EUROANESTHESIA 2005 PERIOPERATIVE LIMITS OF ANAEMIA PROBLEMS ASSOCIATED WITH ALLOGENEIC TRANSFUSION COMPENSATORY MECHANISMS FOR ACUTE ANEMIA

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1 PERIOPERATIVE LIMITS OF ANAEMIA EUROANESTHESIA 2005 Vienna, Austria May RC2 O. HABLER. A. PAPE, J. MEIER AND B. ZWIßLER Clinic of Anesthesiology, Intensive Care and Pain Control Johann Wolfgang Goethe - University Frankfurt a. Main, Germany Saturday May 28, :00-16:45 Room K PROBLEMS ASSOCIATED WITH ALLOGENEIC TRANSFUSION Although safer than ever, allogeneic transfusion is still associated with risks for the recipient (haemolysis, infection, and immunosuppression). The risk of postoperative wound infection correlates with the amount of allogeneic blood products transfused [1]; a correlation with the recurrence rate of malignancy is also proposed [2,3]. Recently it has been reported that unnecessary over-transfusion increases mortality in cardiac risk patients [4]. Moreover the costs for allogeneic blood products are supposed to increase in the future due to an increasing imbalance between blood-donors and potential recipients - particularly elder patients undergoing major surgery [5]. To control both, the immunological risk and costs, allogeneic transfusion should either be completely avoided or at least minimized during surgical procedures. This can be achieved by (1) intraoperative transfusion of autologous blood collected preoperatively (autologous blood donation, acute normovolaemic hemodilution) or intraoperatively (blood salvage), (2) reduction of the amount of blood loss (skillful surgical technique, deliberate hypotension, administration of antifibrinolytic drugs), and (3) tolerance of low intraoperative hemoglobin (Hb) concentrations. COMPENSATORY MECHANISMS FOR ACUTE ANEMIA It has been known for a long time that adequate tissue oxygenation does not depend on a normal hemoglobin (Hb) concentration [6]. Intraoperative blood loss is initially replaced by erythrocyte-free, i.e. cristalloid or colloid solutions (e.g. Ringer s lactate, dextran, hydroxyethyl starch, gelatine). As long as normovolaemia is maintained the resulting dilutional anaemia and the concomitant decrease in arterial oxygen content (CaO 2 ) are compensated without the risk of tissue hypoxia through an increase in cardiac output and enhanced arterial oxygen extraction [7,8]. A progressive dilutional reduction of CaO 2 finally results in a fall of tissue O 2 delivery (DO 2 ). However, since DO 2 exceeds tissue oxygen demand under physiologic conditions by a factor of 3 to 4, tissue oxygen consumption, VO 2, remains first unchanged over a large range of decreasing DO 2 (DO 2 -independent part of VO 2 ) (Figure 1). FIGURE 1 Figure 1. Relationship between oxygen delivery (DO 2 ) and oxygen consumption (VO 2 ) during normovolemic hemodilution (read x-axis from the right to the left). (1) Supply-independent part of VO 2. (2) Supply-dependent part of VO 2 reflecting manifest tissue hypoxia. The inflection point represents critical DO 2 and is the last possibility to transfuse red blood cells before tissue hypoxia is established 179

2 LIMITS OF DILUTIONAL ANEMIA Only at extreme degrees of hemodilution, when passing the value of critical oxygen delivery (DO 2 crit ), does the amount of oxygen delivered become insufficient to meet the O 2 demand of tissues. As a consequence VO 2 starts to decrease as well (DO 2 -dependency of VO 2 ) (Figure 1). This decrease of VO 2 must be interpreted as an indirect sign of manifest tissue hypoxia. Without any treatment the persistence of the critical oxygen delivery finally leads to death within less than 3 hours [9] (Figure 2). From the pathophysiological point of view the ultimate opportunity to transfuse red blood cells before the establishment of manifest tissue hypoxia is therefore DO 2 crit (or Hb crit, Hct crit respectively). Unfortunately the quantification of the critical oxygen delivery point is difficult, because it depends on various factors and varies both intra- and interindividually. FIGURE 2 Figure 2. Survival time (in hours) of pigs (n=7) having been hemodiluted to their individual critical hemoglobin concentration (3.1±0.4 g/dl) and kept there without any further treatment other than replacement of insensitive fluid losses. All animals died within 3 hours [9]. FACTORS INFLUENCING THE CRITICAL OXYGEN DELIVERY 180 Blood volume: the basic requirement for the effective compensation of dilutional anaemia is normovolaemia. During hypovolaemic hemodilution the total body oxygen demand increases due to the release of catecholamines and other stress hormones and the critical oxygen delivery (DO 2 crit ) is met at higher values than when normovolaemic. Depth of anaesthesia: in high doses most of the anaesthetics attenuate the cardiac output response during hemodilution and thus reduce anaemia tolerance [10]. Muscular relaxation: when taking into consideration that skeletal muscles represent up to one third of the total body mass, a complete pharmacologic muscular relaxation should effectively reduce muscular oxygen demand and by that increase anaemia tolerance (compare Table 1). Body temperature: in experimental models mild hypothermia has been shown to increase anaemia tolerance due to a reduction of total body oxygen demand [11]. The opposite should be postulated for hyperthermia. Inspiratory oxygen fraction (FiO 2 ): ventilation of the patient with high FiO 2 (hyperoxic ventilation) rapidly raises CaO 2 by increasing the amount of physically dissolved oxygen in plasma (hyperoxia). Because of the linear relationship between arterial partial pressure of oxygen, pao 2, and CaO 2 in plasma, the quantity of oxygen dissolved depends only on arterial po 2 and plasma volume. Since in haemodiluted subjects the plasma compartment is significantly increased, it becomes an important source of oxygen. High FiO 2 increases the tolerance for anaemia [9,12].

3 Myocardial performance: the heart is at the same time the motor for the compensation of dilutional anaemia (increase of cardiac output) and the organ at highest risk from anaemic tissue hypoxia. Since the myocardial oxygen extraction capability is already almost exhausted under physiologic conditions, myocardial DO 2 depends exclusively on coronary blood flow. In patients with restricted coronary reserve (e.g. coronary artery disease), limited ventricular performance (e.g. congestive heart failure) or taking cardiodepressant medication, tolerance to anaemia is reduced [13]. IDENTIFICATION OF THE CRITICAL O 2 DELIVERY The decay of DO 2 below its critical value is reflected by the sudden decay of VO 2 having been stable until then. Pulmonary artery catheter: total body VO 2 can be calculated from cardiac output, arterial and mixedvenous oxygen content by use of a pulmonary artery catheter. Unfortunately this method allows only for the discontinuous monitoring of VO 2 and thus a sudden decay of VO 2 may be missed in-between two measurements. Moreover at advanced degrees of hemodilution, calculated VO 2 underestimates the real VO 2 [14]. Metabolic monitoring: total body VO 2 may be nearly continuously (in minute-by-minute intervals) measured with metabolic monitors (e.g. DeltaTrac, Oxycon pro). The sudden decay of VO 2 indirectly reflecting DO 2 crit may be identified with high precision by computer software i.e. independently of an observer [15]. This method is however expensive and only used for answering scientific questions. ECG and Trans Esophageal Echocardiography (TEE): the achievement of the critical myocardial DO 2 may be reflected by ST-segment changes in the ECG or by regional wall motion disturbances detected with TEE. However the sensitivity of neither ECG nor TEE exceeds 80-90%. Therefore subendocardial myocardial ischemia may be present despite the lack of pathologic changes in ECG or TEE. LIMITS OF DILUTIONAL ANEMIA IN HEALTHY SUBJECTS In subjects of different species without cardiopulmonary disease critical DO 2 was identified at Hb-concentrations between 1.1 and 3.3 g/dl (Table 1). Babies (1-7 months) [16] and older children (12.5 years) [17] supported Hb-concentrations of 3 g/dl and lower without meeting their critical DO 2. Studies of acute normovolaemic hemodilution in pregnant sheep suggest that fetal oxygen extraction is maintained until the maternal Hct is reduced by more than 50% [18]. LIMITS OF DILUTIONAL ANEMIA IN SUBJECTS WITH CARDIAC DISEASE Dogs with an experimentally induced high-grade (50-80%) coronary artery stenosis experienced myocardial ischemia and/or a deterioration of cardiac performance after haemodilution to Hb-concentrations between 7 and 10 g/dl [19,20]. Similar results were found in clinical investigations. Spahn et al. [21] demonstrated in patients suffering from coronary artery disease that despite chronic beta-blockade the cardiac compensatory mechanisms for dilutional anaemia were completely preserved until a Hb-concentration of 9.9 g/dl. Nelson et al. [22] and Hogue et al. [23] described a higher postoperative cardiac morbidity only at Hct-values lower than 28% (i.e. Hb ~ 9 g/dl). In a retrospective cohort-analysis of cardiac risk patients undergoing non-cardiac surgery and refusing allogeneic transfusion for religious reasons (affiliation to Jehovah s Witnesses) Carson et al. found a significantly higher postoperative mortality, if the postoperative Hb-concentration fell below 8 g/dl [13]. In patients with acute coronary syndromes transfusions were not associated with improved outcome when nadir Hct values were in the range of 20 to 25% (i.e. Hb ~ 7-8 g/dl) [4]. In ICU-patients with cardiac co-morbidity 30-day-mortality was identical with either restrictive (target-hb 7-9 g/dl) or liberal (target-hb g/dl) transfusion strategy [24]. Whether patients with acute myocardial infarction [25] or severe congestive heart failure (NYHA III und IV) [26] profit from higher Hb-concentrations (Hb g/dl) is subject for debate. 181

4 TABLE 1. LIMITS OF DILUTIONAL ANEMIA REFLECTED BY THE CRITICAL HB-CONCENTRATION OR THE CRITICAL HCT IN DIFFERENT SPECIES. ACTUAL GUIDELINES FOR PERIOPERATIVE TRANSFUSION Perioperative red blood cell transfusion is rarely indicated when the Hb-concentration is greater than 10 g/dl and is almost always indicated when it is less than 6 g/dl [27]. In young and healthy subjects perioperative transfusion should be avoided until a Hb-concentration of 6 g/dl (or in particular cases even lower) is reached. In cardiac risk patients the perioperative Hb-concentration should be kept between 8 and 10 g/dl. Every decision to transfuse should be based on 1) the actual Hb-concentration, 2) the existence of cardiopulmonary co-morbidity, 3) the appearance of physiological transfusion triggers [28] and 4) the dynamics of blood-loss. 182

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