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Review Articles

Perioperative Anemia: Prevention, Diagnosis, and Management Throughout the Spectrum of Perioperative Care

Warner, Matthew A. MD*,†; Shore-Lesserson, Linda MD†,‡; Shander, Aryeh MD†,§; Patel, Sephalie Y. MD†,‖; Perelman, Seth I. MD†,¶; Guinn, Nicole R. MD†,#

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doi: 10.1213/ANE.0000000000004727
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Abstract

Anemia is common in surgical patients, yet it is frequently left untreated until the hemoglobin concentration is deemed low enough to warrant transfusion. However, blood transfusion has considerable associated risks and costs with uncertain benefit in the absence of active bleeding or clear anemia-related symptoms.1,2 In an effort to improve blood component utilization, restrictive hemoglobin thresholds for red blood cell (RBC) transfusion (eg, hemoglobin triggers of 7–8 g/dL) have been widely adopted, with studies consistently demonstrating noninferior or superior outcomes compared to more liberal approaches (eg, hemoglobin triggers of 9–10 g/dL).3–7 This focus on transfusion thresholds, however, has been accompanied by decreased emphasis on the importance of preventing, diagnosing, and treating the underlying causes of anemia. In an evolving health care landscape, we must shift away from simple transfusion triggers to a more patient-centered approach to blood management to optimize patient outcomes. To this end, anemia has been identified as a modifiable risk factor for poor perioperative outcomes8,9 that should be continuously addressed as a key component of comprehensive Patient Blood Management (PBM).

Preoperative anemia is common, affecting 25%–75% of patients with an increasing prevalence in the elderly.10,11 In addition to being the strongest predictor of perioperative transfusion, anemia is an independent risk factor for perioperative morbidity and mortality, including acute kidney injury and cardiovascular events.12–15 Guidelines and recommendations have been published in recent years endorsing anemia treatment in surgical patients16,17; yet, information regarding the design and implementation of anemia management strategies is limited. Furthermore, postoperative anemia is markedly common, occurring in up to 90% of patients following major surgery,10 but is often neglected as an inevitable consequence of perioperative care.

In addition to providing a narrative review of published literature regarding preoperative anemia management, this article provides practical information regarding the implementation of anemia management strategies in surgical patients throughout the perioperative period. This includes evidence-based recommendations for the prevention, diagnosis, and treatment of anemia, including the utility of iron supplementation and erythropoiesis-stimulating agents (ESAs).

ANEMIA AS A CLINICAL SYNDROME

Although anemia is a laboratory-based diagnosis, it is truly a clinical syndrome of “blood failure” with far more complexities than can be defined by a simple cutoff value. The hemoglobin value is a concentration, subject to measurement error, and as such, one must take the total blood volume into consideration. For example, hemoglobin concentrations measured in the setting of acute bleeding or intravascular volume shifts provide neither an accurate assessment of red blood cell mass nor tissue oxygen delivery.18–20 A more meaningful physiologic parameter is total red blood cell mass, although this is difficult to measure and not widely available clinically. Hemoglobin concentration remains the standard for initial diagnosis of anemia. It must be recognized that currently used definitions of anemia (ie, hemoglobin <12 g/dL in adult nonpregnant women, <13 g/dL in adult men according to World Health Organization [WHO] criteria)21 are primarily derived from observed distributions of hemoglobin concentrations in epidemiologic studies and not by the physiologic significance of those values. Notably, women presenting for surgery with hemoglobin of 12 g/dL are twice as likely to be transfused as men presenting with hemoglobin of 13 g/dL,14 suggesting that preoperative hemoglobin values of 13 g/dL may be warranted irrespective of sex.

TRANSFUSION VERSUS MANAGEMENT OF ANEMIA

Given that anemia represents an independent risk factor for poor outcomes, it should never be considered acceptable or ignored as an “innocent bystander.”22,23 Historically, anemic patients have been listed for surgery assuming that, if the hemoglobin level is low, it can be easily corrected with an RBC transfusion. The administration of allogeneic blood, however, is associated with inferior outcomes in surgical patients with anemia; thus, transfusion is not an optimal treatment for preoperative anemia.24 The risks of allogeneic transfusion coupled with its association with inferior outcomes in the perioperative setting suggest that transfusion may potentially expose patients to harm without concomitant benefit.23

Increasing awareness of the risks of allogeneic blood has fueled an ongoing quest to identify the safety of lower hemoglobin thresholds for making transfusion decisions across various patient populations. These efforts have culminated in a large number of highly publicized transfusion trials, starting with the landmark Transfusion Requirements in Critical Care (TRICC) study.3 These investigations have largely demonstrated that patients randomly assigned to restrictive transfusion strategies experience similar or improved outcomes compared with those randomly assigned to more liberal transfusion strategies.25

While these trials have undoubtedly played an important role in reducing excessive transfusions, they have also had the unintended consequence of shifting the focus away from the core issue: preventing and treating anemia as a medical condition. Moreover, the significance of anemia has been reduced to a mere transfusion threshold for which transfusion is the seemingly only treatment option available.26 A closer look reveals an alarming pattern of anemia neglect, with little effort by clinical teams beyond transfusion decisions to manage anemia throughout the hospital stay. Instead of being preoccupied and confined by the endless comparisons of restrictive versus liberal transfusion strategies, it is time to explore a new approach: a multifaceted strategy to prevent, diagnose, and treat anemia throughout the health care encounter.27,28

ETIOLOGY-BASED APPROACH TO PREVENTING, DIAGNOSING, AND TREATING ANEMIA

Proper management of anemia, including its prevention, requires consideration of the underlying etiology(s). In surgical patients, anemia is typically multifactorial (eg, blood loss, impaired erythropoiesis, hemodilution, shortened RBC life span), with many of these factors coexisting.29 In hospitalized patients, anemia may be the result of decreased RBC production due to functional iron deficiency (ie, conventionally adequate iron stores with insufficient mobilization to support erythropoietic needs), immune activation, and suppressed erythropoiesis.30,31 This is often referred to as anemia of inflammation (AI), or anemia of chronic disease, and is characterized by elevated levels of hepcidin.30,31

Hospitalized patients are also susceptible to anemia development from less overt sources of blood loss. Iatrogenic anemia is a major preventable cause of anemia that is associated with increased morbidity and length of stay.32 Frequent diagnostic blood sampling is often unnecessarily performed daily in postsurgical patients with little attention paid to the actual sample volume. The sample volume required to run the test is often severalfold lower than what is actually drawn.33 Many strategies are available to minimize this avoidable source of iatrogenic blood loss, including less frequent sampling and the use of minimal volume blood collection tubes and closed-loop sampling devices.34 Future studies are needed to evaluate the efficacy of educational and quality improvement efforts to (1) reduce unnecessary diagnostic testing, (2) minimize interprovider variation, and (3) standardize testing that may actually improve patient care.

Figure 1 depicts a proposed algorithm for the detection, diagnosis, and management of anemia in the perioperative setting. Effective treatment of anemia before surgery is often a race against time as presurgical evaluation may occur only 1–2 weeks before the planned surgical procedure. However, hematinic and erythropoietic therapies require time to augment hemoglobin levels and RBC mass, thus making 3–4 weeks before elective surgery a more appropriate time interval. If anemia is diagnosed, and the therapeutic window is short, it may be necessary or prudent to postpone high blood loss elective surgery to provide anemia treatment.35,36 However, evidence in cardiac surgery suggests that even treatment intervals as short as 1 day before surgery may improve hemoglobin levels and transfusion outcomes37; hence, this supports a short course of preoperative anemia management over no management at all, particularly for surgeries that are urgent in nature.

F1
Figure 1.:
Prevention, detection, evaluation, and management of anemia in the perioperative setting. A step-by-step algorithm for determining etiology and guiding treatment of perioperative anemia. CHr indicates reticulocyte hemoglobin content; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; IV, intravenous; MMA, methylmalonic acid; PCP, primary care provider; PO, per os (oral); TSAT, transferrin saturation.

As previously discussed, the WHO criteria for anemia lack physiologic justification for the utilization of differing hemoglobin thresholds in adult men and nonpregnant women, and women are more often transfused at levels above their threshold value than are men.14,38 Given this, the presented anemia management algorithm (Figure 1) utilizes a consistent hemoglobin threshold of 13 g/dL to define anemia across sexes. Of note, anemia in most surgical patients can be effectively managed using this algorithm, although special considerations may exist for certain patient groups such as congenital heart disease and hereditary hemoglobinopathies. Furthermore, it can be used not just before surgery, but any time anemia is discovered throughout the perioperative period.

Anemia evaluation should occur soon after diagnosis. Screening may be done using a point-of-care hemoglobin test, but should be confirmed with standard laboratory analysis before treatment. Assessment of iron status, storage, and synthetic capacity should be performed using commonly available tests such as serum iron level, ferritin level, transferrin saturation, total iron-binding capacity (TIBC), and reticulocyte hemoglobin content (CHr), to help differentiate between anemia states (Table 1).39,40

Table 1. - Expected Laboratory Findings in Different Forms of Iron Deficiency and Anemia40,149
Condition Hemoglobin Ferritin Serum Iron/TSAT TIBC CHr Hepcidina
Iron deficiency without anemia Normal Decreased Decreased Increased Decreased Decreased
IDA Decreased Decreased Decreased Increased Decreased Decreased
AI/iron sequestration Decreased Increased Normal or decreased Decreased Normal or decreased Increased
Mixed anemia (AI/IDA) Decreased Normal Decreased Variable Decreased Normal
Abbreviations: AI, anemia of inflammation; CHr, reticulocyte hemoglobin content; IDA, iron deficiency anemia; TIBC, total iron-binding capacity; TSAT, transferrin saturation.
aHepcidin testing not widely available.

CHr provides useful information on iron availability and adequacy for hematopoiesis. According to a number of studies, CHr <28–30 pg is a strong indicator of iron-restricted erythropoiesis (due to true or functional iron deficiency) and thus justifies iron supplementation.41,42 When iron, ferritin, or CHr levels are reduced, the patient should be treated for iron deficiency including identification of the source of iron loss. If iron stores are normal and no evidence of iron-restricted erythropoiesis is present, other nutritional deficiencies (folic acid and B12), hemolysis, and renal pathologies should be evaluated.35 If nutritional deficiency or hemolysis is not present, treatment with ESAs may be considered. ESA therapy can be effective in treating patients with AI, anemia of chronic kidney disease, or patients with iron deficiency anemia (IDA) who do not respond to iron therapy alone. Iron supplementation should be given before ESA administration to ensure adequate iron stores for erythropoiesis.

Although treating anemia primarily as an aim to decrease transfusion rates provides an easily measurable and financially motivated outcome, because anemia itself is a predictor of adverse outcomes regardless of transfusion status, all patients amenable to treatment should be offered therapy when feasible.

Specific Treatments: Iron

In addition to its role in erythropoiesis, iron plays a major role in cellular respiration, mitochondrial function, and electron transport. While perioperative anemia may have various etiologies, many anemic patients have at least a component of iron deficiency and may respond to iron administration.36 Of note, not all iron-deficient patients have associated anemia; however, iron deficiency, even in the absence of anemia, is associated with an inability to mount an appropriate erythropoietic response in the setting of blood loss.43 Hence, all patients with iron deficiency should be considered for preoperative iron supplementation. In addition, all patients with iron deficiency should be evaluated for active or recent blood loss. If overt blood loss is not present by history or physical examination, then gastrointestinal consultation should be considered in all populations with IDA, with the possible exception of menstruating women.44

Iron supplementation is the treatment of choice for IDA. The choice between oral iron and intravenous (IV) iron should be one of shared patient decision-making considering patient preferences, the degree of anemia, and the timing of surgery. Oral iron therapy may be considered preoperatively when iron deficiency is mild and there is ample time before elective surgery. Oral therapy has several limitations despite its low cost, ease of access, and relative safety. The major limitation is gastrointestinal side effects, which drive adherence rates to <50%.45 These include nausea, abdominal pain, diarrhea, constipation, and black or tarry stools.46 In addition, oral iron may negatively impact the colonic microbiome, promote intestinal inflammation, and exacerbate colitis in those with inflammatory bowel disease.47 Beyond gastrointestinal side effects, oral supplementation is unlikely to correct IDA in the setting of ongoing bleeding, because the amount of iron absorbed from the gastrointestinal tract is limited to a few milligrams per day. Iron absorption is further diminished with meals, antacids, proton pump inhibitors, and inflammation.

While daily divided dosing of oral therapy has been widely utilized for iron deficiency, this dosing regimen is associated with increased hepcidin levels, which impairs intestinal iron absorption and macrophage RBC iron recycling.48 Hence, one time daily (40–60 mg) or alternate day (80–100 mg) dosing strategies should be considered, with hemoglobin levels rechecked after approximately 4 weeks.49 An inadequate response to oral iron may be a sign of inflammation and iron sequestration.

IV iron is preferred for patients who defer oral therapy, are intolerant or unresponsive to oral therapy, have severe anemia with hemoglobin <10 g/dL, and whose planned surgery is within 6 weeks. All currently available products are safe and effective, and their differences depend on how tightly bound iron is to the carbohydrate shell (Table 2). Formulations with very low labile iron content (low molecular weight iron dextran, ferumoxytol, ferric carboxymaltose, and iron isomaltoside) allow for rapid administration of large single doses, or total dose infusion (TDI).50,51 TDI allows for fewer patient visits and lower treatment costs.52

Table 2. - Intravenous Iron Formulations and Dosing Strategies49,50,150
Iron Gluconate Iron Sucrose LMW Iron Dextran Ferric Carboxymaltose Iron Isomaltoside Ferumoxytol
Brand name Ferrlecita Venofera Cosmofer,a INFeDa Injectafer,a Ferinjecta Monofera FeraHemea
Carbohydrate shell Gluconate Sucrose Dextran Carboxymaltose Isomaltoside Polyglucose sorbitol carboxymethyl ether
Plasma half-life (h) 1 6 20 16 20 15
Ferritin peak 24 h 24 h 7–9 d 24 d n/a 28–25 d
Elemental iron (mg/dL) 12.5 20 50 50 100 30
Maximal single dose (mg) 125 200 20 mg/kg 750 mg or 15 mg/kg (Injectafer); 1000 mg or 20 mg/kg (Ferinject) 20 mg/kg 510
Infusion time for 1000 mg (min) 720 300 90–150 ≥15 ≥15 ≥15
Interval between 2 applications Up to 8 injections in 14 days 200 mg/session, Cumulative 1000 mg/14 d Daily, until calculated dose reached 1 wk 200–1000 mg once/wk 2nd injection after 3–8 days
Total dose infusion No No Yes Yes Yes Yes
Test dose required No No Yes No No No
Abbreviations: LMW, low molecular weight; n/a, not applicable.
Manufacturer information: Ferrlecit (Sanofi-aventis US, Bridgewater, NJ); Venofer (American Regeant, Inc, Shirley, NY); Cosmofer (Pharmacosmos, Holbaek, Denmark); INFeD (Allergan plc, Dublin, Ireland); Injectafer (American Regeant, Inc, Shirley, NY); Ferinject (Vifor Pharma, Opfikon, Switzerland); Monofer (Pharmacosmos, Holbaek, Denmark); FeraHeme (AMAG Pharmaceuticals, Waltham, MA).

While hypersensitivity reactions are possible with all IV iron formulations, many of these adverse reactions were associated with the use of high-molecular-weight iron dextran, which is no longer clinically available worldwide. The incidence of serious adverse events with iron infusion is estimated to be <1:250,000, which is 10-fold lower than the incidence of serious adverse events associated with allogeneic transfusions.53 Nevertheless, all practitioners monitoring iron infusion should be prepared to manage acute infusion reactions as per established protocols. Severe acute hypersensitivity reactions are likely complement mediated, resulting in pseudo-anaphylaxis, termed complement activation-related pseudo allergy (CARPA).54 Minor infusion reactions are more common (1:200) and usually consist of chest or back tightness, arthralgias, myalgias, and/or flushing without associated hypotension, respiratory distress, or periorbital edema.55 After pausing the infusion, these reactions usually spontaneously resolve, at which point the infusion may often be resumed. Treatment with vasopressors and/or antihistamines is inappropriate and may escalate the severity of symptoms.56 The empiric use of steroid pretreatment should be reserved for patients with multiple drug allergies or asthma.57 Consideration should be given for use of a different formulation in patients with a previous reaction.

Concerns regarding increased rates of infection and oxidative stress with short-term IV iron administration have not been substantiated in perioperative care. In a recent meta-analysis of 103 clinical trials, IV iron therapy did not increase the risk of infection or serious adverse events when compared to oral iron, no iron, or placebo.58 Risks of IV iron administration should be weighed against the risks of untreated anemia and concomitant allogeneic transfusion, which also delivers heme and labile iron.49

There are a few considerations unique to specific formulations of IV iron. Ferumoxytol, because of its ferromagnetic qualities, will enhance magnetic resonance signals if a scan is obtained within 3 months of administration. This will not impact its interpretation, but the radiologist should be informed of its use. In addition, there are currently no available safety data regarding ferumoxytol in pregnancy, so other formulations should be considered.57 Hypophosphatemia has been observed in patients receiving ferric carboxymaltose.50 The decline in phosphate levels is gradual, resulting in mild to moderate hypophosphatemia at 14 days that may persist up to 3 months. Patients with severe malnutrition and poorly controlled diabetes are at highest risk.

Ideally, IV iron dosing should be based on the total body iron deficit, which can be calculated using the Ganzoni formula.59 However, calculation of iron deficit is of limited clinical relevance because the maximum allowable iron dose in the United States is limited to 1000 mg.60 It is unclear if patients can even utilize >1000 mg of iron administered in a single session; thus, the recommendation is to administer 1000 mg and then assess for hemoglobin response. Repeat dosing may be necessary. Hemoglobin responses to IV iron are rapid (50% response by 1 week, 75% by 2 weeks),61 and levels should be rechecked approximately 2–3 weeks after the infusion.

Specific Treatments: ESAs

Erythropoietin is a glycoprotein hormone secreted primarily by the kidney that serves as the primary stimulus for RBC production in the bone marrow. Under conditions of cellular hypoxia, levels of hypoxia-inducible transcription factor-1 (HIF-1) rapidly increase, resulting in the upregulation of the erythropoietin (EPO)gene and subsequent erythropoietin production.62 ESAs are exogenous forms of erythropoietin produced by recombinant DNA technology, with the most common forms being epoetin alfa (Epogen; Amgen, Thousand Oaks, CA) and the longer-acting agent darbepoetin alfa (Aranesp; Amgen). Other related formulations (biosimilars) have since been developed outside the United States with similar safety and efficacy profiles.63 ESAs have been used to treat anemia in multiple clinical settings, including chronic kidney disease and malignancy. With increased attention on the importance of anemia management before surgery, ESAs have increasingly been utilized in the management of preoperative anemia. In a recently published PBM consensus document,17 the use of ESAs preoperatively in anemic patients undergoing elective surgery was discouraged except in those undergoing major orthopedic surgery, in whom the risk of using ESAs was deemed acceptable. The primary stated risk was thromboembolism; however, this recommendation was made without consideration for the risk of thromboembolic events associated with RBC transfusion64 or for the modulation of thromboembolic risk in surgical patients receiving pharmacologic venous thromboembolism (VTE) prophylaxis.

A distinction must be made between short-term perioperative ESA use and long-term use. In those with chronic kidney disease65–70 and malignancy,71–73 prolonged ESA use targeting normal hemoglobin levels (ie, >13 g/dL) has been associated with thromboembolic events. There is no compelling evidence to support the notion that a short course of perioperative ESAs heightens a patient’s risk for VTE. In fact, the risks and benefits for ESAs are likely dependent on the surgical population, individual patient characteristics, and the etiology and severity of anemia. Specifically, the importance of perioperative VTE prophylaxis must not be overlooked. In a trial of nearly 700 major spine surgery patients randomly assigned to 4 doses of preoperative epoetin alfa versus standard of care, the rate of deep venous thrombosis was nearly doubled with ESAs (4.1% vs 2.1%).74 However, none of these patients received perioperative pharmacologic VTE prophylaxis, highlighting its importance in high-risk surgical populations.

A summary of prospective investigations and clinical trials evaluating preoperative ESA use is provided in Table 3. Seven of the 21 studies are in major orthopedic surgery, with ESA use showing consistently improved hemoglobin levels and decreases in perioperative transfusions with no significant differences in adverse events including thromboembolic complications.75–81 Despite concerns with ESA use in cardiovascular surgery, there is a growing body of evidence for improved anemia, reductions in perioperative transfusions, and no differences in adverse events following ESA use in this high-risk surgical population.37,82–84

Table 3. - Studies of ESA Use Before Elective Surgery
Author, Year Study Design Surgery Type N (Treatment/Control) Inclusion Hb ESA Dose, Frequency Concomitant Therapies Transfusion, Hb Outcomes With ESA Use Adverse Events
Bedair et al,75 2015 Prospective, nonrandomized Orthopedic (primary THA and TKA) 24/56 <13 g/dL Unknown, 2–4 total doses None Decreased transfusions, increased postoperative Hb, increased cost Not reported
Christodoulakis et al,88 2005 Randomized, open label Oncology (colorectal surgery) 69 (150 U/kg) and 67 (300 U/kg)/68 control 9 ≤ Hb ≤ 12 g/dL 150 or 300 U/kg daily for 10 days Oral iron Decreased transfusion (300 U/kg group), increased postoperative Hb (both ESA groups) None related to study drug (5 deaths in treatment groups: 4 cardiac arrest, 1 embolism)
Dousias et al,87 2003 Randomized, double blind, placebo controlled Gynecologic (hysterectomy) 23/27 9 ≤ Hb < 12 g/dL 600 U/kg weekly × 3 weeks Oral iron Decreased transfusion, increased Hb None; no major complications in either group
Faris et al,76 1996 Randomized, double blind Orthopedic 60 (300 U/kg) and 71 (100 U/kg)/69 control Not described 300 or 100 U/kg daily × 15 days None Decreased transfusion One patient with increased BP in treatment group
Feagan et al,77 2000 Randomized, double blind, placebo controlled Orthopedic (primary THA) 44 (40,000 U) and 79 (20,000 U)/78 control 9.8 ≤ Hb ≤ 13.7 g/dL 40,000 or 20,000 U weekly × 4 weeks Oral iron Decreased transfusion (lowest with high-dose ESA) None; no significant difference in thromboembolic events
Heiss et al,89 1996 Randomized, double blind, placebo controlled Oncology (colorectal surgery) 17/10 9 ≤ Hb ≤ 13 g/dL 150 U/kg every 2 days × 5 doses Oral iron and oral folate Increased Hb, no difference in transfusions 1 DVT, 2 episodes of HTN in treatment group
Kettelhack et al,90 1998 Prospective, randomized, double blind Oncology (colorectal surgery) 48/54 8.5 < Hb ≤ 13.5 g/dL 20,000 U/d × 10 days Oral iron for iron deficiency and 40 mg IV iron sulfate to all patients on POD 1 No difference in transfusion, increase in reticulocyte count in EPO group 1 arterial thrombosis, 1 episode of “chills with fever” possibly related to study drug
Kosmadakis et al,91 2003 Randomized, double blind Oncology (GI malignancy) 31/32 8.5 < Hb ≤ 13 g/dL 300 IU/kg, 7 days before and 7 days after surgery 100 mg IV iron for both groups Decreased transfusions, decreased postoperative complications, and improved 1-year survival None
Larson et al,86 2001 Randomized, open label Gynecologic (hysterectomy for uterine myoma) 15/16 <12 g/dL 5000 U 2×/wk, 4 weeks preoperatively 100 mg oral iron twice daily for both groups Increased Hb in both groups, but greater in ESA group None
Laupacis et al,78 1993 Multicenter, randomized, double blind, placebo controlled Orthopedic (primary or revision THA) 77 (300 U/kg × 14 days) and 53 (300 U/kg × 9 days)/78 control 11.0 < Hb < 16 g/dL Treatment began 10 days preoperatively; 300 U/kg daily × 14 days; placebo on preoperative days 10 to 6, then 300 U/kg daily × 9 days Oral iron Decreased frequency of perioperative transfusions No significant difference in DVT between groups
Na et al,79 2011 Randomized, open label Orthopedic (bilateral TKA, women) 54/54 Hb >10 g/dL and ferritin <100 ng/mL or ferritin 100–300 with transferrin saturation <20% 3000 U intraoperatively, up to 2 more times on POD 1, 2, 3, and 5 if Hb 7–8 g/dL 200 mg IV iron sucrose Higher postoperative Hb, decreased transfusion requirements Not reported
Qvist et al,87 1999 Randomized, double blind Colorectal surgery 38/43 ≤8.5 g/dL 300 U/kg on preoperative day 4, then 150 IU/kg × 7 days 200 mg oral iron for 4 days before surgery in both groups Decreased transfusions, increased intraoperative, and postoperative Hb No adverse events related to study drug
Scott et al,92 2002 Randomized, double blind, placebo controlled Oncologic (head/neck) 29/29 10 ≤ Hb ≤ 13.5 g/dL 600 U/kg × 3 doses within 19 days preoperatively 150 mg oral iron twice daily in both groups Increased Hb, increased transfusion avoidance, fewer units transfused None related to study drug (3 deaths in ESA group; 1 carotid anastomotic disruption, 1 myocardial infarction—known history, 1 stroke—known history)
So-Osman et al,80 2014 Multicenter, randomized Orthopedic (elective THA and TKA) 339/344 10 ≤ Hb ≤ 13 g/dL 40,000 U weekly × 4 doses 100 mg oral iron 3 times daily Decrease in % transfused, however, ESA use increased costs (£785 per patient and £7300 per avoided transfusion) No significant difference in thromboembolic events; 1 patient did not undergo surgery due to stroke after 1 ESA dose (Hb 12.2 g/dL)
Spahn et al,84 2019 Randomized, double blind Cardiac 243/241 <12 g/dL (female), <13 g/dL (male), or isolated iron deficiency (ferritin <100) 40,000 U × 1 dose the day before surgery 20 mg/kg IV iron, 1 mg subcutaneous vitamin B12, 5 mg oral folic acid Reduced RBC transfusions, higher Hb No significant differences in thromboembolic events
Stowell et al,74 2009 Multicenter randomized, open label Spine 340/340 Anticipated blood loss 2–4 U and Hb 10–13 g/dL 600 U/kg/wk × 4 doses on preoperative days 21, 14, 7, and 0 Oral iron in all patients Transfusion rates not measured, DVT primary outcome (see adverse events) Increased DVT in ESA group (4.7% vs 2.1%; no pharmacologic DVT prophylaxis); no differences in other thromboembolic events
Weber et al,81 2005 Multicenter randomized, open label Orthopedic, spine (hip, knee, spine) 460/235 10 ≤ Hb ≤ 13 g/dL 40,000 U weekly × 4 doses Oral iron × 3 weeks, also offered to control group if routine Higher Hb, lower transfusion rates No significant differences
Weltert et al,83 2010 Randomized, single blinded Cardiac (off pump CABG) 158/162 ≤14.5 g/dL 14,000 U daily × 2 (preoperative days 2 and 1), 8000 U day of surgery, 8000 U POD 1 and 2 None Decreased transfusions, increased postoperative Hb No significant difference in adverse events including thrombosis
Weltert et al,82 2015 Randomized, single blinded Cardiac Surgery 300/300 ≤14.5 g/dL 80,000 U given 2 days preoperatively Oral iron Decreased transfusions (effect only observed in patients with starting Hb <13 g/dL), higher postoperative Hb No significant differences
Wurnig et al,93 2001 Multicenter randomized Elective surgery (mainly orthopedic and cardiac) 70 (125 U/kg) and 64 (250 U/kg)/60 control 30 < Hct <42% 125 U/kg or 250 U/kg weekly × 3–4 weeks Oral iron daily Higher Hb (both ESA groups), reduced transfusion frequency (both ESA groups) No significant difference between groups, no thrombotic events related to study drug
Yoo et al,85 2011 Randomized single blinded Cardiac (valve surgery) 37/37 <12 g/dL (female), <13 g/dL (male) 500 U/kg 16–24 hours before surgery 200 mg IV iron 16–24 hours before surgery Lower transfusion frequency and units transfused reduced through day POD4 No significant differences
Abbreviations: CABG, coronary artery bypass grafting; DVT, deep venous thrombosis; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; GI, gastrointestinal; Hb, hemoglobin; Hct, hematocrit; HTN, hypertension; POD, postoperative day; RBC, red blood cell; THA, total hip arthroplasty; TKA, total knee arthroplasty.

In gynecologic surgery, ESA use combined with iron supplementation is accompanied by transfusion reduction with no significant differences in adverse events when compared to control groups.85,86 It should be noted, however, that IDA is highly prevalent in this population and utilization of an iron replacement strategy alone may be sufficient for anemia management while allowing avoidance of ESA therapy in patients who may have additional risk factors for thromboembolic complications such as hormone replacement therapy or malignancy. Similarly, multiple trials exist regarding ESA use before oncologic surgery,87–92 with most showing significant hemoglobin increases and transfusion reduction.87,88,91,92 Two investigations, although limited in size, noted a single thromboembolic event potentially related to ESA therapy.89,90 Of note, the majority of trials were performed for gastrointestinal or colorectal malignancies,87–91 a group that is at high risk for IDA. It is essential to focus anemia management efforts on identifying the etiology of anemia so that treatments may be tailored appropriately to address the underlying cause(s) rather than applying a one-size-fits-all approach.

For preoperative patients with AI, we recommend that epoetin alfa be administered at a dose of 600 units/kg subcutaneous weekly at least 3 weeks before surgery. This should always occur after iron repletion, because adequate iron stores are required for the production of erythroid progenitor cells. For those with glomerular filtration rate (GFR) <30 mL/min/1.73 m2 not already receiving ESA therapy chronically, therapy should target a hemoglobin of not >11 g/dL.94 Optimal dosing strategies for children are unclear, although several strategies have been described. One strategy recommends 100–300 units/kg 3 times weekly, while another suggests 600 units/kg once weekly for 1–3 weeks before surgery.95–98 Epoetin does not cross the placenta and has been used for severe pregnancy-associated anemia,99–101 although multidose vials should not be utilized due to the presence of benzyl alcohol. Due to potential thrombotic risk, ESA therapy may not be appropriate for patients with uncontrolled hypertension, recent coronary or cerebral ischemic events, and those with an inability to receive perioperative prophylactic anticoagulant therapy.

Other Treatment Options

While many patients with preoperative anemia have IDA and/or AI that may be treated with iron or ESAs, there are other causes of anemia that must be considered. Folate and vitamin B12 deficiencies (macrocytic anemia, defined by mean corpuscular volumes [MCVs] >100 fL), renal disease, and hematologic conditions may also cause anemia and should be evaluated.35

Folate deficiency may develop subacutely (within weeks) because there is limited storage of the vitamin in the body. Treatment depends on the severity of presenting symptoms. Most patients are asymptomatic, and hence they may be treated with oral folic acid 1 mg daily.102 For patients with severe anemia, neonates or infants, pregnant women, or those with neurologic findings, parenteral therapy may be considered. Vitamin B12 deficiency takes months to years to develop. For adults with normal gastrointestinal absorption, oral replacement is acceptable (1000 µg daily).103 For those with severe symptomatic anemia, a weekly 1000 µg intramuscular injection may be performed until levels normalize, followed by monthly or every other month maintenance administration. The duration of folate and vitamin B12 therapy will depend on the resolution or persistence of the underlying cause with irreversible causes leading to lifelong therapy. After starting treatment, hemoglobin concentrations may begin to improve as early as 10 days.104

An elevated reticulocyte count should raise suspicion for ongoing hemolysis that can be detected by performing a direct antiglobulin test, a peripheral blood smear, or by measuring lactate dehydrogenase, haptoglobin, and bilirubin. Those with coexistent thrombocytopenia or leukopenia may have an underlying blood dyscrasia. Further investigation of each of these conditions should be performed in consultation with a hematologist. In those with chronic kidney disease, GFR is positively associated with hemoglobin and erythropoietin levels.105 For patients with newly diagnosed renal disease discovered during an anemia workup, referral to a nephrologist may be warranted.

Additional Intraoperative Considerations

As a general principle in medicine, prevention is often the best treatment. This is particularly true with anemia. However, the appropriate evaluation and management of preoperative anemia is only one aspect of comprehensive perioperative PBM efforts. Multiple safe and effective strategies are available to reduce surgical blood loss and address anemia and coagulation status throughout the perioperative period (Figure 2).106 Intraoperatively, efforts must focus on preserving RBC mass and optimizing hemostasis.

F2
Figure 2.:
A Patient Blood Management approach to perioperative care. A description of commonly used techniques in patient blood management throughout the preoperative, intraoperative, and postoperative phases of care. ANH indicates acute normovolemic hemodilution; ESA, erythropoiesis-stimulating agent; PCC, prothrombin complex concentrates; RBC, red blood cell; VTE, venous thromboembolism.

Intraoperative preservation of RBC mass includes use of cell salvage and acute normovolemic hemodilution (ANH). Although not widely adopted clinically, meta-analyses have demonstrated that ANH reduces allogeneic blood transfusions in both cardiac and noncardiac surgery.107,108 The efficacy of ANH is largely dependent on the preoperative hemoglobin, the volume of sequestered blood, and the surgical procedure. As ANH is most effective with higher hemoglobin levels, this further highlights the importance of preoperative anemia management. Perioperative cell salvage is also consistently associated with transfusion reduction and is recommended for surgical procedures with high intraoperative blood loss.109 There are few absolute contraindications (eg, admixing with bone cement or topical hemostatics, contamination with contraindicated fluids), and it has been used safely in oncologic surgery110 and obstetrics.111

Another important aspect of PBM includes optimizing coagulation.112 Lysine analog antifibrinolytic agents such as tranexamic acid and epsilon aminocaproic acid are used prophylactically and therapeutically to stabilize bleeding in many surgical arenas. Abundant literature supports their use in cardiac, orthopedic, and spine surgery, and in maternal obstetrical hemorrhage and trauma.113–117 Point-of-care viscoelastic testing allows for the identification of patients with hyperfibrinolysis in whom antifibrinolytic therapy is most appropriate.118 Additional techniques to minimize bleeding include permissive hypotension in trauma surgery119 and maintenance of low central venous pressure during hepatic surgery.120 In the face of coagulopathy, targeted management of specific hemostatic defects identified using point-of-care testing is preferred. Treatment algorithms often contain pharmacologic agents instead of blood components (eg, prothrombin complex concentrates instead of plasma), thereby limiting the transfusion of allogeneic blood products.121,122

Postoperative Anemia Management

It is essential to frame anemia as a preventable and treatable clinical condition throughout the entire perioperative encounter. To that end, we must apply the same vigilance that we have for preoperative and intraoperative anemia to the postoperative period, recognizing that this represents the critical period of patient recovery. Postoperative anemia is remarkably common, yet little is done to evaluate and treat the underlying causes. Efforts should focus on the minimization of iatrogenic blood loss and the promotion of new RBC production.

Many patients with large intraoperative blood loss or persistent postoperative bleeding are prone to the development of absolute or functional iron deficiency and may thereby benefit from iron supplementation. Previous investigations across a variety of surgeries have shown that the administration of IV iron postoperatively is associated with improved hemoglobin recovery and reduced transfusion requirements.123,124 Although laboratory triggers for postoperative IV iron supplementation have not been definitively established, ferritin levels <100 μg/L in the presence of postsurgical anemia are likely suggestive of iron-restricted erythropoiesis and may be utilized to determine treatment.125 Future work is needed to further identify optimal target populations for postoperative iron supplementation and to assess the relationships between iron administration and recovery of hemoglobin and function capacity after surgery.

Similar to other hospitalized patients, surgical patients are at high risk for progressive anemia throughout hospitalization. In a multicenter observational study of nearly 190,000 unique hospitalizations, approximately three-quarters of patients without preexisting anemia developed anemia during hospitalization, with that number approaching 90% for surgical patients.32 Moreover, the severity of hospital-acquired anemia was associated with increased mortality and resource utilization, further highlighting the importance of attenuating the degree of anemia development. Although hospital-acquired anemia is often multifactorial, iatrogenic blood loss through phlebotomy is a substantial contributor,32 and in the critically ill, iatrogenic losses may account for up to 40% of RBC transfusion requirements.126 It is therefore essential to minimize both the volume and frequency of phlebotomy for all hospitalized patients, which may include the use of minimal volume blood draws, closed-loop sampling systems, and the use of clinical decision support to verify the necessity of laboratory testing. Routine postoperative laboratory testing should never be performed without a clear indication.

Other causes of anemia in the postoperative period include inadequate nutritional status and the development of AI for those with prolonged hospitalization or critical illness. Studies in the critically ill have shown consistent improvement in hemoglobin concentrations with ESA and/or iron use,127 but the efficacy and safety of postoperative ESA use in postsurgical patients is limited outside of select patient groups (ie, those of the Jehovah’s Witness faith). For now, postoperative management should focus on preventing iatrogenic blood loss and ensuring adequate iron stores and nutritional status to support erythropoiesis.

Special Populations

Certain specific patient groups present unique considerations for perioperative anemia management, including pediatric and oncologic surgical patients and those for whom blood is not an option (eg, Jehovah’s Witnesses). While it is beyond the scope of this work to discuss comprehensive management of these patient groups, there are several important considerations that should be made. First, anemia is common in pediatric populations, occurring preoperatively in approximately one-quarter of patients with available hemoglobin assessments,128 and is associated with increased perioperative mortality.129 While previous studies have noted reductions in transfusion requirements with ESAs and/or iron utilization in select pediatric groups,97,130–132 there are not enough data to make recommendations regarding the routine use of these agents in pediatric patients.

Anemia is also common in oncology patients, with one-third presenting with anemia at diagnosis and two-thirds at 6-month follow-up.133 Etiology of anemia includes blood loss, nutritional deficiencies, chronic inflammation, bone marrow involvement, and chemotherapy.134 Regardless of the cause, anemia remains an independent risk factor for poor prognosis in cancer patients, particularly in the perioperative setting,135 and increases the risk of allogeneic blood transfusions, which in turn are associated with poor clinical outcomes and increased risk of tumor recurrence.136,137

The use of ESAs in cancer patients is hotly debated due to published yet controversial potential adverse effects including tumor progression, tumor recurrence, myocardial infarction, stroke, VTE, and early mortality.138 Notably, many of these concerns were derived from trials in nonsurgical oncologic patients utilizing large doses of ESAs for extended periods of time, particularly when targeting normal or near-normal hemoglobin levels.139–141 Current evidence supports the safety of short-term on-label preoperative ESA use in oncology patients with anemia.142

A third patient population that requires unique consideration is patients for whom blood transfusion is not an option. This includes patients who would decline blood transfusion secondary to moral or religious beliefs, predominately those of the Jehovah’s Witness faith, and patients for whom adequately cross-matched blood is not available. Anemia is predominately treated with weekly ESAs and IV iron,143 although for urgent procedures, epoetin alfa may be dosed daily (300 units/kg). Outcomes are generally favorable in these populations when managed with blood conservation techniques144,145; however, studies have shown increased morbidity and mortality in patients with severe anemia unable to be transfused,146–148 and therefore, this population may warrant more aggressive treatment of anemia before undergoing procedures with the potential for high blood loss. Of note, treating anemia is only one part of the larger blood conservation protocol that should be used to safely and successfully care for patients who decline blood transfusion.

CONCLUSIONS

Perioperative anemia is common and associated with poor patient outcomes. It is essential to recognize and evaluate anemia at all time points during the perioperative encounter. Patients undergoing elective surgery should be screened for preoperative anemia, and treatment should be tailored to the underlying etiology. The risks and benefits of treatment must be carefully considered for each individual patient, a process that requires thorough evaluation of anemia-related features, surgical details, and unique patient characteristics. Finally, it should be recognized that preoperative anemia management only comprises 1 piece of broader PBM initiatives, and multiple aspects of PBM should be simultaneously considered at all stages of perioperative care for the optimization of blood health and improved perioperative outcomes.

ACKNOWLEDGMENTS

The authors would like to thank the members of the American Society of Anesthesiologists Committee on Patient Blood Management for developing this educational concept and identifying the need for education.

DISCLOSURES

Name: Matthew A. Warner, MD.

Contribution: This author helped conceive and design the review, write and revise the manuscript, and approve the final draft.

Conflicts of Interest: None.

Name: Linda Shore-Lesserson, MD.

Contribution: This author helped conceive and design the review, write and revise the manuscript, and approve the final draft.

Conflicts of Interest: None.

Name: Aryeh Shander, MD.

Contribution: This author helped conceive and design the review, write and revise the manuscript, and approve the final draft.

Conflicts of Interest: A. Shander is a consultant for AMAG, CSL Behring, HbO2 Therapeutics, LLC, Instrumentation Laboratory, Masimo Corporation, Portola Pharmaceuticals, and Vifor Pharma; is on the speakers’ bureau for CSL Behring, Masimo, Merck, and Portola Pharmaceuticals; and has grants/ research related to CSL Behring, HbO2 Therapeutics, LLC, Instrumentation Laboratory, and Masimo.

Name: Sephalie Y. Patel, MD.

Contribution: This author helped conceive and design the review, write and revise the manuscript, and approve the final draft.

Conflicts of Interest: None.

Name: Seth I. Perelman, MD.

Contribution: This author helped conceive and design the review, write and revise the manuscript, and approve the final draft.

Conflicts of Interest: None.

Name: Nicole R. Guinn, MD.

Contribution: This author helped conceive and design the review, write and revise the manuscript, and approve the final draft.

Conflicts of Interest: None.

This manuscript was handled by: Susan Goobie, MD, FRCPC.

FOOTNOTES

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