Patient Blood Management in Cardiac Surgery in Turkiye

Patient blood management (PBM) is defined as "the timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin concentration, optimize haemostasis and minimize blood loss in an effort to improve patient's outcome" (1,2). Patient blood management has recently been introduced in several areas where blood transfusions are important, such as anaesthesiology, cardiac surgery, orthopedic surgery, or traumatology (3).

Its adoption has been recommended by the WHO since 2010, as well as by national health regulation agencies, international professional societies, and the European Commission (4-7). In literature, there is mounting evidence that multimodal PBM programs can be effective at improving postoperative outcomes and reducing perioperative blood transfusions and costs (8).

Turkish Society of Anaesthesiology and Reanimation (TARD) PBM Task Force has been working on this subject and studied transfusion practices in major surgery patients and the prevalence of perioperative anemia (9). In the TULIP study, unfortunately, high usage of transfusions in major surgical patients in Turkey was documented. As demonstrated in the TULIP study, one of the surgeries that had high transfusion use, was cardiac surgery. Specific procedures with the highest RBC use were also coronary artery bypass grafting (16.9% of all units). Low hemoglobin concentration was the most common indication for intra-operative RBC transfusion (57%).

Preoperative anemia is common in cardiac surgery, with a prevalence between 10% and 50% (depending on the applied definition). Using the standard World Health Organization definition, the prevalence of anemia in the adult cardiac surgery population seems to be around 20% to 30% (10). Preoperative anemia is an independent risk factor for the transfusion of RBC, postoperative morbidity, and mortality (11, 12). An analysis of 9,144 cardiac surgery patients demonstrated that patients with low hematocrit values (<25%) during surgery who were exposed to RBC transfusion had an increased morbidity (cardiac and renal) and hospital mortality (13). Preoperative anemia is mostly the result of inadequate erythropoiesis owing to iron deficiency, malnutrition, malabsorption, inflammation, bone marrow disorders, or chronic blood loss. Importantly, anemic patients with iron deficiency need to be identified as early as possible by the cardiologist, surgeon, or anesthesiologist. With the introduction of a special PBM anemia walk-in clinic, anemia management can be initiated at an early stage. This would allow for timely optimization of iron stores to compensate for iron deficiency (14) or other treatable forms of anemia. Diagnosis and treatment of preoperative anemia are currently not part of standard care but are a core element of PBM to increase Hb values in cardiac surgery patients. In recent years, many studies investigated preoperative anemia and its effects on the outcome of adult cardiac surgery patients (Table 1).

Table 1. Preoperative anemia and its effects on the outcome of adult cardiac surgery patients

Author Study Design Sample Size Primary Outcome

• Kulier et al. 2007 (14) Prospective, observational 5,065 Cardiac and noncardiac adverse events ↑
• van Straten et al. 2009 (15) Prospective, observational 10,025 Early and late mortality ↑
• Carrascal et al. 2010 (16) Cohort study (retrospective) 1,388 Red cell transfusion ↑ Hospital stay ↑
• Piednoir et al. 2011 (17) Cohort study (retrospective) 100 Transfusion rate ↑ Postoperative fatigue ↑
• Hung et al. 2011 (18) Cohort study (retrospective) 2,688 Transfusion ↑ Death ↑ ICU stay ↑
• David et al. 2013 (19) Cohort study (retrospective) 943 Transfusion rate ↑
• Kim et al. 2015 (20) Cohort study (retrospective) 712 Transfusion rates ↑ Morbidity ↑
• Hallward et al. 2016 (21) Cohort study (retrospective) 1,972 Blood transfusion ↑ ICU stay ↑ Hospital stay ↑

When the interventional studies investigating the effect of PBM in cardiac surgery patients are examined, the studies showing visible differences are shown in Table 2.

Table 2. The effect of PBM in cardiac surgery patients

Author Study Design Sample Size Intervention Primary Outcome

• Karkouti et al. 2006 (22) Randomized, interventional 31 Iron ± EPO Hb level →
• Cladellas et al. 2012 (23) Cohort study (retrospective) 134 EPO + IV iron Renal failure ↓ Red blood cell transfusion ↓
• Garrido-Martin et al. 2012 (24) Randomized, interventional 159 Oral or IV iron IV iron Hb level →
• Johansson et al. 2015 (25) Randomized, interventional 60 IV iron Hb level ↑
• Duce et al. 2017 (26) Cohort study retrospective 159 EPO vs. blood cell transfusion Mortality → Thrombotic events →
• Spahn et al. 2019 (27) Randomized, interventional 1,006 IV iron, erythropoietin alpha, vitamin B12 and folic acid Red blood cell transfusions ↓ Hb level ↑ Reticulocytes ↑ Reticulocyte Hb ↑

In literature, IV iron treatment is recommended for cardiac surgery patients. Examples of these studies can be given as follows: Iron supplementation, especially in combination with EPO is recommended when anemia of chronic disease is accompanied by iron deficiency with complete depletion of iron stores (28).

The Hb concentration after iron supplementation rise approximately 1 to 2 g/dL within 2 to 4 weeks. Very recently, a trial investigating the effect of ultra-short-term treatment (combination of iron, erythropoietin, vitamin B12, and folic acid administration) of 505 patients with iron deficiency or anemia undergoing cardiac surgery showed significantly reduced RBC transfusions, higher Hb concentration, higher reticulocyte count, and a higher reticulocytes Hb content during the first 7 days (27). This study suggests that an iron supplementation even immediately before cardiac surgery has beneficial effects, however, an early start to therapy could be more effective (29,30).

Whether different thresholds of Hb defining anemia in men and women lead to an undertreatment of female patients has been investigated in many studies and is the subject of current discussions. Most of these studies were conducted with cardiac surgery patients (31,32). The latest data show that women have worse outcomes compared with men having anemia.

Although other factors have an impact on this result (e.g., higher age, higher incidence of comorbidities, more acute and symptomatic stage in women), it is proposed that for all patients, regardless of sex, a Hb threshold of 13 g/dL should be applied (33). This is particularly important in those undergoing surgery with the use of cardiopulmonary bypass where dependent on the system, in most cases, the same volume of fluid is added to the pump. Perioperative bleeding has been shown to be an independent predictor of hospital mortality. In a study including more than 9000 patients undergoing cardiac surgery with CPB, massive blood loss (defined by the transfusion of at least five units of packed red blood cells on the day of surgery) was associated with an 8-fold increase in mortality (34). Other studies have also reported excess morbidity, particularly in terms of thromboembolic complications, infections, and higher rates of surgical re-exploration (35). Notably, surgical re-exploration and transfusion following bleeding are also associated with increased infection, mortality, and a longer stay in ICU and hospital (36,37).

Excessive postoperative hemorrhage in cardiac surgery has a significant economic impact: a retrospective German analysis of more than 1100 patients estimated its average additional cost to be €6251 per patient (38).

Oral iron therapy is inexpensive and easy to administer, but its gastrointestinal side effects limit the routine use of oral iron therapy (39). Several studies reported the good efficacy of intravenous iron therapy (IVIT) in increasing hemoglobin levels and reducing blood transfusions in patients with anemia (40-42). However, the recovery profiles according to the status of the disease or condition of the patients are controversial regarding the efficacy of IVIT in transfusion practices. While some elements of PBM have a strong evidence base in cardiac surgery, such as the use of tranexamic acid (TXA) and reduced transfusion thresholds (43,33), the evidence for preoperative anemia optimization with IVIT is less in Turkiye. Sert et al. from Turkiye, evaluated retrospectively the data of patients who underwent elective open-heart surgery. Their primary aim was to compare the patient outcomes, the requirement for transfusion, and the cost of transfusion between two different periods with and without PBM protocols. The authors found that the transfusion of unnecessary blood and blood products was reduced, and the cost decreased with the PBM protocol, although blood product usage did not affect 30-day mortality (44). It was observed that 37.1% of the patients were anemic, 50.6% were using anticoagulant drugs, and 78% had at least an additional disease. Although these factors were regarded as risk factors for transfusion, it was determined that patients with anemia had more frequently required transfusions than those without anemia.

In the general framework, five main risk factors for high risk of bleeding or transfusion are very consistently identified independently of the country: pre-operative anemia, prior cardiac surgery, clopidogrel 5 days or less before surgery, use of other P2Y12 inhibitors at any point, and thrombocytopenia <100.000 platelets/mm3. In conclusion, more efforts are needed to clarify and complement the currently available guidelines and to define a homogenous landscape for PBM practices implementation (45).

Potential barriers to the implementation of PBM are lack of knowledge, under-representation of anemia management in the education of young physicians, inadequate interpretation of controversial evidence, errors in reasoning, oversimplification, wide variations in belief, and lack of agreement of hospitals, self-efficiency, outcome expectancy, and stability of the previous practice (46).

Therefore, we plan to perform a large-scale, prospective study in which a well-designed PBM program is used to confirm the efficacy of perioperative IVIT in patients with CABG surgery. As a second step, PABMiCS study is proposed to identify the benefits of PBM implementation, including preoperative anemia management, in major cardiac surgeries in Turkiye.