**2. Preoperative strategies**

### **2.1 Correction of preoperative anemia**

In the preanesthetic evaluation we will provide a guideline for preoperative evaluation and preparation of the patient, and we will include him/she to a **blood-saving program** by stimulating their erythropoietin (EPO) production, giving iron (Fe) or autologous blood predonation. It is important to check on hemoglobin levels, as well as iron deposits (ferritin, soluble transferrin receptor and transferrin saturation) and associated pathologies (comorbidity).

Hemoglobin concentration is one of the most predictive factors for autologous blood transfusion (ABT). Patients with preoperative anemia show an increase in postoperative morbimortality and a decrease in quality of life (Shander et al., 2004). Age is a predisposing factor for anemia and the prevalence of postoperative anemia increases with age (Goodnough et al., 2005; Rosencher et al., 2003). Iron deficiency and chronic inflammation, with or without iron deficiency, are the most frequent causes of preoperative anemia in these patients. Folic acid and vitamin B12 deficiency can also be present, especially in elderly people.

A preoperative anemia must be treated before undergoing surgery, if it is possible, limiting exposure risk to allogeneic blood.

 **Human recombinant erythropoietin (rhEPO)** – For the past several years, we have at our disposal the human recombinant erythropoietin (rhEPO), obtained from genetic engineering, identical to the endogenous, which stimulates erythrocyte production in a dose-dependent way. It was considered that its use in surgical patients would arise preoperative hemoglobin values and/or facilitate autologous blood predonation, and this way decreasing the chances of an allogeneic transfusion. It is used in programmed patients undergoing major orthopedic surgeries in which initial hemoglobin is between 10 and 13 g/dl, and the prediction of perioperative blood loss is significant (Laupacis & Fergusson, 1998).

Its main function is stimulating the bone marrow's erythropoietic activity, acting on specific receptors of erythrocyte-formation precursor target cells. Plasma levels of EPO do not vary with age or sex. In healthy individuals the rank goes from 5 – 25 mU/ml. EPO's dosage varies according to its indication and it must be supplemented with iron to avoid stimulating an iron-deficient erythropoiesis. After undergoing a preoperative treatment with EPO, ferritin concentration decreases to half. The speed at which iron from this deposits can be activated becomes a limiting factor. Patients with serious cardiovascular disease, poorly controlled hypertension and history of thromboembolic disease or deep vein thrombosis cannot be treated with EPO.

 **Iron, vitamin B12 and folic acid** – So that erythropoiesis works properly, besides EPO, it is necessary an appropriate iron intake (fundamental component in the hemoglobin molecule), as well as vitamin B12 and folic acid. Its deficiency affects the proliferation and cellular differentiation in erythropoiesis resulting in central arregenerative anemia (decreased reticulocytes). Total amount of iron in our organism is approximately 4-5 grams. 65% is found as hemoglobin, whereas 15-30% is stored in the hepatic parenchyma and rethiculoendotelial system as ferritin and the rest of it binds to transferrin in blood plasma. It is absorbed in the small intestine.

The aim of this chapter is to inform on saving techniques of hematic components and its

In the preanesthetic evaluation we will provide a guideline for preoperative evaluation and preparation of the patient, and we will include him/she to a **blood-saving program** by stimulating their erythropoietin (EPO) production, giving iron (Fe) or autologous blood predonation. It is important to check on hemoglobin levels, as well as iron deposits (ferritin, soluble transferrin receptor and transferrin saturation) and associated pathologies

Hemoglobin concentration is one of the most predictive factors for autologous blood transfusion (ABT). Patients with preoperative anemia show an increase in postoperative morbimortality and a decrease in quality of life (Shander et al., 2004). Age is a predisposing factor for anemia and the prevalence of postoperative anemia increases with age (Goodnough et al., 2005; Rosencher et al., 2003). Iron deficiency and chronic inflammation, with or without iron deficiency, are the most frequent causes of preoperative anemia in these patients. Folic

A preoperative anemia must be treated before undergoing surgery, if it is possible, limiting

 **Human recombinant erythropoietin (rhEPO)** – For the past several years, we have at our disposal the human recombinant erythropoietin (rhEPO), obtained from genetic engineering, identical to the endogenous, which stimulates erythrocyte production in a dose-dependent way. It was considered that its use in surgical patients would arise preoperative hemoglobin values and/or facilitate autologous blood predonation, and this way decreasing the chances of an allogeneic transfusion. It is used in programmed patients undergoing major orthopedic surgeries in which initial hemoglobin is between 10 and 13 g/dl, and the prediction of perioperative blood loss is significant (Laupacis &

Its main function is stimulating the bone marrow's erythropoietic activity, acting on specific receptors of erythrocyte-formation precursor target cells. Plasma levels of EPO do not vary with age or sex. In healthy individuals the rank goes from 5 – 25 mU/ml. EPO's dosage varies according to its indication and it must be supplemented with iron to avoid stimulating an iron-deficient erythropoiesis. After undergoing a preoperative treatment with EPO, ferritin concentration decreases to half. The speed at which iron from this deposits can be activated becomes a limiting factor. Patients with serious cardiovascular disease, poorly controlled hypertension and history of thromboembolic

 **Iron, vitamin B12 and folic acid** – So that erythropoiesis works properly, besides EPO, it is necessary an appropriate iron intake (fundamental component in the hemoglobin molecule), as well as vitamin B12 and folic acid. Its deficiency affects the proliferation and cellular differentiation in erythropoiesis resulting in central arregenerative anemia (decreased reticulocytes). Total amount of iron in our organism is approximately 4-5 grams. 65% is found as hemoglobin, whereas 15-30% is stored in the hepatic parenchyma and rethiculoendotelial system as ferritin and the rest of it binds to

acid and vitamin B12 deficiency can also be present, especially in elderly people.

disease or deep vein thrombosis cannot be treated with EPO.

transferrin in blood plasma. It is absorbed in the small intestine.

implantation in scheduled orthopedic surgery, summarized in table 1.

**2. Preoperative strategies** 

exposure risk to allogeneic blood.

Fergusson, 1998).

(comorbidity).

**2.1 Correction of preoperative anemia** 

Iron-deficiency anemia affects approximately 25% of world population. Furthermore, there is a status defined as 'functional iron-deficient states', which is described as a situation where iron deposits are normal (or even increased), but iron supply to bone marrow is inadequate to satisfy the erythroid precursor demands; and another anemia associated to 'chronic processes' where erythropoiesis is deficient because of proinflammatory cytokinesmediated mechanisms.

Nowadays it has been proven its high profitability and efficiency index, mainly to optimize or as support in the erythropoietin treatment and autologous predonation. Administration of oral iron is effective in decreasing allogeneic blood transfusions and/or the number of transfused patients in orthopedic major surgery (Okuyama et al., 2005). Orally or intravenous use of iron will depend at the moment in which the treatment is taking place, oral iron absorptive capacity and existence of any gastric disease that could contraindicate oral iron treatment (Cuenca et al., 2004). If treatment is done with intravenous iron, once it is finished we must prescribe oral iron.

The total amount of administered iron will depend on initial hemoglobin value and existence of an iron-deficient condition. If using saccharose iron, dosage varies from 100 to 200 mg in alternate days, with a maximum dose of 600 mg per week and 200 mg every 2 days. At present there is also carboxymaltose iron, which contains greater amounts of iron (500-1000 mg) to administer in a single dose. In case of a folic acid and/or vitamin B12 deficiency we must supply substitutive treatment to correct it.

### **2.2 Autologous blood predonation**

This means the presurgical patient's blood predonation or autodonation. Some weeks prior to intervention, a blood extraction (one or more units of blood) is performed to the patient to be used at his/her surgery or postoperatively.

To be included in the program the patient must fulfill both medical and analytical special requirements; hemoglobin levels before starting predonation process above 11 mg/dl, as well as an appropriate programming of surgery to avoid expiration of the predonated units (35 days - maximum time permitted for storage). Due to this fact, quite a reasonable amount of patients who have undergone autologous blood donation preoperatively, reach surgery time with hemoglobin values under their initial levels (before predonation), therefore increasing transfusion requirements. The patient carries out the donations once or more times during the days and weeks prior to intervention. 350-400 mL extractions are made not less than 3-day intervals, which is the time needed for protein synthesis and mobilization and to return to normal. This way, they can benefit from erythropoiesis stimulation with erythropoietin. All patients must receive an appropriate iron supplement.

Despite the fact that this technique was at its peak during the nineties, its use has been diminishing progressively for several reasons. In first place, the high number of blood bags that were dismissed because of an imbalance between extracted bags and transfusion requirements, since a good coordination in surgery programming and between all professionals taking part is needed. This difficulty has made this method a very expensive one in resource-consumption and less effective than it was thought to be at first. On the other hand, the establishment of intravenous iron and erythropoietin, decrease in transfusion threshold and improvement of the surgical method too, have pushed into the background autologous donation preoperatively, leaving it as last option in some cases such as complex spinal surgery with a mass blood loss forecast and those patients whose blood group have compatibility difficulties.

Blood Transfusion in Knee Arthroplasty 113

hemostasis. There is a straightforward relationship between hematic loss and surgical time; a longer surgical time is associated to a greater hematic loss. During surgery, local hemostatic agents, such as fibrin sealants, which reduce surgical bleeding, can be used. We

These are substances able to replace the use of allogeneic blood components. They are obtained from human blood, transgenic animals or recombinant technology. Currently still under development. There are hemoglobin solutions and perfluorocarbonate emulsion.

Several prohemostatic drugs have been used in order to try reducing or preventing intraoperative bleeding. In orthopedic surgery, antifibrinolytic and desmopressin are the

Perioperative bleeding is partially attributed to the fibrinolytic system activation. Several work groups have administered antifibrinolytics, and as a result observed a decrease in perioperative bleeding and blood bags transfused (Henry et al., 2001). In other recent revisions, which evaluate antifibrinolytics drugs in orthopedic surgery ( Kagoma et al., 2009; Zufferey et al., 2006), they conclude that using tranexamic acid or aprotinin reduces the percentage of patients requiring blood transfusions and also are efficient decreasing bleeding. When using epsilon-aminocaproic acid (EACA) there are no signs of a significant reduction in hemorrhagic risk, although not many studies have been done. All of them can have relatively infrequent but very serious side effects, such as arterial thrombosis, renal

It is a 58 amino acid polypeptide. It is found mainly in mammalian mastocytes and it is commercialized from bovine lung. Aprotinin works inhibiting trypsin, plasmin and tissue and plasma kallikrein. In addition to this, it holds an anti-inflammatory effect attenuating inflammatory response in major surgery, particularly at high-doses. It is the antifibrinolytic drug most widely studied to reduce bleeding and diminish transfusion needs. However, in comparison to tranexamic acid or EACA, it increases mortality risk. After the adverse results in mortality in patients who had undergone cardiac surgery in an observational study over more than 4000 patients (Mangano et al., 2006), and in a randomized double blind trial with

Synthetic analogs of lysine. Tranexamic acid and EACA are able to block fibrinolysis by

*Tranexamic acid* is 10 times stronger in vitro than EACA. In total knee arthroplasty, prophylactic administration significantly reduces blood loss up to 50% and decreases transfusion requirements without increasing the risk of thromboembolic signs (Alvarez et al., 2008; Cid & Lozano, 2005; Lozano et al., 2008). Optimal technique would be with two tranexamic acid bolus (each of them 10-15 mg/Kg), one before surgery and another when letting the air out of the tourniquet. In total hip prosthesis, tranexamic acid results in a

over 3000 patients (Fergusson et al., 2008), the drug was withdrawn worldwide.

competitively antagonizing the binding of plasminogen to fibrin.

will develop this part further on.

**3.4 Erythrocytes' substitutes** 

mainly used.

**3.5.1 Antifibrinolytics** 

failure or rhabdomyolysis.

**3.5.1.2** *Synthetic antifibrinolytics* 

**3.5.1.1 Aprotinin** 

**3.5 Pharmaceutical measurements** 

The existence of predonation units increases the likelihood of transfusion, as perception of risk decrease; there is less chance of rejection or blood incompatibility, as well as less infections. Moreover, it is exposed to the same errors in the processes of extraction, storage, identification and reinfusion to the autologous blood transfusion. Predonation of autologous blood has the following contraindications: serious cardiac disease, hepatitis B history and positive markers for HCV, HIV-I/II, HTLV-I/II and active bacterial infection.
