Advertisement

Treatment Strategies in Anemic Patients Before Cardiac Surgery

Open AccessPublished:September 22, 2022DOI:https://doi.org/10.1053/j.jvca.2022.09.085
      Both preoperative anemia and the transfusion of red blood cells have been associated with increased morbidity and mortality after cardiac surgery. To reduce the need for blood transfusion during surgery and improve patient outcomes, patient blood management programs have been developed. A primary focus of patient blood management in the preoperative period is the identification, diagnosis, and treatment of preoperative anemia, as anemia is associated with an increased risk of preoperative blood transfusion. In this narrative review, the authors focus on the laboratory screening of anemia before surgery and the evidence and limitations of different treatment strategies in anemic patients scheduled for cardiac surgery. To accurately correct preoperative anemia, the timely detection and definition of the etiology of anemia before elective cardiac surgery are crucial. Multiple randomized studies have been performed using preoperative iron supplementation and/or administration of erythropoiesis-stimulating agents in patients undergoing cardiac surgery. Although preoperative iron substitution in patients with iron deficiency is recommended, the evidence of its effectiveness is limited. In patients with nonpure iron deficiency anemia, combined therapy with erythropoiesis-stimulating agents and intravenous iron is recommended. Combined therapy might effectively reduce the need for red blood cell transfusion, even if applied shortly before cardiac surgery. The therapeutic effect on morbidity and mortality remains unclear. Nonetheless, the timely preoperative assessment of anemia and determination of iron status, eventually leading to targeted therapy, should become a standard of care and might potentially improve patient outcomes.

      Key Words

      CARDIAC SURGERY IS associated with high rates of transfused allogeneic blood products.
      • Tinegate H
      • Pendry K
      • Murphy M
      • et al.
      Where do all the red blood cells (RBCs) go? Results of a survey of RBC use in England and North Wales in 2014.
      Red blood cells (RBC) are administered to about 30%-to-50% of all patients.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      • Klein AA
      • Collier T
      • Yeates J
      • et al.
      The ACTA PORT-score for predicting perioperative risk of blood transfusion for adult cardiac surgery.
      • Tanaka KA
      • Alejo D
      • Ghoreishi M
      • et al.
      Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
      • Klein AA
      • Collier TJ
      • Brar MS
      • et al.
      The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK - the first Association of Cardiothoracic Anaesthetists national audit.
      • Kattou F
      • Montandrau O
      • Rekik M
      • et al.
      Critical preoperative hemoglobin value to predict anemia-related complications after cardiac surgery.
      • Hare GMT
      • Mazer CD.
      Anemia: Perioperative risk and treatment opportunity.
      • Ripoll JG
      • Smith MM
      • Hanson AC
      • et al.
      Sex-specific associations between preoperative anemia and postoperative clinical outcomes in patients undergoing cardiac surgery.
      Former studies have shown impaired outcomes with RBC transfusion in cardiac surgery.
      • Murphy GJ
      • Reeves BC
      • Rogers CA
      • et al.
      Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery.
      • LaPar DJ
      • Hawkins RB
      • McMurry TL
      • et al.
      Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery?.
      • Koch CG
      • Li L
      • Duncan AI
      • et al.
      Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting.
      In order to reduce RBC transfusion and improve patient outcomes, patient blood management (PBM) has been developed.
      • Bolliger D
      • Buser A
      • Erb JM.
      Patient blood management in cardiac surgery.
      • Bolliger D
      • Erb JM
      • Buser A.
      Controversies in the clinical practice of patient blood management.
      • Frietsch T
      • Shander A
      • Faraoni D
      • et al.
      Patient blood management is not about blood transfusion: It is about patients' outcomes.
      Patient blood management is an evidence-based concept aiming for preoperative conservation or boosting of a patient's own blood reserves, optimization of perioperative hemostasis, and minimization of blood loss. The clinical introduction of PBM programs has reduced the rate of allogeneic RBC transfusion and hospital length of stay in several studies,
      • Roman MA
      • Abbasciano RG
      • Pathak S
      • et al.
      Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis.
      ,
      • Gross I
      • Seifert B
      • Hofmann A
      • et al.
      Patient blood management in cardiac surgery results in fewer transfusions and better outcome.
      but did not result in relevantly lower morbidity and mortality.
      • Roman MA
      • Abbasciano RG
      • Pathak S
      • et al.
      Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis.
      ,
      • Spahn DR
      • Schoenrath F
      • Spahn GH
      • et al.
      Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial.
      Further, the cost-effectiveness of PBM interventions has been questioned.
      • Roman MA
      • Abbasciano RG
      • Pathak S
      • et al.
      Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis.
      Nonetheless, PBM is an important concept and might eventually improve patient outcomes,
      • Bolliger D
      • Erb JM
      • Buser A.
      Controversies in the clinical practice of patient blood management.
      especially in cardiac surgery.
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      One important cornerstone of PBM in cardiac surgery is the diagnosis and treatment of preoperative anemia. In this narrative review, the authors focused on the laboratory screening of anemia before surgery and the evidence and limitations of different treatment strategies in anemic patients scheduled for cardiac surgery.

      Search Strategy

      An extensive literature search in PubMed was performed using the following terms: (preoperative) AND (anemia) AND (cardiac surgery) on May 1, 2022. The search identified 720 publications. The authors excluded publications that were written in languages other than English and pediatric cardiac surgery studies, and focused on clinical studies, clinical trials, meta-analyses, randomized controlled trials (RCTs), and systematic and nonsystematic reviews published after 2012. After reading the abstracts, the authors identified 65 publications investigating the potential impact of preoperative anemia on postoperative outcomes and interventions to improve RBC mass in patients before cardiac surgery. Publications of potential interest were assessed critically and eventually included in this review.

      Impact of Anemia in Cardiac Surgery Patients

      The World Health Organization (WHO) definition of anemia (hemoglobin values <13 g/dL in men, <12 g/dL in women) is most commonly used for diagnosing preoperative anemia.
      • Bolliger D
      • Mauermann E
      • Buser A.
      Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
      When assessed according to these criteria, about 20%-to-50% of patients undergoing cardiac surgery suffer from preoperative anemia,
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Tanaka KA
      • Alejo D
      • Ghoreishi M
      • et al.
      Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
      ,
      • Klein AA
      • Collier TJ
      • Brar MS
      • et al.
      The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK - the first Association of Cardiothoracic Anaesthetists national audit.
      ,
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      ,
      • Padmanabhan H
      • Siau K
      • Curtis J
      • et al.
      Preoperative anemia and outcomes in cardiovascular surgery: Systematic review and meta-analysis.
      ,
      • Ranucci M
      • Pavesi M
      • Pistuddi V
      • et al.
      Preoperative anemia correction in cardiac surgery: A propensity-matched study.
      with especially high incidences in older patients or in patients with chronic diseases and/or multiple comorbidities.
      • Guralnik JM
      • Eisenstaedt RS
      • Ferrucci L
      • et al.
      Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia.
      Preoperative anemia can be divided into mild (hemoglobin 11-12.9 g/dL in men, 11-11.9 g/dL in women) and moderate-to-severe anemia (hemoglobin <11 g/dL in men and women).
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Scrascia G
      • Guida P
      • Caparrotti SM
      • et al.
      Incremental value of anemia in cardiac surgical risk prediction with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II model.
      ,
      • von Heymann C
      • Kaufner L
      • Sander M
      • et al.
      Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
      Multiple studies have shown preoperative anemia to be associated with increased perioperative RBC transfusion, postoperative morbidity, including stroke, myocardial infarction, acute kidney injury (AKI), infections, and reduced short- and long-term survival after cardiac surgery.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Kattou F
      • Montandrau O
      • Rekik M
      • et al.
      Critical preoperative hemoglobin value to predict anemia-related complications after cardiac surgery.
      ,
      • Ripoll JG
      • Smith MM
      • Hanson AC
      • et al.
      Sex-specific associations between preoperative anemia and postoperative clinical outcomes in patients undergoing cardiac surgery.
      ,
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      ,
      • Padmanabhan H
      • Siau K
      • Curtis J
      • et al.
      Preoperative anemia and outcomes in cardiovascular surgery: Systematic review and meta-analysis.
      ,
      • Ranucci M
      • Pavesi M
      • Pistuddi V
      • et al.
      Preoperative anemia correction in cardiac surgery: A propensity-matched study.
      ,
      • Ranucci M
      • Di Dedda U
      • Castelvecchio S
      • et al.
      Impact of preoperative anemia on outcome in adult cardiac surgery: A propensity-matched analysis.
      When compared with mild anemia (hemoglobin >11 g/dL), severe preoperative anemia was associated repeatedly with a higher risk of perioperative transfusion and postoperative morbidity and mortality.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Scrascia G
      • Guida P
      • Caparrotti SM
      • et al.
      Incremental value of anemia in cardiac surgical risk prediction with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II model.
      ,
      • von Heymann C
      • Kaufner L
      • Sander M
      • et al.
      Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
      These findings were confirmed recently by a large nation-wide Dutch observational study including >35,000 patients. Preoperative anemia was associated independently with 120-day mortality (adjusted odds ratio 1.7; 95% CI: 1.4-2.0; p < 0.001). Furthermore, anemia increased the risk of AKI, postoperative myocardial infarction, redo thoracotomy, pneumonia, prolonged tracheal intubation, and readmission to the intensive care unit. Finally, severe anemia was associated with worse postoperative outcomes compared to moderate or mild anemia.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      Of note, the WHO criteria for anemia might not be an ideal preoperative risk assessment tool. The optimal preoperative hemoglobin levels and targets to avoid or minimize perioperative RBC transfusion and postoperative complications have yet to be defined.
      • Butcher A
      • Richards T
      • Stanworth SJ
      • et al.
      Diagnostic criteria for pre-operative anaemia-time to end sex discrimination.
      • Munoz M
      • Acheson AG
      • Auerbach M
      • et al.
      International consensus statement on the peri-operative management of anaemia and iron deficiency.
      • Munting KE
      • Klein AA.
      Optimisation of pre-operative anaemia in patients before elective major surgery - why, who, when and how?.
      They might vary with the type of surgery, sex, age, and dynamics of preoperative hemoglobin decline.
      • Zakai NA
      • French B
      • Arnold AM
      • et al.
      Hemoglobin decline, function, and mortality in the elderly: The cardiovascular health study.
      A recent retrospective health data analysis has suggested that the calculated RBC mass, rather than the absolute hemoglobin value, might be better suited to predict the probability of perioperative transfusion.
      • Tanaka KA
      • Alejo D
      • Ghoreishi M
      • et al.
      Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
      Thereby, differences between the sexes could be, at least partially, eliminated.
      • Butcher A
      • Richards T
      • Stanworth SJ
      • et al.
      Diagnostic criteria for pre-operative anaemia-time to end sex discrimination.
      ,
      • O'Shaughnessy S
      • Tangel V
      • Dzotsi S
      • et al.
      Non-white race/ethnicity and female sex are associated with increased allogeneic red blood cell transfusion in cardiac surgery patients: 2007-2018.
      Both the presence of anemia and the perioperative transfusion of RBC are predictors of organ injury, adverse outcomes, and mortality after cardiac surgery.
      • Murphy GJ
      • Reeves BC
      • Rogers CA
      • et al.
      Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery.
      ,
      • LaPar DJ
      • Hawkins RB
      • McMurry TL
      • et al.
      Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery?.
      ,
      • von Heymann C
      • Kaufner L
      • Sander M
      • et al.
      Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
      ,
      • Padmanabhan H
      • Brookes MJ
      • Nevill AM
      • et al.
      Association between anemia and blood transfusion with long-term mortality after cardiac surgery.
      ,
      • Engoren M
      • Schwann TA
      • Habib RH
      • et al.
      The independent effects of anemia and transfusion on mortality after coronary artery bypass.
      Comorbidities, such as heart failure, chronic diseases, renal failure, and cancer, are more common in anemic patients and have a relevant impact on postoperative outcomes.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Bolliger D
      • Mauermann E
      • Buser A.
      Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
      ,
      • Michalak SS
      • Rupa-Matysek J
      • Gil L.
      Comorbidities, repeated hospitalizations, and age ≥80 years as indicators of anemia development in the older population.
      It remains difficult to determine whether anemia is a direct risk factor or whether it is a sign of the severity of associated comorbidities.
      • Bolliger D
      • Mauermann E
      • Buser A.
      Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
      Furthermore, separating the risk of increased postoperative morbidity and mortality as a result of preoperative anemia from the risk associated with perioperative RBC transfusion remains difficult.
      • Bolliger D
      • Mauermann E
      • Buser A.
      Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
      ,
      • von Heymann C
      • Kaufner L
      • Sander M
      • et al.
      Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
      Although some publications have suggested a relevant additional impact of RBC transfusion in anemic patients,
      • LaPar DJ
      • Hawkins RB
      • McMurry TL
      • et al.
      Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery?.
      ,
      • Engoren M
      • Schwann TA
      • Habib RH
      • et al.
      The independent effects of anemia and transfusion on mortality after coronary artery bypass.
      other studies have not been able to demonstrate that transfused anemic patients had higher mortality compared with transfused nonanemic patients.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Padmanabhan H
      • Brookes MJ
      • Nevill AM
      • et al.
      Association between anemia and blood transfusion with long-term mortality after cardiac surgery.

      Diagnostic Assessment in Preoperative Anemia

      Anemia before cardiac surgery is often multifactorial.
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      ,
      • Tanaka KA
      • Alejo D
      • Ghoreishi M
      • et al.
      Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
      ,
      • Klein AA
      • Collier TJ
      • Brar MS
      • et al.
      The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK - the first Association of Cardiothoracic Anaesthetists national audit.
      ,
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      ,
      • Padmanabhan H
      • Siau K
      • Curtis J
      • et al.
      Preoperative anemia and outcomes in cardiovascular surgery: Systematic review and meta-analysis.
      ,
      • Ranucci M
      • Pavesi M
      • Pistuddi V
      • et al.
      Preoperative anemia correction in cardiac surgery: A propensity-matched study.
      Common causes of anemia include chronic bleeding (especially gastrointestinal), the deficiency of specific substrates, including iron, folic acid, or vitamin B12, erythropoietin deficiency (eg, in chronic renal failure patients), chronic hemolysis, concomitant chronic diseases (anemia of chronic disease), and advanced age (anemia of the older patient) (Fig 1).
      • Camaschella C.
      Iron-deficiency anemia.
      • Goodnough LT
      • Schrier SL.
      Evaluation and management of anemia in the elderly.
      • Weiss G
      • Goodnough LT.
      Anemia of chronic disease.
      • Karski JM
      • Mathieu M
      • Cheng D
      • et al.
      Etiology of preoperative anemia in patients undergoing scheduled cardiac surgery.
      Timely detection and defining the etiology of anemia before elective cardiac surgery are crucial to allow for preoperative treatment. Ideally, diagnostic testing followed by corrective measures should be initiated 4-to-6 weeks before elective surgery for the potentially successful correction of anemia, or at least a relevant increase of RBC mass.
      • Goodnough LT
      • Maniatis A
      • Earnshaw P
      • et al.
      Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines.
      ,
      • Munoz M
      • Gomez-Ramirez S
      • Kozek-Langeneker S.
      Pre-operative haematological assessment in patients scheduled for major surgery.
      Fig 1
      Fig 1Diagnostic approach to anemia. The algorithm shows a laboratory-based approach to anemic patients in the general population. This algorithm might not be applicable in most patients before surgery due to time requirements (several weeks) and the need for specific consultations with hematologists. ACD, anemia of chronic disease; CRP, C-reactive protein; DD, differential diagnosis; Hb, hemoglobin; MCH, mean cell hemoglobin; MCV, mean cell volume; MDS; myelodysplastic syndrome.
      Multiple screening algorithms have been described to differentiate among the different etiologies of anemia. Table 1 shows typical laboratory findings with different types of anemia. It is commonly recommended to perform a full blood count, including reticulocyte count, ferritin levels, transferrin concentration, transferrin saturation, and levels of soluble transferrin receptor. More elaborate laboratory tests might be helpful in specific hematologic patients to exclude particular hematologic diseases (eg, myelodysplastic syndromes). It might also be recommended to determine C-reactive protein (CRP) and creatinine levels.
      Table 1Laboratory Characteristics of Iron-Deficiency Anemia and Anemia of Chronic Disease
      • Weiss G
      • Goodnough LT.
      Anemia of chronic disease.
      VariableIron-Deficiency AnemiaAnemia of Chronic DiseaseAnemia Due to Both Conditions
      Hemoglobin
      Mean corpuscular volume↓/normal
      Reticulocyte count
      Serum iron level
      Ferritinnormal/↑↓/normal
      Transferrin↓/normal↓/normal
      Transferrin saturation
      Soluble transferrin receptornormalnormal/↑
      Erythropoietin levelsnormal/slightly ↑↑/normal
      C-reactive proteinnormal↑/normalnormal/↑
      NOTE. Modified after Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-23.36
      Despite different pathophysiologic pathways, many or even most of these etiologies will result in an absolute or functional iron deficiency. Absolute iron deficiency can be found in patients with reduced dietary iron intake or chronic blood loss, whereas functional iron deficiency is caused mainly by chronic inflammation, malignancy, renal failure, and advanced age. It has been described that inflammatory cytokines will activate hepatic hepcidin expression, eventually leading to impaired iron absorption from the gut and iron integration into hemoglobin. This cytokine-mediated functional iron deficiency might be common in patients presenting for cardiac surgery due to multiple comorbidities and chronic inflammatory reactions.
      • Weiss G
      • Goodnough LT.
      Anemia of chronic disease.
      ,
      • Fertrin KY.
      Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): Is too little iron making your patient sick?.
      It has been suggested that about one-third of patients scheduled for cardiac surgery present with iron deficiency anemia. These patients might have a higher risk for RBC transfusion than non-iron deficient anemic patients with similar hemoglobin values.
      • Abraham J
      • Sinha R
      • Robinson K
      • et al.
      Aetiology of preoperative anaemia in patients undergoing elective cardiac surgery-the challenge of pillar one of patient blood management.
      The above-mentioned laboratory tests might also be helpful in defining absolute or functional iron deficiency in patients not fulfilling the WHO criteria for anemia.
      Some laboratories offer the determination of erythropoietin levels (Table 1). Hypoxia is the basic stimulant in the production of erythropoietin, eventually resulting in the increased production of erythrocytes. The increased capacity to carry oxygen to peripheral organs, resulting in reduced hypoxic stimulus, provides negative feedback for stopping erythropoietin production. In a recent study including 562 patients with and without renal insufficiency, erythropoietin levels were correlated negatively with hemoglobin values (ie, erythropoietin levels were lower with higher hemoglobin concentration) in patients with normal or slightly impaired renal function.
      • Panjeta M
      • Tahirovic I
      • Karamehic J
      • et al.
      The relation of erythropoietin towards hemoglobin and hematocrit in varying degrees of renal insufficiency.
      In patients with chronic renal failure, hypo-regenerative anemia is commonly due to inadequate erythropoietin production. Accordingly, no correlation between hemoglobin values and erythropoietin levels was found in patients with relevantly impaired renal function.
      • Panjeta M
      • Tahirovic I
      • Karamehic J
      • et al.
      The relation of erythropoietin towards hemoglobin and hematocrit in varying degrees of renal insufficiency.
      However, erythropoietin levels are difficult to interpret in patients with chronic anemia, and determination of erythropoietin levels might have limited benefits in the perioperative setting.
      Findings in laboratory testing might differ in patients before cardiac surgery as compared to the general population. It has been shown that about 45% of patients have above upper normal level CRP values before cardiac surgery, suggesting an increased inflammatory state.
      • Rossler J
      • Hegemann I
      • Schoenrath F
      • et al.
      Efficacy of quadruple treatment on different types of pre-operative anaemia: Secondary analysis of a randomised controlled trial.
      Similarly, about one-fourth of patients have low endogenous erythropoietin levels before cardiac surgery. Accordingly, algorithms and thresholds used in the general population (Fig 1) might not be transferred directly to patients before cardiac surgery. Simplified algorithms, including full blood count, ferritin, transferrin saturation, creatinine, and CRP, might be better suited in the preoperative patient for reasons of time, therapeutic opportunities, and cost-effectiveness.
      • Ranucci M
      • Pavesi M
      • Pistuddi V
      • et al.
      Preoperative anemia correction in cardiac surgery: A propensity-matched study.
      ,
      • Goodnough LT
      • Maniatis A
      • Earnshaw P
      • et al.
      Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines.
      ,
      • Munoz M
      • Gomez-Ramirez S
      • Kozek-Langeneker S.
      Pre-operative haematological assessment in patients scheduled for major surgery.
      ,
      • Rossler J
      • Hegemann I
      • Schoenrath F
      • et al.
      Efficacy of quadruple treatment on different types of pre-operative anaemia: Secondary analysis of a randomised controlled trial.
      Thereby, patients usually can be assigned to groups of iron deficiency without anemia, iron-deficiency anemia, renal anemia, anemia of inflammation, and non-iron-deficient nonanemic patients. The latter might allow for simplified and rapid treatment decisions without the consultation of a hematologist. The treatment of preoperative anemia in cardiac surgery based on simple laboratory screening tests should become a standard of care. Figure 2 shows the modified version of an algorithm used at the authors’ institution. The algorithm primarily aims to identify patients with iron-deficiency anemia who might be treated easily with iron infusion shortly before surgery. As the use of erythropoiesis-stimulating agents (ESA) before cardiac surgery requires specific time-consuming approvals by the insurance providers in Switzerland, these agents are used only in a minority of patients in the authors’ institution.
      Fig 2
      Fig 2Modified algorithm from the Pre-Anesthesia Clinic at the University Hospital Basel. The authors’ algorithm primarily aims to identify patients with iron-deficiency anemia and patients with severe anemia. Intravenous iron therapy can be directly performed after rapid laboratory testing in the preoperative anesthesia clinic. IV, intravenous.

      Treatment Strategies

      Defining the subtypes of anemia based on laboratory testing (Table 1) seems to be the key for specific and individualized therapy. However, the hemoglobin thresholds at which to start treating are not well- defined and might differ considering the underlying pathology and patient conditions.
      Iron deficiency is common before cardiac surgery, but exclusive iron substitution only might be beneficial for specific subtypes of anemia. Iron supplementation should be initiated as soon as possible according to published formulas that calculate the iron deficit. Although preoperative iron substitution in patients with iron-deficiency anemia scheduled for surgery with a transfusion probability >10% is recommended,
      American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*.
      ,
      • Kotze A
      • Harris A
      • Baker C
      • et al.
      British Committee for Standards in Haematology G Guidelines on the identification and management of pre-operative anaemia.
      the evidence of its effectiveness with respect to reduction of perioperative RBC transfusion and improved outcomes is scarce.
      • Ng O
      • Keeler BD
      • Mishra A
      • et al.
      Iron therapy for pre-operative anaemia.
      Oral iron therapy has long been the standard way of treatment in iron-deficient therapy, and is still recommended in some guidelines. However, the longer duration of therapy, the lower bioavailability, and the limited tolerance to oral iron in many patients often render this approach insufficient for rapid and effective preoperative iron substitution.
      • Hare GMT
      • Mazer CD.
      Anemia: Perioperative risk and treatment opportunity.
      Intravenous (IV) iron therapy is favored for replenishing iron stores and for improving hemoglobin values shortly before surgery,
      • Hare GMT
      • Mazer CD.
      Anemia: Perioperative risk and treatment opportunity.
      ,
      • Kotze A
      • Harris A
      • Baker C
      • et al.
      British Committee for Standards in Haematology G Guidelines on the identification and management of pre-operative anaemia.
      but might be associated with a higher risk of anaphylactic reactions and higher costs.
      Iron deficiency without anemia also has been identified as a risk factor for adverse outcomes in cardiac surgery patients.
      • Rossler J
      • Schoenrath F
      • Seifert B
      • et al.
      Iron deficiency is associated with higher mortality in patients undergoing cardiac surgery: A prospective study.
      A prospective observational study with 730 patients undergoing elective cardiac surgery showed that the diagnosis of preoperative iron deficiency increased the risk of 90-day mortality from 2%-to-5% in patients without anemia, and from 4%-to-14% in patients with anemia. Moreover, iron deficiency led to an increased incidence of serious adverse events, including major adverse cardiac and cerebrovascular events, increased transfusions, and prolonged hospital stay.
      • Rossler J
      • Schoenrath F
      • Seifert B
      • et al.
      Iron deficiency is associated with higher mortality in patients undergoing cardiac surgery: A prospective study.
      Thus, iron supplementation might be indicated even in nonanemic patients before cardiac surgery.
      • Anand IS
      • Gupta P.
      Anemia and iron deficiency in heart failure: Current concepts and emerging therapies.
      Most patients undergoing cardiac surgery, however, present with anemia of chronic disease and with absolute or relative erythropoietin deficiency. In these patients, anemia treatment should include ESA in combination with low-dose IV iron to stimulate erythropoiesis and increase hemoglobin levels. Anemia treatment with ESA generally can be divided into 2 different regimens. First, short-term intervention with 200 to 500 U/kg ESA for 1-to-3 days in combination with or without iron substitution; and second, long-term interventions with 100-to-150 U/kg once to twice per week over 2-to-4 weeks in combination with iron substitution.
      • Feagan BG
      • Wong CJ
      • Kirkley A
      • et al.
      Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial.
      ,
      • Rosenthal C
      • von Heymann C
      • Kaufner L.
      [Diagnostics and treatment of preoperative anemia].
      It is currently unclear which strategy is more efficacious. Such a therapeutic strategy also should be considered in patients with mild anemia (11 g/dL in women and in men) before cardiac and major noncardiac surgery
      • Kaufner L
      • von Heymann C
      • Henkelmann A
      • et al.
      Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery.
      and in patients with renal insufficiency. Of note, therapeutic strategies, including ESAs, are often expensive, and cost-effectiveness remains questionable.
      • Roman MA
      • Abbasciano RG
      • Pathak S
      • et al.
      Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis.
      Furthermore, such treatment strategies might be associated with relevant side effects, including thromboembolic events, myocardial infarction, and anaphylaxis.
      • Bolliger D
      • Buser A
      • Erb JM.
      Patient blood management in cardiac surgery.
      ,
      • Bolliger D
      • Erb JM
      • Buser A.
      Controversies in the clinical practice of patient blood management.
      ,
      • Kaufner L
      • von Heymann C
      • Henkelmann A
      • et al.
      Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery.
      If substrate deficiencies other than iron are supposed or confirmed, treatment with the respective agent (eg, subcutaneous vitamin B12 or oral folic acid) should be considered. An indiscriminate administration of these vitamins is not recommended.
      In case of a primary blood disorder as the underlying cause of anemia, referral to a hematologist is advised. Further diagnostic tests might include bone marrow investigation, including molecular testing to characterize and treat primary hematologic disease (eg, plasma cell disorders, mature B-cell neoplasms, myelodysplastic syndromes, and other malignancies). If a primary blood disease is diagnosed, interdisciplinary approaches are suggested on how to best proceed with the treatment of both the hematologic and the cardiac disease.

      Studies With Perioperative Interventions in Anemia

      Iron Supplementation

      Preoperative iron supplementation in iron-deficient patients might offer a special window of opportunity, and appears to be an attractive and simple intervention that might apply to a relevant proportion of anemic patients undergoing cardiac surgery.
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      ,
      • von Heymann C
      • Kaufner L
      • Sander M
      • et al.
      Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
      Recent international PBM guidelines for adult cardiac surgery support preoperative iron supplementation in mildly and in severely anemic patients (recommendation IIA
      • Tibi P
      • McClure RS
      • Huang J
      • et al.
      STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
      and IIB
      • Boer C
      • Meesters MI
      • Milojevic M
      • et al.
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      ). The recent review by Meybohm et al. nicely summarized the current evidence.
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      The authors reported on 3 retrospective and 4 randomized interventional trials that included nearly 2,500 patients. Of these patients, about 40% were treated with pure iron supplementation, and about 60% were treated with a combination of iron and ESA. In most patients with preoperative iron supplementation, the IV application was used. The above-mentioned review partially found evidence that preoperative iron supplementation might increase hemoglobin values and reduce the requirements for perioperative RBC transfusions.
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      A recent and more restrictive systematic review and meta-analysis including just 5 RCTs with 554 patients found only some effects on surrogate laboratory parameters (eg, improved transferrin saturation) but no effect on hemoglobin values or avoidance of RBC transfusion.
      • Yang SS
      • Al Kharusi L
      • Gosselin A
      • et al.
      Iron supplementation for patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
      Of note, the application and dosages of iron supplementation were rather heterogeneous among the different studies.
      • Yang SS
      • Al Kharusi L
      • Gosselin A
      • et al.
      Iron supplementation for patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
      For example, Garrido-Martin et al. administered iron either orally (105 mg/d preoperatively and postoperatively), intravenously (3 doses of 100 mg IV iron/d during preoperative and postoperative hospitalization), or as a combination of both.
      • Garrido-Martin P
      • Nassar-Mansur MI
      • de la Llana-Ducros R
      • et al.
      The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: A randomized clinical trial.
      It might be speculated that the iron treatment partially was ineffective due to the oral application or due to low IV doses.
      • Garrido-Martin P
      • Nassar-Mansur MI
      • de la Llana-Ducros R
      • et al.
      The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: A randomized clinical trial.
      A recent Canadian retrospective analysis suggested that preoperative IV iron dosages >600 mg were necessary to effectively increase hemoglobin before cardiac surgery.
      • Peel JK
      • Trudeau J
      • Tano R
      • et al.
      Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
      Although IV iron supplementation might increase postoperative hemoglobin values and reduce requirements for RBC transfusion, the benefits of more rapid hemoglobin recovery after cardiac surgery or higher hemoglobin values in the early postoperative period on patient outcome remain unclear.
      • Yang SS
      • Al Kharusi L
      • Gosselin A
      • et al.
      Iron supplementation for patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
      ,
      • Johansson PI
      • Rasmussen AS
      • Thomsen LL.
      Intravenous iron isomaltoside 1000 (Monofer(R)) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: A randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
      The evidence for improved patient-centered outcomes or reduced adverse events and mortality after cardiac surgery by perioperative iron supplementation is very limited.
      • Meybohm P
      • Westphal S
      • Ravn HB
      • et al.
      Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
      ,
      • Johansson PI
      • Rasmussen AS
      • Thomsen LL.
      Intravenous iron isomaltoside 1000 (Monofer(R)) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: A randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
      ,
      • Klein AA
      • Chau M
      • Yeates JA
      • et al.
      Preoperative intravenous iron before cardiac surgery: A prospective multicentre feasibility study.
      One retrospective cohort study suggested less renal failure in patients with iron supplementation in combination with erythropoietin.
      • Cladellas M
      • Farre N
      • Comin-Colet J
      • et al.
      Effects of preoperative intravenous erythropoietin plus iron on outcome in anemic patients after cardiac valve replacement.
      In major noncardiac surgery, a recent meta-analysis suggested that preoperative iron substitution reduced the risk of transfusion (p = 0.0004) but also the rate of postoperative infections and even mortality (p = 0.04).
      • Schack A
      • Berkfors AA
      • Ekeloef S
      • et al.
      T The effect of perioperative iron therapy in acute major non-cardiac surgery on allogenic blood transfusion and postoperative haemoglobin levels: A systematic review and meta-analysis.
      Although there is no evidence to support or refute the routine use of iron therapy at the moment,
      • Yang SS
      • Al Kharusi L
      • Gosselin A
      • et al.
      Iron supplementation for patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
      the indiscriminate application of IV iron to all patients before cardiac surgery does not seem to be beneficial.
      • Song JW
      • Soh S
      • Shim JK
      • et al.
      Effect of perioperative intravenous iron supplementation for complex cardiac surgery on transfusion requirements: A randomized, double-blinded placebo-controlled trial.
      In a recent RCT, 204 patients undergoing complex cardiac surgery were randomized to receive either 20 mg/kg of IV iron twice (3 days before surgery and after surgery) or placebo.
      • Song JW
      • Soh S
      • Shim JK
      • et al.
      Effect of perioperative intravenous iron supplementation for complex cardiac surgery on transfusion requirements: A randomized, double-blinded placebo-controlled trial.
      The authors found that IV iron supplementation replenished iron stores and increased erythropoiesis, resulting in higher postoperative hemoglobin values, but failed to show reduced requirements for RBC transfusion during hospitalization. Preoperative laboratory testing and iron supplementation might be most beneficial in selected high-risk patients.
      • Yang SS
      • Al Kharusi L
      • Gosselin A
      • et al.
      Iron supplementation for patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
      Finally, the combined use of iron and ESA seems indicated, especially in patients with anemia due to inflammation or chronic disease.
      • Spahn DR
      • Kaserer A.
      Intravenous iron for all in cardiac surgery?.
      ,
      • Weiss G
      • Ganz T
      • Goodnough LT.
      Anemia of inflammation.

      Treatment With ESA

      A recent meta-analysis, including 8 RCTs published between 2009 and 2016, with a total of 610 cardiac surgery patients, showed that preoperative ESA administration significantly reduced intraoperative RBC transfusion, the incidence of perioperative AKI, and hospital length of stay. When ESAs were administered during and after surgery, such effects could not be found.
      • Shin HJ
      • Ko E
      • Jun I
      • et al.
      Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis.
      Of note, the primary aim of that meta-analysis was to evaluate the effect of ESA on AKI in cardiac surgery. Six of 8 included studies were performed in countries in Eastern Asia and 2 in Europe, potentially limiting the generalizability of the findings of this meta-analysis. Furthermore, ESAs were given within 3 days before surgery in 6 of these studies, and between anesthesia induction and surgical incision in two-thirds. Nevertheless, it remains questionable whether this short time interval allows for improved perioperative hematopoiesis. The meta-analysis found a mean difference of -0.3 (95% CI -0.55 to 0.05) for intraoperative RBC transfusion, as evaluated in 3 of the 8 included studies. Similarly, postoperative RBC transfusion was reduced, but the meta-analysis did not report on perioperative hemoglobin values.
      • Shin HJ
      • Ko E
      • Jun I
      • et al.
      Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis.
      Finally, no effect on mortality was found.
      Based on the present evidence, the optimal timing and dosing for ESA administration in cardiac surgery remain poorly defined. The effects of ESA with respect to increased erythropoiesis might require several days-to-weeks, but most studies evaluated the ESA administration close to surgery.
      • Hare GMT
      • Mazer CD.
      Anemia: Perioperative risk and treatment opportunity.
      In addition, a retrospective Canadian analysis suggested that erythropoietin alfa at doses of at least 80,000 U were necessary to increase hemoglobin values in patients before cardiac surgery.
      • Peel JK
      • Trudeau J
      • Tano R
      • et al.
      Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
      Finally, the administration of ESA might be associated with potential adverse effects such as hypertension and thromboembolic events in patients with stable congestive heart failure and coronary artery disease.
      • Rymer JA
      • Rao SV.
      Anemia and coronary artery disease: Pathophysiology, prognosis, and treatment.
      ,
      • Murillo-Berlioz A
      • Guinn NR
      • Levy JH
      • et al.
      Arterial and venous thrombosis complicating coronary artery bypass grafting after use of epoetin alfa-epbx.

      Combined Iron and ESA Supplementation

      In the recent PBM guidelines, the combined therapy of ESA and iron supplementation in patients with non-pure iron-deficient anemia has been recommended (recommendation IIA).
      • Tibi P
      • McClure RS
      • Huang J
      • et al.
      STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
      ,
      • Boer C
      • Meesters MI
      • Milojevic M
      • et al.
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      These recommendations were supported by a meta-analysis and a large cohort study in cardiac surgery patients, showing that iron supplementation was effective in reducing the need for RBC transfusion when combined with ESA.
      • Cho BC
      • Serini J
      • Zorrilla-Vaca A
      • et al.
      Impact of preoperative erythropoietin on allogeneic blood transfusions in surgical patients: Results from a systematic review and meta-analysis.
      ,
      • Dai L
      • Mick SL
      • McCrae KR
      • et al.
      Preoperative anemia in cardiac operation: Does hemoglobin tell the whole story?.
      The above-mentioned recommendations are further supported by a very recent single-center RCT comparing the administration of 1,000 mg IV iron in combination with 200 µg darbepoetin subcutaneously with 600 mg oral iron daily.
      • Kong R
      • Hutchinson N
      • Hill A
      • et al.
      Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).
      Therapy was started 2-to-10 weeks before cardiac surgery. The combined single-dose treatment was more effective at increasing hemoglobin values and decreasing the proportion of patients who received a perioperative blood transfusion as compared to oral iron substitution.
      • Kong R
      • Hutchinson N
      • Hill A
      • et al.
      Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).
      The optimal timing and dosing of concomitant supplementation of IV iron and ESA are poorly defined. A recent retrospective analysis suggested that IV iron at a dose of at least 600 mg and erythropoietin alfa doses of at least 80,000 U are necessary to increase hemoglobin values in patients before cardiac surgery.
      • Peel JK
      • Trudeau J
      • Tano R
      • et al.
      Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
      These doses are relevantly higher than those used in earlier studies.
      • Garrido-Martin P
      • Nassar-Mansur MI
      • de la Llana-Ducros R
      • et al.
      The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: A randomized clinical trial.
      ,
      • Sowade O
      • Warnke H
      • Scigalla P
      • et al.
      Avoidance of allogeneic blood transfusions by treatment with epoetin beta (recombinant human erythropoietin) in patients undergoing open-heart surgery.
      Of note, treatment should start as early as possible. Two recent studies applied regimens with combined iron and ESA supplementation shortly before surgery. Yoo et al. administered a single IV dose of 500 U/kg ESA in combination with 200 mg of IV iron 16-to-24 hours before valvular heart surgery.
      • Yoo YC
      • Shim JK
      • Kim JC
      • et al.
      Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery.
      Using this regimen, they found a significantly decreased incidence of perioperative RBC transfusion and postoperative AKI.
      • Yoo YC
      • Shim JK
      • Kim JC
      • et al.
      Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery.
      Similarly, the acute treatment of anemia using combined therapy on the day of admission was evaluated by a large single-center study by Spahn et al. In their RCT, about 500 cardiac surgery patients with anemia or isolated iron deficiency were randomized to either combination therapy with 20 mg/kg of IV iron, 40,000 U of subcutaneous erythropoietin alpha, 1 mg of subcutaneous vitamin B12, and 5 mg of oral folic acid or placebo on the day before surgery.
      • Spahn DR
      • Schoenrath F
      • Spahn GH
      • et al.
      Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial.
      The authors found higher hemoglobin values and reduced RBC transfusion (median minus one RBC) in the intervention group. Furthermore, the proportion of patients exposed to any allogeneic blood products within the first 7 postoperative days was reduced from 54% in the control group to 46% in the intervention group. However, no beneficial effects on morbidity or mortality were reported.
      • Spahn DR
      • Schoenrath F
      • Spahn GH
      • et al.
      Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial.

      Preoperative RBC Transfusion

      A small RCT found that the preoperative transfusion of 2 units of RBCs reduced intraoperative RBC transfusion by a median of 2 units of RBCs.
      • Karkouti K
      • Wijeysundera DN
      • Yau TM
      • et al.
      Advance targeted transfusion in anemic cardiac surgical patients for kidney protection: An unblinded randomized pilot clinical trial.
      No effect on AKI was found, but the study was not powered for this outcome.
      • Karkouti K
      • Wijeysundera DN
      • Yau TM
      • et al.
      Advance targeted transfusion in anemic cardiac surgical patients for kidney protection: An unblinded randomized pilot clinical trial.
      Based on this very limited evidence, 2 recent PBM guidelines recommended not to administer preoperative RBC transfusion in anemic patients except in case of emergent surgery or life-threatening anemia.
      • Tibi P
      • McClure RS
      • Huang J
      • et al.
      STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
      ,
      • Boer C
      • Meesters MI
      • Milojevic M
      • et al.
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      Furthermore, preoperative autologous blood donation is not recommended in anemic patients.

      Limitations of Preoperative Anemia Treatment in Cardiac Surgery

      Despite the fact that multiple studies showed the negative effect of preoperative anemia on blood transfusion requirements and on postoperative morbidity and mortality, the studies investigating the treatment of preoperative anemia widely failed to show relevantly improved patient outcomes. Table 2 Effective anemia treatment is limited by different intrinsic issues. First, preoperative anemia clinics, which are able to determine and treat anemic patients before cardiac surgery according to specific treatment protocols, are not yet established in many countries and institutions. Recently, a prospective study in the United Kingdom showed that it was feasible to develop a pathway for IV iron treatment in cardiac surgery patients in 7 out of 11 hospitals over a period of 2 years.
      • Klein AA
      • Chau M
      • Yeates JA
      • et al.
      Preoperative intravenous iron before cardiac surgery: A prospective multicentre feasibility study.
      The IV iron treatment before cardiac surgery was limited to selected high-risk patients in most of these institutions, and the number of included patients in this study was low.
      • Klein AA
      • Chau M
      • Yeates JA
      • et al.
      Preoperative intravenous iron before cardiac surgery: A prospective multicentre feasibility study.
      Table 2Randomized Controlled Trials with Perioperative Iron Supplementation (#1-5), Administration of Erythropoiesis-Stimulating Agents (#6-11) or Combination Therapy (#12-15)
      First Author, YearSampleInterventionControlTimepoint of InterventionResults in Primary OutcomeAdditional Findings
      1Garrido-Martin, 2012
      • Garrido-Martin P
      • Nassar-Mansur MI
      • de la Llana-Ducros R
      • et al.
      The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: A randomized clinical trial.
      159 (54/53/52)A.100 mg IV iron 3 × 100 mg/d (n = 54) + 100 mg oral iron/d

      B. 100 mg oral iron/d + IV placebo (n = 53)
      IV and oral PlaceboDuring pre- and postoperative hospitalization, oral iron until 1 mo after dischargeNo difference in postoperative hemoglobin between groupsHigher serum ferritin levels in the IV iron group at hospital discharge and 1 mo later, no difference in RBC transfusion
      2Johansson, 2015
      • Johansson PI
      • Rasmussen AS
      • Thomsen LL.
      Intravenous iron isomaltoside 1000 (Monofer(R)) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: A randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
      60 (30/30)1000 mg IV iron, single-dosePlaceboDay before surgery or directly before surgeryHemoglobin higher in iv iron group after 4 wkNo differences in RBC transfusion, higher ferritin levels/transferrin saturation in iv iron group
      3Padmanabhan, 2019
      • Padmanabhan H
      • Brookes MJ
      • Nevill AM
      • et al.
      Association between anemia and blood transfusion with long-term mortality after cardiac surgery.
      50 (25/25)1000-2000 mg IV iron in 1 to 2 doses200 mg oral iron twice daily until surgery3-8 wk before surgeryNo difference in hemoglobin increase after treatmentNo difference in patients who remained anemic, higher ferritin and lower transferrin levels in the IV iron group
      4Song, 2022
      • Song JW
      • Soh S
      • Shim JK
      • et al.
      Effect of perioperative intravenous iron supplementation for complex cardiac surgery on transfusion requirements: A randomized, double-blinded placebo-controlled trial.
      204 (103/101)20 mg/kg IV iron before and after surgeryPlacebo3 d before and after surgeryNo difference in RBC transfusion up to postoperative day 10Hemoglobin levels, 3 wk after surgery, reticulocyte count at postoperative day 10, transferrin saturation, and serum ferritin were higher in IV iron group
      5Xu, 2019
      • Xu H
      • Duan Y
      • Yuan X
      • et al.
      Intravenous iron versus placebo in the management of postoperative functional iron deficiency anemia in patients undergoing cardiac valvular surgery: A prospective, single-blinded, randomized controlled trial.
      150 (75/75)200 mg IV iron once daily until calculated dose (according to iron deficiency) was reachedPlaceboStart on the day after surgeryHemoglobin levels on postoperative day 14 higher in IV iron groupProportion of patients with corrected anemia on postoperative day 14 higher, ferritin levels higher in IV iron group
      6Song, 2009
      • Song YR
      • Lee T
      • You SJ
      • et al.
      Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: A pilot study.
      71 (35/36)300 U/kg ESA, single-dosePlaceboBefore surgical skin incisionLess AKI in ESA groupLower postoperative serum creatinine levels
      6Oh, 2012
      • Oh SW
      • Chin HJ
      • Chae DW
      • et al.
      Erythropoietin improves long-term outcomes in patients with acute kidney injury after coronary artery bypass grafting.
      71 (36/35)300 U/kg ESA, single-dosePlaceboBefore surgical skin incisionLess AKI in ESA groupLower postoperative serum creatinine levels
      7de Seigneux, 2012
      • de Seigneux S
      • Ponte B
      • Weiss L
      • et al.
      Epoetin administrated after cardiac surgery: Effects on renal function and inflammation in a randomized controlled study.
      80 (20/20/40)A. 20,000 U ESA single-dose (n = 20)

      B. 40,000 U ESA, single-dose (n = 20)
      PlaceboDirectly after surgeryNo difference in AKINo differences in urinary NGAL, serum creatinine levels, and RBC transfusion
      8Tasanarong, 2013
      • Tasanarong A
      • Duangchana S
      • Sumransurp S
      • et al.
      Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery: A randomized, double-blind controlled trial.
      100 (50/50)200 U/kg ESA before and 100 U/kg ESA during surgeryPlacebo3 d before surgery and intraoperativelyLess AKI in ESA groupNo difference in serum creatinine levels
      9Kim, 2013
      • Kim JH
      • Shim JK
      • Song JW
      • et al.
      Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: A double blind, randomized clinical trial of efficacy and safety.
      98 (49/49)300 U/kg ESA, single-dosePlaceboBefore surgical skin incisionNo difference in AKINo difference in serum creatinine levels
      10Dardashti, 2014
      • Dardashti A
      • Ederoth P
      • Algotsson L
      • et al.
      Erythropoietin and protection of renal function in cardiac surgery (the EPRICS Trial).
      70 (35/35)400 U/kg ESA, single- dosePlaceboBefore surgical skin incisionNo difference in AKINo difference in plasma cystatin levels
      11Kim et al, 2016
      • Kim JE
      • Song SW
      • Kim JY
      • et al.
      Effect of a single bolus of erythropoietin on renoprotection in patients undergoing thoracic aortic surgery with moderate hypothermic circulatory arrest.
      60 (31/29)500 U/kg ESA, single- dosePlaceboDuring surgeryNo difference in AKINo difference in serum creatinine levels and frequency of RRT
      12Karkouti, 2006
      • Karkouti K
      • McCluskey SA
      • Ghannam M
      • et al.
      Intravenous iron and recombinant erythropoietin for the treatment of postoperative anemia.
      38 (13/13/12) (cardiac, orthopedic and spinal surgery)A: 600 U/kg ESA on POD 1 and 3 + 200 mg IV iron on POD 1.2 and 3

      B: 200 mg IV iron on POD 1.2 and 3
      PlaceboAfter surgeryNo difference in postoperative increase of hemoglobin levelsNo difference in RBC transfusion, higher reticulocyte count in combination group
      13Yoo, 2011
      • Yoo YC
      • Shim JK
      • Kim JC
      • et al.
      Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery.
      74 (37/37)500 U/kg ESA + 200 mg IV iron, single-dosePlaceboDay before surgeryLower proportion of transfused patients and less RBC requirements in intervention groupHigher reticulocyte count in intervention group
      14Spahn, 2019
      • Spahn DR
      • Schoenrath F
      • Spahn GH
      • et al.
      Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial.
      484 (243/241)20 mg/kg IV iron + 40,000 U ESA sc + 1 mg vitamin B12 sc + 5 mg folic acid orallyPlaceboDay before surgeryLess RBC transfusion in intervention groupHigher postoperative hemoglobin levels and reticulocyte count
      15Kong, 2022
      • Kong R
      • Hutchinson N
      • Hill A
      • et al.
      Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).
      158 (79/77)1,000 mg IV iron + 200 mg ESA, single dose600 mg oral iron2-10 wk before surgeryFewer RBC transfusion in intervention groupHigher increase in preoperative hemoglobin levels
      Abbreviations: AKI, acute kidney injury; ESA, erythropoiesis-stimulating agents; IV, intravenous; NGAL, neutrophil gelatinase-associated lipocalin; POD, postoperative day; RBC, red blood cell; RRT, renal replacement therapy; sc, subcutaneous.
      Second, the timely assessment and treatment of cardiac surgery patients, even with effectively functioning preoperative anemia clinics, remains challenging. An estimated percentage of up to 40% of patients are nonelective in some centers.
      • Ranucci M
      • Pavesi M
      • Pistuddi V
      • et al.
      Preoperative anemia correction in cardiac surgery: A propensity-matched study.
      Furthermore, the access of elective patients to preoperative anemia clinics is limited. A recent retrospective analysis included only about 530 patients recruited over about 10 years at a large Canadian center.
      • Peel JK
      • Trudeau J
      • Tano R
      • et al.
      Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
      A recent Italian study reported that only about 20% of elective surgery patients had access to preoperative anemia screening clinics due to organizational and time issues.
      • Ranucci M
      • Pavesi M
      • Pistuddi V
      • et al.
      Preoperative anemia correction in cardiac surgery: A propensity-matched study.
      Ultimately, a large proportion of patients undergo cardiac surgery without preoperative anemia correction despite recommendations to treat preoperative anemia treatment with iron supplementation and/or ESA administration by many important societies.
      • Tibi P
      • McClure RS
      • Huang J
      • et al.
      STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
      ,
      • Boer C
      • Meesters MI
      • Milojevic M
      • et al.
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      ,
      • Ferraris VA
      • Brown JR
      • Despotis GJ
      • et al.
      2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      ,
      • Raphael J
      • Mazer CD
      • Subramani S
      • et al.
      Society of Cardiovascular Anesthesiologists clinical practice improvement advisory for management of perioperative bleeding and hemostasis in cardiac surgery patients.
      Third, time intervals between the initial visit and the day of surgery are usually short, potentially limiting effective anemia treatment. In a recent study including nearly 800 patients who underwent elective cardiac surgery at a Canadian tertiary hospital, the median interval between the initial visit and the day of surgery was 7 days.
      • Nguyen Q
      • Meng E
      • Berube J
      • et al.
      Preoperative anemia and transfusion in cardiac surgery: A single-centre retrospective study.
      Only 8% of patients with anemia were referred preoperatively to the blood conservation clinic, and treatment was initiated in only 3% of anemic patients,
      • Nguyen Q
      • Meng E
      • Berube J
      • et al.
      Preoperative anemia and transfusion in cardiac surgery: A single-centre retrospective study.
      mostly probably due to time restriction.
      Fourth, optimal thresholds and targets of interventions remain poorly defined. The WHO criteria for anemia might not be ideal for preoperative patients undergoing high-risk cardiac surgery and should not be applied universally. For example, preoperative hemoglobin optimization might be important but also insufficient to reduce the transfusion of allogeneic blood products in patients with low body mass index.
      • Tanaka KA
      • Alejo D
      • Ghoreishi M
      • et al.
      Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
      It is essential to understand the individual interaction of hemoglobin values, body mass index, and total RBC mass. The latter might help to predict better which patients are at increased risk of perioperative transfusion and might benefit most from preoperative blood optimization.
      • Tanaka KA
      • Alejo D
      • Ghoreishi M
      • et al.
      Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
      Fifth, the optimal treatment strategy remains unclear. Pure iron supplementation seems not to be very effective in most cardiac surgery patients. Combined therapy, including IV iron and subcutaneous ESA at higher doses, seems most promising to increase RBC mass and reduce transfusion requirements.
      • Peel JK
      • Trudeau J
      • Tano R
      • et al.
      Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
      ,
      • Kong R
      • Hutchinson N
      • Hill A
      • et al.
      Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).
      However, higher doses of IV iron and ESA might increase the risk of adverse side effects and question the cost-effectiveness of such interventions.
      • Roman MA
      • Abbasciano RG
      • Pathak S
      • et al.
      Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis.
      In many European countries and in North America, the indication of erythropoietin administration is currently limited to anemia related to chronic kidney diseases and chemotherapy in cancer patients. For use in cardiac surgery patients, specific approvals are often required.
      • Shin HJ
      • Ko E
      • Jun I
      • et al.
      Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis.
      Given the limited evidence of improved patient outcomes in cardiac surgery patients with preoperative administration of IV iron and/or ESA, such therapies potentially should be used primarily in high-risk patients after individual assessment.
      • Peel JK
      • Trudeau J
      • Tano R
      • et al.
      Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
      ,
      • Klein AA
      • Chau M
      • Yeates JA
      • et al.
      Preoperative intravenous iron before cardiac surgery: A prospective multicentre feasibility study.
      Finally, missing the effects of preoperative hemoglobin optimization in many studies in cardiac surgery patients might arise from the ambiguity of hemoglobin as a marker for adequate oxygenation of sensitive organs.
      • Bolliger D
      • Mauermann E
      • Buser A.
      Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
      ,
      • Meier J
      • Filipescu D
      • Kozek-Langenecker S
      • et al.
      Intraoperative transfusion practices in Europe.
      Markers of inadequate balance between tissue oxygen delivery and demand, such as central venous oxygen saturation, lactate, or near-infrared spectroscopy, potentially should be implemented in transfusion decision-making and might be beneficial for the patient
      • Bolliger D
      • Mauermann E
      • Buser A.
      Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
      rather than hemoglobin values in the range between 7 and 10 g/dL.
      • Bolliger D
      • Buser A
      • Erb JM.
      Patient blood management in cardiac surgery.
      ,
      • Bolliger D
      • Erb JM
      • Buser A.
      Controversies in the clinical practice of patient blood management.
      Finally, low hemoglobin values during and after surgery might not have the same impact on patient outcomes as preoperative anemia.

      Conclusions

      Patients presenting for cardiac surgery are often at high risk of anemia due to age and multiple comorbidities. Given the strong association between low preoperative hemoglobin values and postoperative complications, the timely diagnosis and therapy of treatable forms of anemia (especially iron deficiency anemia) are recommended to improve patient outcomes.
      • Tibi P
      • McClure RS
      • Huang J
      • et al.
      STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
      ,
      • Boer C
      • Meesters MI
      • Milojevic M
      • et al.
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      However, anemia in cardiac surgery is often multifactorial and might be a surrogate of reduced patient conditions, comorbidities, and chronic diseases. Correcting anemia remains difficult and is often unsuccessful. A combined administration of IV iron and ESA seems most promising. However, even with intensified therapies, positive effects in published studies have been limited generally to a reduction in RBC requirements during and after surgery. Nonetheless, the preoperative assessment of anemia and determination of the anemic patient's iron status, eventually leading to targeted therapy, should become standard of care. Clinics must advise facilities to screen for anemia and the cause thereof. Although therapeutic interventions shortly before surgery have been suggested,
      • Spahn DR
      • Schoenrath F
      • Spahn GH
      • et al.
      Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial.
      treatments should be initiated within several weeks before surgery to effectively improve RBC mass and hemoglobin values. Hopefully, the remaining questions can be answered, and limiting factors might be managed successfully in the next years, eventually leading to improved outcomes.

      Conflict of Interest

      None.

      Acknowledgment

      The authors wish to thank Allison Dwileski of the Clinic for Anesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Basel, Switzerland, for editorial assistance.

      References

        • Tinegate H
        • Pendry K
        • Murphy M
        • et al.
        Where do all the red blood cells (RBCs) go? Results of a survey of RBC use in England and North Wales in 2014.
        Transfusion. 2016; 56: 139-145
        • Hazen Y
        • Noordzij PG
        • Gerritse BM
        • et al.
        Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
        Br J Anaesth. 2022; 128: 636-643
        • Klein AA
        • Collier T
        • Yeates J
        • et al.
        The ACTA PORT-score for predicting perioperative risk of blood transfusion for adult cardiac surgery.
        Br J Anaesth. 2017; 119: 394-401
        • Tanaka KA
        • Alejo D
        • Ghoreishi M
        • et al.
        Impact of preoperative hematocrit, body mass index and red cell mass on allogeneic blood product usage in adult cardiac surgical patients: Report from a statewide quality initiative.
        J Cardiothorac Vasc Anesth. 2022; (epub ahead of print)
        • Klein AA
        • Collier TJ
        • Brar MS
        • et al.
        The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK - the first Association of Cardiothoracic Anaesthetists national audit.
        Anaesthesia. 2016; 71: 627-635
        • Kattou F
        • Montandrau O
        • Rekik M
        • et al.
        Critical preoperative hemoglobin value to predict anemia-related complications after cardiac surgery.
        J Cardiothorac Vasc Anesth. 2022; 36: 1901-1907
        • Hare GMT
        • Mazer CD.
        Anemia: Perioperative risk and treatment opportunity.
        Anesthesiology. 2021; 135: 520-530
        • Ripoll JG
        • Smith MM
        • Hanson AC
        • et al.
        Sex-specific associations between preoperative anemia and postoperative clinical outcomes in patients undergoing cardiac surgery.
        Anesth Analg. 2021; 132: 1101-1111
        • Murphy GJ
        • Reeves BC
        • Rogers CA
        • et al.
        Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery.
        Circulation. 2007; 116: 2544-2552
        • LaPar DJ
        • Hawkins RB
        • McMurry TL
        • et al.
        Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery?.
        J Thorac Cardiovasc Surg. 2018; 156 (e2): 66-74
        • Koch CG
        • Li L
        • Duncan AI
        • et al.
        Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting.
        Crit Care Med. 2006; 34: 1608-1616
        • Bolliger D
        • Buser A
        • Erb JM.
        Patient blood management in cardiac surgery.
        Curr Anesthesiol Rep. 2019; 9: 215-222
        • Bolliger D
        • Erb JM
        • Buser A.
        Controversies in the clinical practice of patient blood management.
        J Cardiothorac Vasc Anesth. 2021; 35: 1933-1941
        • Frietsch T
        • Shander A
        • Faraoni D
        • et al.
        Patient blood management is not about blood transfusion: It is about patients' outcomes.
        Blood Transfus. 2019; 17: 331-333
        • Roman MA
        • Abbasciano RG
        • Pathak S
        • et al.
        Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis.
        Br J Anaesth. 2021; 126: 149-156
        • Gross I
        • Seifert B
        • Hofmann A
        • et al.
        Patient blood management in cardiac surgery results in fewer transfusions and better outcome.
        Transfusion. 2015; 55: 1075-1081
        • Spahn DR
        • Schoenrath F
        • Spahn GH
        • et al.
        Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial.
        Lancet. 2019; 393: 2201-2212
        • Meybohm P
        • Westphal S
        • Ravn HB
        • et al.
        Perioperative anemia management as part of PBM in cardiac surgery - a narrative updated review.
        J Cardiothorac Vasc Anesth. 2020; 34: 1060-1073
        • Bolliger D
        • Mauermann E
        • Buser A.
        Preoperative anaemia in cardiac surgery: Preoperative assessment, treatment and outcome.
        Br J Anaesth. 2022; 128: 599-602
        • Padmanabhan H
        • Siau K
        • Curtis J
        • et al.
        Preoperative anemia and outcomes in cardiovascular surgery: Systematic review and meta-analysis.
        Ann Thorac Surg. 2019; 108: 1840-1848
        • Ranucci M
        • Pavesi M
        • Pistuddi V
        • et al.
        Preoperative anemia correction in cardiac surgery: A propensity-matched study.
        J Cardiothorac Vasc Anesth. 2021; 35: 874-881
        • Guralnik JM
        • Eisenstaedt RS
        • Ferrucci L
        • et al.
        Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia.
        Blood. 2004; 104: 2263-2268
        • Scrascia G
        • Guida P
        • Caparrotti SM
        • et al.
        Incremental value of anemia in cardiac surgical risk prediction with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II model.
        Ann Thorac Surg. 2014; 98: 869-875
        • von Heymann C
        • Kaufner L
        • Sander M
        • et al.
        Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
        J Thorac Cardiovasc Surg. 2016; 152: 1412-1420
        • Ranucci M
        • Di Dedda U
        • Castelvecchio S
        • et al.
        Impact of preoperative anemia on outcome in adult cardiac surgery: A propensity-matched analysis.
        Ann Thorac Surg. 2012; 94: 1134-1141
        • Butcher A
        • Richards T
        • Stanworth SJ
        • et al.
        Diagnostic criteria for pre-operative anaemia-time to end sex discrimination.
        Anaesthesia. 2017; 72: 811-814
        • Munoz M
        • Acheson AG
        • Auerbach M
        • et al.
        International consensus statement on the peri-operative management of anaemia and iron deficiency.
        Anaesthesia. 2017; 72: 233-247
        • Munting KE
        • Klein AA.
        Optimisation of pre-operative anaemia in patients before elective major surgery - why, who, when and how?.
        Anaesthesia. 2019; 74: 49-57
        • Zakai NA
        • French B
        • Arnold AM
        • et al.
        Hemoglobin decline, function, and mortality in the elderly: The cardiovascular health study.
        Am J Hematol. 2013; 88: 5-9
        • O'Shaughnessy S
        • Tangel V
        • Dzotsi S
        • et al.
        Non-white race/ethnicity and female sex are associated with increased allogeneic red blood cell transfusion in cardiac surgery patients: 2007-2018.
        J Cardiothorac Vasc Anesth. 2022; 36: 1908-1918
        • Padmanabhan H
        • Brookes MJ
        • Nevill AM
        • et al.
        Association between anemia and blood transfusion with long-term mortality after cardiac surgery.
        Ann Thorac Surg. 2019; 108: 687-692
        • Engoren M
        • Schwann TA
        • Habib RH
        • et al.
        The independent effects of anemia and transfusion on mortality after coronary artery bypass.
        Ann Thorac Surg. 2014; 97: 514-520
        • Michalak SS
        • Rupa-Matysek J
        • Gil L.
        Comorbidities, repeated hospitalizations, and age ≥80 years as indicators of anemia development in the older population.
        Ann Hematol. 2018; 97: 1337-1347
        • Camaschella C.
        Iron-deficiency anemia.
        N Engl J Med. 2015; 372: 1832-1843
        • Goodnough LT
        • Schrier SL.
        Evaluation and management of anemia in the elderly.
        Am J Hematol. 2014; 89: 88-96
        • Weiss G
        • Goodnough LT.
        Anemia of chronic disease.
        N Engl J Med. 2005; 352: 1011-1023
        • Karski JM
        • Mathieu M
        • Cheng D
        • et al.
        Etiology of preoperative anemia in patients undergoing scheduled cardiac surgery.
        Can J Anaesth. 1999; 46: 979-982
        • Goodnough LT
        • Maniatis A
        • Earnshaw P
        • et al.
        Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines.
        Br J Anaesth. 2011; 106: 13-22
        • Munoz M
        • Gomez-Ramirez S
        • Kozek-Langeneker S.
        Pre-operative haematological assessment in patients scheduled for major surgery.
        Anaesthesia. 2016; 71: 19-28
        • Fertrin KY.
        Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): Is too little iron making your patient sick?.
        Hematology Am Soc Hematol Educ Program. 2020; 2020: 478-486
        • Abraham J
        • Sinha R
        • Robinson K
        • et al.
        Aetiology of preoperative anaemia in patients undergoing elective cardiac surgery-the challenge of pillar one of patient blood management.
        Anaesth Intensive Care. 2017; 45: 46-51
        • Panjeta M
        • Tahirovic I
        • Karamehic J
        • et al.
        The relation of erythropoietin towards hemoglobin and hematocrit in varying degrees of renal insufficiency.
        Mater Sociomed. 2015; 27: 144-148
        • Rossler J
        • Hegemann I
        • Schoenrath F
        • et al.
        Efficacy of quadruple treatment on different types of pre-operative anaemia: Secondary analysis of a randomised controlled trial.
        Anaesthesia. 2020; 75: 1039-1049
      1. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*.
        Anesthesiology. 2015; 122: 241-275
        • Kotze A
        • Harris A
        • Baker C
        • et al.
        British Committee for Standards in Haematology G Guidelines on the identification and management of pre-operative anaemia.
        Br J Haematol. 2015; 171: 322-331
        • Ng O
        • Keeler BD
        • Mishra A
        • et al.
        Iron therapy for pre-operative anaemia.
        Cochrane Database Syst Rev. 2015; CD011588
        • Rossler J
        • Schoenrath F
        • Seifert B
        • et al.
        Iron deficiency is associated with higher mortality in patients undergoing cardiac surgery: A prospective study.
        Br J Anaesth. 2020; 124: 25-34
        • Anand IS
        • Gupta P.
        Anemia and iron deficiency in heart failure: Current concepts and emerging therapies.
        Circulation. 2018; 138: 80-98
        • Feagan BG
        • Wong CJ
        • Kirkley A
        • et al.
        Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial.
        Ann Intern Med. 2000; 133: 845-854
        • Rosenthal C
        • von Heymann C
        • Kaufner L.
        [Diagnostics and treatment of preoperative anemia].
        Anaesthesist. 2019; 68: 555-567
        • Kaufner L
        • von Heymann C
        • Henkelmann A
        • et al.
        Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery.
        Cochrane Database Syst Rev. 2020; 8CD012451
        • Tibi P
        • McClure RS
        • Huang J
        • et al.
        STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
        J Cardiothorac Vasc Anesth. 2021; 35: 2569-2591
        • Boer C
        • Meesters MI
        • Milojevic M
        • et al.
        2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
        J Cardiothorac Vasc Anesth. 2018; 32: 88-120
        • Yang SS
        • Al Kharusi L
        • Gosselin A
        • et al.
        Iron supplementation for patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
        Can J Anaesth. 2022; 69: 129-139
        • Garrido-Martin P
        • Nassar-Mansur MI
        • de la Llana-Ducros R
        • et al.
        The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: A randomized clinical trial.
        Interact Cardiovasc Thorac Surg. 2012; 15: 1013-1018
        • Peel JK
        • Trudeau J
        • Tano R
        • et al.
        Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: A retrospective cohort study.
        J Cardiothorac Vasc Anesth. 2021; 35: 2631-2639
        • Johansson PI
        • Rasmussen AS
        • Thomsen LL.
        Intravenous iron isomaltoside 1000 (Monofer(R)) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: A randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
        Vox Sang. 2015; 109: 257-266
        • Klein AA
        • Chau M
        • Yeates JA
        • et al.
        Preoperative intravenous iron before cardiac surgery: A prospective multicentre feasibility study.
        Br J Anaesth. 2020; 124: 243-250
        • Cladellas M
        • Farre N
        • Comin-Colet J
        • et al.
        Effects of preoperative intravenous erythropoietin plus iron on outcome in anemic patients after cardiac valve replacement.
        Am J Cardiol. 2012; 110: 1021-1026
        • Schack A
        • Berkfors AA
        • Ekeloef S
        • et al.
        T The effect of perioperative iron therapy in acute major non-cardiac surgery on allogenic blood transfusion and postoperative haemoglobin levels: A systematic review and meta-analysis.
        World J Surg. 2019; 43: 1677-1691
        • Song JW
        • Soh S
        • Shim JK
        • et al.
        Effect of perioperative intravenous iron supplementation for complex cardiac surgery on transfusion requirements: A randomized, double-blinded placebo-controlled trial.
        Ann Surg. 2022; 275: 232-239
        • Spahn DR
        • Kaserer A.
        Intravenous iron for all in cardiac surgery?.
        Ann Surg. 2022; 275: 240-241
        • Weiss G
        • Ganz T
        • Goodnough LT.
        Anemia of inflammation.
        Blood. 2019; 133: 40-50
        • Shin HJ
        • Ko E
        • Jun I
        • et al.
        Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis.
        Medicine (Baltimore). 2022; 101: e28920
        • Rymer JA
        • Rao SV.
        Anemia and coronary artery disease: Pathophysiology, prognosis, and treatment.
        Coron Artery Dis. 2018; 29: 161-167
        • Murillo-Berlioz A
        • Guinn NR
        • Levy JH
        • et al.
        Arterial and venous thrombosis complicating coronary artery bypass grafting after use of epoetin alfa-epbx.
        JTCVS Tech. 2020; 4: 154-155
        • Cho BC
        • Serini J
        • Zorrilla-Vaca A
        • et al.
        Impact of preoperative erythropoietin on allogeneic blood transfusions in surgical patients: Results from a systematic review and meta-analysis.
        Anesth Analg. 2019; 128: 981-992
        • Dai L
        • Mick SL
        • McCrae KR
        • et al.
        Preoperative anemia in cardiac operation: Does hemoglobin tell the whole story?.
        Ann Thorac Surg. 2018; 105: 100-107
        • Kong R
        • Hutchinson N
        • Hill A
        • et al.
        Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).
        Br J Anaesth. 2022; 128: 796-805
        • Sowade O
        • Warnke H
        • Scigalla P
        • et al.
        Avoidance of allogeneic blood transfusions by treatment with epoetin beta (recombinant human erythropoietin) in patients undergoing open-heart surgery.
        Blood. 1997; 89: 411-418
        • Yoo YC
        • Shim JK
        • Kim JC
        • et al.
        Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery.
        Anesthesiology. 2011; 115: 929-937
        • Karkouti K
        • Wijeysundera DN
        • Yau TM
        • et al.
        Advance targeted transfusion in anemic cardiac surgical patients for kidney protection: An unblinded randomized pilot clinical trial.
        Anesthesiology. 2012; 116: 613-621
        • Ferraris VA
        • Brown JR
        • Despotis GJ
        • et al.
        2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
        Ann Thorac Surg. 2011; 91: 944-982
        • Raphael J
        • Mazer CD
        • Subramani S
        • et al.
        Society of Cardiovascular Anesthesiologists clinical practice improvement advisory for management of perioperative bleeding and hemostasis in cardiac surgery patients.
        J Cardiothorac Vasc Anesth. 2019; 33: 2887-2899
        • Nguyen Q
        • Meng E
        • Berube J
        • et al.
        Preoperative anemia and transfusion in cardiac surgery: A single-centre retrospective study.
        J Cardiothorac Surg. 2021; 16: 109
        • Meier J
        • Filipescu D
        • Kozek-Langenecker S
        • et al.
        Intraoperative transfusion practices in Europe.
        Br J Anaesth. 2016; 116: 255-261
        • Xu H
        • Duan Y
        • Yuan X
        • et al.
        Intravenous iron versus placebo in the management of postoperative functional iron deficiency anemia in patients undergoing cardiac valvular surgery: A prospective, single-blinded, randomized controlled trial.
        J Cardiothorac Vasc Anesth. 2019; 33: 2941-2948
        • Song YR
        • Lee T
        • You SJ
        • et al.
        Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: A pilot study.
        Am J Nephrol. 2009; 30: 253-260
        • Oh SW
        • Chin HJ
        • Chae DW
        • et al.
        Erythropoietin improves long-term outcomes in patients with acute kidney injury after coronary artery bypass grafting.
        J Korean Med Sci. 2012; 27: 506-511
        • de Seigneux S
        • Ponte B
        • Weiss L
        • et al.
        Epoetin administrated after cardiac surgery: Effects on renal function and inflammation in a randomized controlled study.
        BMC Nephrol. 2012; 13: 132
        • Tasanarong A
        • Duangchana S
        • Sumransurp S
        • et al.
        Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery: A randomized, double-blind controlled trial.
        BMC Nephrol. 2013; 14: 136
        • Kim JH
        • Shim JK
        • Song JW
        • et al.
        Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: A double blind, randomized clinical trial of efficacy and safety.
        Crit Care. 2013; 17: R254
        • Dardashti A
        • Ederoth P
        • Algotsson L
        • et al.
        Erythropoietin and protection of renal function in cardiac surgery (the EPRICS Trial).
        Anesthesiology. 2014; 121: 582-590
        • Kim JE
        • Song SW
        • Kim JY
        • et al.
        Effect of a single bolus of erythropoietin on renoprotection in patients undergoing thoracic aortic surgery with moderate hypothermic circulatory arrest.
        Ann Thorac Surg. 2016; 101: 690-696
        • Karkouti K
        • McCluskey SA
        • Ghannam M
        • et al.
        Intravenous iron and recombinant erythropoietin for the treatment of postoperative anemia.
        Can J Anaesth. 2006; 53: 11-19

      Linked Article

      • Preoperative Anemia Treatment in Cardiac Surgery: Past Due and Time to Act
        Journal of Cardiothoracic and Vascular AnesthesiaVol. 37Issue 2
        • Preview
          FOR DECADES, the mainstay role of preoperative clinics was to identify comorbid medical conditions, evaluate their severity, and convey an opinion on fitness for surgery. Anesthesiologists who staffed preoperative clinics frequently consulted with primary care physicians and/or subspecialty consultants to obtain the coveted “surgical clearance” so that a proposed surgery could move forward. The “raison d'etre” of preoperative clinics was to avoid day of surgery cancellations, which justified funding for years.
        • Full-Text
        • PDF