Preoperative anemia is a contraindication to elective surgery. Nonetheless, it is very common, affecting up to 39% of patients candidate to general surgery,1,2 34% to noncardiac surgery,3 33% to vascular surgery,4 26% to cardiac surgery,5 and 24% to gynecological surgery.6 Logically, it is the strongest predictor of blood transfusions (five-fold) in the postoperative period2 and, as a consequence, it is associated to several risks and morbidity,7,8 such as infections (two-fold) and kidney injury (four-fold), as well as a 22% longer hospital stay (1). More importantly, perioperative anemia is now recognized as strongly and independently related to postoperative mortality (adjusted odd ratio 2.36), also besides transfusions.1,2
Postoperative anemia regards up to 90% of patients after major surgery.3 The main recognized causes can be preoperative anemia, perioperative blood loss, poor nutritional intake in the postoperative period, frequent blood sampling for laboratory tests, and increased hepcidin due to inflammatory response to surgery. These effects can last for a few weeks after major surgery and aggravate postoperative iron deficiency anemia. The immediate and most widely used treatment for postoperative anemia is blood transfusion. Blood transfusions carry several complications, culminating in a high incidence of morbidity and mortality.9–13 In particular, they are related to increased length of hospital stay and rate of discharge to an inpatient facility, worse surgical and medical outcomes, allergic reactions, transfusion-related acute lung injury, volemic overload, venous thromboembolism, graft versus host disease, immunosuppression, and postoperative infections. In addition, blood transfusions are responsible of an increased burden on the health care system.
What is patient blood management
In the recent years, various strategies have been studied to reduce the use of blood transfusions to prevent transfusion-related adverse events, increase patient safety, and reduce cost. As a consequence, a new concept was born: the patient blood management (PBM). According to the World Health Organization, PBM is defined as the timely application of evidence-based medical and surgical concepts designed to maintain a patient’s hemoglobin (Hb) concentration, optimize hemostasis, and minimize blood loss in an effort to improve the outcome. More in detail, PBM focuses on three pillars14-18:
- - optimizing red cell mass;
- - minimizing blood loss and bleeding;
- - optimizing tolerance of anemia.
The implementation of the three pillars of PBM leads to improved patient’ outcomes by relying on his/her own blood rather than on that of a donor. PBM goes beyond the concept of appropriate use of blood products, because it precedes and strongly reduces the use of transfusions by correcting modifiable risk factors long before a transfusion may even be considered.14-18 Importantly, the PBM is transversal to diseases, procedures, and disciplines. It is solely aimed at managing a patient’s resource (i.e., his/her blood), shifting the attention from the blood component to the patient himself/herself. Pragmatically, the PBM consists in different approaches according to the considered pillar and to the time with respect to surgery (Table 1).
Table 1 -
The application of PBM.
||- Detect anemia- Identify and manage underlying disorder(s)
- Refer for further evaluation if necessary
- Treat suboptimal iron stores, ID, anemia of chronic disease, iron-restricted erythropoiesis
- Treat other hematinic deficiencies
|- Identify and manage bleeding risk
- Minimize iatrogenic blood loss
- Procedure planning and rehearsal
|- Assess/optimize patient’s physiological reserve and risk factors
- Compare estimated blood loss with patient-specific tolerable blood loss- Formulate patient-specific management plan using appropriate blood conservation modalities to minimize blood loss, optimize red cell mass and manage anemia
||- Time surgery with hematological optimization
||- Meticulous hemostasis and surgical techniques
- Blood-sparing surgical devices- Anesthetic blood conserving strategies
- Autologous blood options
- Maintain normothermia
- Pharmacological/hemostatic agents
|- Optimize cardiac output- Optimize ventilation and oxygenation
||- Optimize erythropoiesis- Be aware of drug interactions that can increase anemia
||- Vigilant monitoring and management of postoperative bleeding
- Avoid secondary hemorrhage
- Rapid warming, maintain normothermia (unless hypothermia specifically indicated)
- Autologous blood salvage- Minimize iatrogenic blood loss
- Hemostasis/anticoagulation management
- Prophylaxis of upper GI hemorrhage
- Avoid/treat infections promptly
- Be aware of adverse effects of medication
|- Optimize anemia reserve- Maximize oxygen delivery
- Minimize oxygen consumption- Avoid/treat infections promptly
- Restrictive transfusion thresholds
Adapted with permission from Oncologist. 2011;16:3–11 and ISBT Sci Ser. 2009;4:423–435.
GI indicates gastrointestinal; ID, iron deficiency; PBM, patient blood management.
The recent and growing interest in PBM is principally driven by its notable impact on several outcomes.19 According to different studies, PBM is able to reduce mortality up to 68%, reoperation up to 43%, readmissions up to 43%, composite morbidity up to 41%, infection rate up to 80%, average length of stay by 16%–33%, transfusion from 10% to 95%, and costs from 10% to 84% (dependently from the healthcare system).20 Consistently, from patient’s safety and better outcomes, the PBM achieves the aim of costs saving and fast track policies adoption, satisfying some key performance indicators.
What is ERAS and why PBM should be part of it
The concept of Enhanced Recovery After Surgery (ERAS), or multimodal surgery, has the aim of reducing the impact of a surgical operation on the patient. It involves both the use of different strategies to decrease the psychological and physiological stress to reduce catabolism, and a set of measures to provide a more rapid and stress-free recovery.21 In the field of colorectal surgery, randomized clinical trials have demonstrated that the application of the ERAS protocols is associated with a reduction of up to 52% (95% confidence interval [CI] = 0.36, 0.73) in 30-day morbidity rates and up to 2.5 days (95% CI = 3.9, 1.1) in hospital stay.22 For this success, the ERAS team is becoming a leader figure within each surgical discipline and it is composed by at least surgeons, anesthesiologists, and nurses. Dedicated guidelines have been created and updated.21,23
PBM is an enveloping multidisciplinary concept, including evidence-based actions. Consequently, it meets the standards of surgery programs like Fast Track established by ERAS, since these are based on the application of scientific evidence throughout the entire perioperative period. PBM should be included in this protocol according to the type of surgery. Although the evidence suggests the adoption of these measures to decrease the blood transfusion rate, length of stay and readmission, there are no studies linking the two programs.
The role of ferric carboxymaltose in this context
The first pillar of PBM directly involves preoperative anesthetic action and requires a multidisciplinary approach. Since performing additional tests required on short notice to surgery impedes their correct evaluation, time is required to perform a successful detection, evaluation, and treatment of preoperative anemia. Hb and iron status should be evaluated before any major surgical procedure24 because timely diagnosis and treatment of anemia are the only effective strategy to avoid perioperative anemia and transfusion needs.25 The main etiological factors of anemia in surgical patients are the presence of a chronic inflammatory process (64%) and the presence of iron deficiency (23%–33%). The most useful tests to diagnose the iron status are serum ferritin and transferrin saturation (TSAT). Serum ferritin level evaluates iron stores, while TSAT reflects iron availability for erythropoiesis. In fact, iron deficiency is defined as either a true paucity of iron stores (absolute) or as a relative deficiency (functional) in which the patient exhibits an impaired iron release from body stores that is unable to meet the demand for erythropoiesis (also called reticuloendothelial cell iron blockade).26,27 Functional iron deficiency not only leads to ineffective erythropoiesis, but also to an inadequate immune response, increasing length of stay, and mortality rates. Iron deficiency necessitates iron supplementation (Figure 1). According to the Italian National Blood Centre, patients requiring iron therapy should be administrated by intravenous formulations letting iron storage recovery with high single doses.29 Indeed, it is known that many patients will not respond to oral iron treatment, especially those patients who have functional iron deficiency and chronic illness.30 Moreover, oral iron supplementation can be attempted,24 but an intravenous iron course is suggested when a quicker response is needed.31 On the other hand, recent intravenous iron preparations have a low risk of adverse reactions32 and are more effective than oral iron in restoring Hb concentrations in both iron deficiency anemia and chronic disease anemia. Thanks to the carbohydrate shell, the compound, particularly ferric carboxymaltose (FCM), is stable allowing the rapid infusion of high iron doses, has a physiological pH, and is iso-osmolar to avoid phlebitis, and determines the lowest amount of “free” iron which is toxic.33,34 In clinical practice, a dose of 1000–1500 mg of FCM is sufficient to restore iron stores in most surgical patients (Figure 1) and can usually be given in one or in two divided doses.35 In a meta-analysis of 103 trials published from 1966 to 2013,36 iv iron was not associated with an increased risk of severe adverse events (relative risk [RR] = 1.04; 95% CI = 0.93, 1.17) compared with control treatments (i.e., oral iron, intramuscular iron, placebo, or no iron). The risk of serious infusion reactions was increased with iv iron (RR = 2.47; 95% CI = 1.43, 4.28), particularly with ferric gluconate (RR = 5.32; 95% CI = 1.49, 18.99), but not with other iron formulations. Additionally, the risk of serious infection was not increased by iv iron (RR = 0.96; 95% CI = 0.63, 1.46). These findings provide reassurance of the safety of iv iron, particularly the new formulations, making it a viable alternative for patients who do not respond well to oral iron therapy. An international consensus on postoperative PBM recently provided a flowchart (Figure 2) to guide the use of iv iron and/or blood transfusion in this context.37 If operative blood loss is at least 500 ml or the surgical act lasts for at least 2 hours, Hb and iron metabolism should be screened and anemia classified into mild, moderate, or severe using 80 and 110 g/L as cutoffs. Blood transfusion is required only for severe symptomatic anemia, whereas iv iron is suggested for moderate to severe anemia and for mild anemia with iron deficiency.
Ideally, the PBM team should act as main character during the whole perioperative timespan. In other words, a complete preoperative evaluation should be performed, together with the estimation of intraoperative blood loss and the management of the postoperative anemia with the transfusionists. In this way, a comprehensive patient journey (i.e., PBM) should be defined and included into ERAS protocols. Ad hoc trials must be run to definitely demonstrate that PBM improves the outcomes and reduces the transfusion rate. Moreover, a more precise cutoff to standardize the need for transfusions is required. The Italian ColoRectal Anastomotic Leakage (iCral) study group is currently launching a prospective observational multicentre study (iCral4),38 to investigate the effects of adherence to the two programs in colorectal surgery.
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