end organ ischemia.45 The French Health Authority recommends a transfusion trigger of 7.0 g/dL in patients without coronary artery disease, 8.0 g/dL in those with coronary artery disease and 10.0 g/dL in patients with angina, heart failure or in those that are beta-blocked.44 The Scottish Intercollegiate Guidelines Network recommend a threshold of 7.0 g/dL in patients without cardiovascular disease and 9.0 g/dL with cardiovascular disease (including those with high risk of occult cardiovascular disease, ie, elderly or those with peripheral vascular disease).47

One guideline makes reference to the use of hemoglobin concentration to aide in decision to transfuse, without providing clear directives.43 The American Society of Anesthesiologists Task Force on Perioperative Blood Management states that a restrictive RBC transfusion strategy may be safe, and further specifies, “the determination of whether hemoglobin concentration between 6.0 to 10.0 g/dL justify or require RBC transfusion should be based on potential or actual ongoing bleeding, intravascular volume status, signs of organ ischemia, and adequacy of cardiopulmonary reserve.43

The remaining 3 guidelines make no mention of employing a given transfusion strategy based on hemoglobin or hematocrit concentration.41,46,48 Recommendations from the Society for Maternal-Fetal Medicine on placenta accreta recommend “early blood product replacement” based on intraoperative blood loss.46 They suggest monitoring hemoglobin and hematocrit concentration without directives on indications or threshold for transfusion. A CPG from The American College of Physicians published in 1992 recommend using hemodynamic status to determine need for transfusion in patients under general anesthesia.48 Furthermore, they indicate that in patients with stable vitals, “in the absence of risk factors for myocardial or cerebral ischemia, transfusion is not indicated, independent of hemoglobin level.” Lastly, a guideline from The Pediatric Critical Care Transfusion and Anemia Expertise Initiative recommends the “development and adoption of intraoperative blood sparing and blood conservation procedures and guidelines” without reference to objective hemoglobin targets.41

Four guidelines reported hemoglobin concentrations at which transfusion would be considered contraindicated.40,43,45,47 Three reported that transfusing a patient with a hemoglobin >10.0 g/dL was unjustified43,45,47 One reported “transfusion for a hemoglobin ≥9.5 g/dL is inappropriate in the absence of ST changes or significant bleeding.40” It also specified that “transfusion for hemoglobin ≥8.5 g/dL requires strong justification.”

None of the included guidelines provided recommendations on the most appropriate tool to monitor hemoglobin, discussed the acceptability of point of care testing, or recommended a particular timing of pre- and post-transfusion hemoglobin testing.

Blood Loss

The majority of guidelines (n = 7) recommended considering blood loss when deciding whether or not to transfuse a patient in the operating room.39,40,42,43,45–47 The Ottawa Criteria for Appropriate Transfusion in Hepatectomy states “significant blood loss” would be an appropriate indication for transfusion, quantifying significant as ≥1500 mL within the body of the guideline.40 Another guideline indicates transfusing patients on CPB with a hemoglobin above 6.0 g/dL would be appropriate in the context of “massive blood loss.”45 The remaining guidelines recommend monitoring blood loss without providing indication for transfusion. For example, they advise the clinician to “perform repeated measurements of the dynamics of blood loss” or “pay attention” to blood loss.42,46 The American Society of Anesthesiologists Task Force on Perioperative Blood Management recommends conducting a “visual assessment of the surgical field, including the extent of blood present, presence of microvascular bleeding, surgical sponges, clot size and shape, and volume in suction canister.43

Three guidelines make no mention of blood loss.”41,44,48 The guideline from The Pediatric Critical Care Transfusion and Anemia Expertise Initiative recommends considering markers influenced by blood loss.41 They recommend “considering overall clinical context in addition to hemoglobin concentration (ie, symptoms, signs, physiological markers, lab results).” Similarly, the remaining 2 guidelines focus exclusively on other physiologic parameters – specifically hemoglobin triggers and targets and vital signs.44,48

The use of cell salvage or reinfusion of recovered red cells was discussed in 6 guidelines, all of which endorsed their use as part of a blood conservation strategy.39,41–43,45,47

Hemodynamics or end Organ Ischemia

Eight guidelines recommended factoring in patients’ hemodynamic status or parameters suggestive of end organ ischemia when deciding whether a transfusion is indicated.40–45,47,48 Ottawa Criteria for Appropriate Transfusion in Hepatectomy provides the directive to transfuse when ST changes are seen on cardiac monitoring as an indication of cardiac ischemia.40 The remaining guidelines recommend monitoring or considering end-organ perfusion in some capacity, either via physical examination, laboratory values (eg, lactate), or other diagnostic modalities such as intraoperative echocardiogram. There was no mention of the influence of vasopressors on the decision to transfuse in any of the included guidelines.

The guidelines on the management of Placenta Accreta46 and Abdominal Aortic Aneurysm39 did not comment on the role of hemodynamics or end organ ischemia on deciding the need for transfusion.

Subgroup Analysis

A planned subgroup analysis of cardiac surgery guidelines could not be carried out, as only 1 guideline included recommendations for this patient population.41

Recommendation on Dosing of Transfusions

Three guidelines recommended single unit transfusions, with reassessment before additional units are given.43,47,48 The remainder did not provide an indication of how to dose transfusions.

Evaluation of Evidence Supporting Intraoperative Recommendations

Evidence supporting indications for intraoperative RBC transfusion was derived from a combination of interventional studies (n = 5 guidelines)40,42,43,44,48 and observational data (n = 7 guidelines),40,41,43,45,47,48 as cited in included guidelines (Supplemental Table 3, http://links.lww.com/SLA/C847). Two guidelines did not provide any accompanying references to support the recommended intraoperative transfusion strategy.39,46 Of the interventional studies cited, 3 investigated transfusion strategies in the intraoperative setting.49–51 Eight referenced studies compared transfusion strategies in surgical patients in the nonoperative setting, randomizing them to restrictive or liberal transfusion strategies postoperatively.52–59 Three supporting trials evaluated transfusion triggers in medical patients, more specifically: critical care (n = 1),60 upper gastrointestinal bleeding (n = 1),61 and patients undergoing cardiac catheterization (n = 1)62 Two systematic reviews comparing transfusion triggers63,64 were referenced as supporting evidence in 2 of the guidelines.42,44 Although both reviews performed subgroup analysis by “patient type” (eg, cardiac, critical care, orthopedic, etc), identification of studies that applied triggers in the intraoperative phase was not performed. Careful examination of these systematic reviews identified 5 interventional studies evaluating transfusion strategies in the intraoperative setting: 3 in orthopedic surgery,50,52,65 1 in cardiac surgery,53 and 1 in vascular surgery49 (Supplement Table 4, http://links.lww.com/SLA/C848). Of note, the definitions of liberal and restrictive transfusion strategies varied across studies. Studies used the following definitions for liberal transfusion strategy: hemoglobin <10 g/dL,49,52,65 hematocrit <30%,53 and in 1 study the definition varied across sites.50 Restrictive transfusion strategies varied between a hemoglobin trigger of 6.4 g/dL and 9 g/dL49,50,52,65 and a hematocrit trigger of <24%.53

Evaluation of Quality With AGREE II

Supplemental Table 5, http://links.lww.com/SLA/C849 displays the median and scaled scores of each of the 6 domains (higher scores indicate higher assigned quality). Scores ranged from 1–7 and scaled scores ranged from 2% to 96%. The overall guideline assessment score was 5 (range 2–7). For 8 of 10 publications,39–45,47 all reviewers indicated that they would either recommend the guideline or recommend the guideline with modifications. Seventy-five percent of assessors indicated they would not recommend the guideline by Belfort et al for use.46

“Clarity of presentation” was the highest scoring domain, with an average score of 6.1 (range 6–7) and scaled score of 83% ± 9%. The domain “clarity of presentation” is comprised of 3 independent questions, assessing a guideline on the specificity of recommendations, presentation of options for management, and identifiability of recommendations within the body of the manuscript.

The domain “applicability” was poorly executed across all guidelines. The average score was 2 (range 1–5.5) and scaled score was 23% ± 23%. This domain assesses the guideline for the following: description of facilitators and barriers to application, advice on implementation of the guideline, resource implications associated with applying the guideline, and inclusion of advice for monitoring or auditing implementation of the guideline.

DISCUSSION

This systematic review has identified 10 guidelines containing recommendations pertaining to the indications for RBC transfusion in the intraoperative setting. Six CPGs provided specific triggers or transfusion rules, 5 of which were exclusively based on hemoglobin values. All recommended hemoglobin triggers or targets were based on data extrapolated largely from the postoperative and nonsurgical settings. Recommended hemoglobin thresholds prompting transfusion varied widely ranging from 6.0 to 10.0 g/dL. The majority of guidelines made reference to considering intraoperative blood loss and/or end-organ perfusion. Less than a third of guidelines included recommendations on how transfusions should be dosed. These were all in agreement with single unit transfusion, with reassessment before additional units are given. Lastly, the quality of guidelines, as appraised by the AGREE II tool, varied considerably.

It has been over 20 years since Sudhindran's “plea for perioperative blood transfusion guidelines.”66 Since that time, there has been significant evolution in our understanding of tolerance to anemia during and after surgery.6 Landmark trials such as TRICC have provided support for the use of restrictive transfusion strategies in critical care.60 Multiple clinical trials have subsequently examined restrictive transfusion triggers in various clinical settings and populations.67 Prominent guidelines and systematic reviews have supported the safety and efficacy of restrictive transfusion thresholds outside of the operating room.5,67 In contrast, examination of the evidence base supporting the guidelines included in the current review highlights a paucity of trials evaluating transfusion strategies in the operative setting. The majority of the interventional studies referenced herein investigated transfusion strategies in the nonoperative setting, either in nonsurgical or postoperative surgical patients.52–62

Surgical patients require special consideration. Specifically, their unique clinical needs should be tailored as they transition through the pre-, intra-, and postoperative periods.68–70 As with all medical interventions, context matters greatly when deciding to transfuse. Too little attention has been paid to this distinction in the literature and in transfusion teachings. The American Association of Blood Banks has recommended a transfusion trigger of 8.0 g/dL in patients undergoing orthopedic or cardiac surgery.23 Patient Blood Management recommendations from the 2018 Frankfurt Consensus Committee have supported a restrictive transfusion threshold of 7.5 g/dL in cardiac surgery, and a restrictive threshold of 8.0 g/dL in patients with hip fracture and cardiovascular disease.71 Careful review of these documents suggests that the authors used the term “surgery” as an umbrella term to include all phases of surgical care. Other factors that may influence transfusion during surgery were not discussed. This recommendation limits the surgeon or anesthesiologist's ability to make informed shared decisions regarding transfusion in the operating room. Furthermore, the evidence supporting these recommendations is drawn largely from the postoperative period.58,59,72–74 Of the 5 trials identified investigating transfusion triggers in the intraoperative period, 1 reported increased mortality in the restrictive group (transfusion for hemoglobin <8.0 g/dL) (8% vs 0%, P = 0.02),65 while the other 4 showed no difference.49,52,53,74 Perhaps more importantly, all cited trials that included an intraoperative transfusion protocol carried it forward to the postoperative phase, making it very difficult to tease out the relative effect of a restrictive intraoperative transfusion intervention.

Although major strides have been made over the past 2 decades, this review has identified a wide degree of variation in intraoperative transfusion recommendations, highlighting a lack of consensus on appropriate transfusion approaches and thresholds in the operating room. Indeed, some of the identified guidelines have recommended triggers, while others have favored targets. Some have advised the use of hemoglobin concentration, while others use hematocrit. Some have provided recommendations conditional on cardiovascular history, while others have not. It is also noteworthy that no guideline has addressed indications for or recommended frequency of hemoglobin testing. This is surprising and highlights a gap between published guidelines and clinical practice, where anesthesiologists have previously indicated that the hemoglobin is the most important factor in deciding whether to transfuse.75 Among clinical trials that evaluated intraoperative hemoglobin transfusion triggers (Supplement Table 4, http://links.lww.com/SLA/C848), hemoglobin testing frequency and indications were either not described49,50,52 or only described in a vague nonreproducible fashion.53,65 We have also noted a lack of discussion surrounding methodology for measuring hemoglobin concentration. No guideline has addressed the role or limitations of point of care testing or continuous hemoglobin monitoring during surgery, which remain the subject of controversy.76 A lack of directive regarding the influence of surgical bleeding, how to estimate it,77 its relationship to patient weight, or the definition of significant bleeding on triggering transfusion was also noted. Finally, it is worth noting that although 4 guidelines included both surgeons and anesthesiologists as stakeholders in their development,40,45,47 none provided guidance on shared transfusion decision-making. Shared decision-making and communication about transfusion have previously been identified as important quality-improvement areas among surgeons and anesthesiologists.75,78 Supplemental Table 6, http://links.lww.com/SLA/C850.

Over- and under-transfusion during surgery are issues of concern for surgeons, anesthesiologists, transfusion specialists, patients, and healthcare administrators alike.6,12 Any decision to transfuse during surgery requires a careful and thoughtful risk-benefit analysis. This analysis must consider the benefits of replacing lost blood against the short-term and possibly long-term risks of transfusion. Given the high frequency with which blood is transfused in the operating room, the findings of this review highlight an important knowledge gap in the literature. This review has highlighted that the current practice environment lacks a high-quality evidence base and, as a result, guidelines either fail to make recommendations or extrapolate from inadequate evidence. In the absence of clear guidance, transfusion decision-making likely relies primarily on individual and institutional practice patterns24 and continues to further the previously observed variation in intraoperative transfusion.17–20 Transfusion decision-making in surgery is undoubtedly a complex and dynamic process that is unlikely to be distillable to a single universal transfusion trigger or simple linear algorithm.43 However, the widespread evidence of provider- and institutional-level variation in transfusion practice during surgery, together with the findings of this review, argue in favor of the development and rigorous testing of evidence-based transfusion rules for the operating room. Although a “one-size fits all” rule is probably not realistic in surgery, it is likely that transfusion algorithms can be derived for the intraoperative environment, with core elements that would be applicable to various types of operations. Other components would likely have to remain individualized or be more specialty-specific (eg, transplant, pediatric surgery, etc), but we contend that the deriving and testing of such common elements would likely go a long way to reducing the observed variability in intraoperative transfusion. The current work supports further clinical trials focusing on the intraoperative period, and making the production and dissemination of evidence-based recommendations in this field a priority agenda.

This review has several limitations. First, it is inherently limited by the available guidelines pertaining to transfusion in the literature. These are highly heterogeneous with respect to scope, patient populations, target operations, and interpretation of the literature. Second, many included guidelines addressed intraoperative transfusion as part of a broader examination of transfusion practice. In many instances, intraoperative transfusion was only a small paragraph within a much larger document and may have lacked a detailed discussion or explicit reasoning. This unfortunately limited our ability to examine and report nuances in recommendations. Third, this review had a specific definition of CPGs and used specific search terms for guidelines. It is thus possible that other documents that were not self-described as “guidelines” may have been missed. Finally, although this systematic review sought to examine all existing CPGs, it should be acknowledged that CPGs do not form the sum-total of the information used to guide practitioners in making clinical decisions about transfusion. Indeed, clinicians commonly rely upon other types of literature, which may be of a lower evidence hierarchy level, to inform their practice (narrative reviews, textbook chapters, conference presentations, experience, apprenticeship, etc.).

CONCLUSIONS

This review has identified several clinical practice guidelines providing recommendations for intraoperative transfusion. The existing guidelines were noted to be highly variable in their recommendations and to lack a sufficient evidence base from the intraoperative setting. This represents a major knowledge gap in the literature.

AUTHOR CONTRIBUTIONS

The study was a chapter within a Master's thesis in Epidemiology recently completed by LB. The study was designed by LB, DIM, AT, DAF, and GM. The protocol was drafted and registered by LB, DAF, and GM. GM and DAF shared senior authorship for this manuscript. GM is the guarantor of the protocol. AD designed and implemented the search strategy. LB and LP screened citations and performed data abstraction. LP, HA, RG, and AM assessed the quality of included CPGs using AGREE II. LB, DAF, and GM analyzed the data. LB, DAF, and GM drafted the manuscript. DIM, AT, DAF, and GM provided content expertise and reviewed the manuscript critically for quality. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors reviewed and approved the final manuscript.

TRANSPARENCY DECLARATION

GM is the guarantor of this manuscript and he affirms it is an honest, accurate and transparent account of the study. No important aspects of the study have been omitted. The study has been conducted as originally planned.

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Keywords:

anesthesiology; blood; clinical practice guideline; decision-making; surgery; transfusion

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