Allogeneic blood transfusions are associated with risks,

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1 REVIEW ARTICLE Martin J. London, MD Section Editor Acute Normovolemic Hemodilution: Physiology, Limitations, and Clinical Use Marina Jamnicki, MD,* Roman Kocian, MD, Philippe van der Linden, MD, Michael Zaugg, MD,* and Donat R. Spahn, MD, FRCA Allogeneic blood transfusions are associated with risks, considerable costs, intermittent blood shortages, and are of questionable efficacy. 1-3 Therefore, multiple alternatives have been developed, and acute normovolemic hemodilution (ANH) is one of these options. 4 This article aims at describing physiology, limits, and possible clinical uses of ANH focusing on human data whenever possible. BASIC PRINCIPLES OF ANH The amount of red blood cells and other plasma constituents lost during surgical bleeding is reduced by preoperative dilution of the circulating blood volume. ANH is traditionally performed immediately before surgery, either before or shortly after anesthesia induction. Conceptually, it is crucial to do ANH before the major surgical bleeding phase. Therefore, it is also conceivable to perform ANH intraoperatively during an initial, nonhemorrhagic phase. The blood withdrawn is simultaneously replaced with an appropriate volume of crystalloid or colloid fluids (alone or in combination) to maintain normovolemia. 5,6 Maintaining perioperative normovolemia is crucial because recent studies have shown that an optimal filling of the heart improves cardiac function, decreases postoperative morbidity, and shortens hospital stay. 7-9 The target hematocrit with ANH is variable but is often around 25% to 30%. More extreme hemodilution (eg, 20%) is likely to be more efficacious with regards to blood conservation, but the risks are greater, particularly for patients with preexisting medical conditions such as coronary heart disease. 5 In addition, it requires larger quantities of blood to be withdrawn rendering it time consuming (10-15 minutes per bag of 450 ml) and increasing the risk of compromising coagulation by the infusion of large quantities of colloids ḊO 2 CaO 2 Q where Q is cardiac output. Oxygen consumption (V O 2 ) is maintained not only by a compensatory increase in cardiac output but also by an increase in the oxygen extraction (Fig 1), resulting in a lower mixed venous oxygen saturation: V O 2 Hb 1.34 SaO 2 SvO 2 PaO 2 PvO Q where SvO 2 is mixed venous oxygen saturation (%) and PvO 2 mixed venous O 2 partial pressure (mmhg). Most often, cardiac output and oxygen extraction increase simultaneously during ANH (Fig 1). 6,13,14 An increase in cardiac output in anesthetized humans is achieved primarily via an increase in stroke volume. 6,15 Any increase in heart rate should be viewed as a sign of hypovolemia, rather than a compensatory mechanism. 6 In contrast, in awake humans, heart rate increases even when normovolemia is maintained. 13,16 During ANH, blood viscosity declines, improving venous return and reducing afterload. As well, NO-induced vasodilation has also been shown to reduce systemic vascular resistance 17 and sympathetic stimulation of the heart increases. 6,18 All these mechanisms increase cardiac output. The second key mechanism maintaining adequate oxygen consumption during ANH is an increase in oxygen extraction (Fig 1). 6,13 This mechanism aims at a better matching of oxygen delivery to oxygen demand at tissue level. Observed in all species and in patients, it implies regional blood flow redistribution and microvascular adjustment like an increase in red blood cell velocity. A decrease in tissue PO 2 is likely not the CARDIOVASCULAR PHYSIOLOGY DURING ANH By diminishing hemoglobin concentration, oxygen content (CaO 2 ) of the arterial blood is reduced according to the formula: CaO 2 Hb 1.34 SaO 2 PaO where Hb is hemoglobin concentration (g/dl), SaO 2 is arterial oxygen saturation (%), and PaO 2 arterial oxygen partial pressure (mmhg). Oxygen delivery (ḊO 2 ) is reduced unless cardiac output increases in response: From the *Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland; Department of Anesthesiology, University Hospital Lausanne (CHUV), Lausanne, Switzerland; and Department of Cardiac Anesthesia, University Hospital Charleroi, Charleroi, Belgium. Address reprint requests to Donat R. Spahn, MD, FRCA, Department of Anesthesiology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland. donat.spahn@chuv.hospvd.ch 2003 Elsevier Inc. All rights reserved /03/ $30.00/0 doi: /j.jvca Key words: hemodilution, blood, transfusion, cardiac surgery Journal of Cardiothoracic and Vascular Anesthesia, Vol 17, No 6 (December), 2003: pp

2 748 JAMNICKI ET AL Fig 1. Relative changes of (A) cardiac output (CO, % of baseline), (B) O 2 extraction (O 2 -Ex, % of baseline), (C) O 2 delivery (ḊO 2, % of baseline), and (D) O 2 consumption (V O 2, % of baseline) during progressive ANH in pigs ( ), dogs (}), baboons (Œ), and man ( ). Note that the combined increases of CO and O 2 extraction allow maintenance of V O 2 even at very low hemoglobin levels. (Modified according to Moss et al, 94 Weiskopf et al, 13 van der Linden et al, 24 and van Woerkens et al. 38 ) primary mechanism because tissue oxygenation is usually well maintained during ANH and oxygen extraction increases well before tissue oxygenation declines The increase in O 2 extraction allows maintenance of V O 2 despite a decreased ḊO 2 over a wide range of hemoglobin values and in a variety of species including man (Fig 1). Only at extremely low hemoglobin values do V O 2 decrease and blood lactate levels increase, indicating insufficient oxygenation of the organism because of extreme ANH (Fig 2). EFFECTS OF ANESTHESIA ON THE COMPENSATORY MECHANISMS DURING ANH In animal preparations, general anesthesia influences compensatory mechanisms during ANH. 14,23,24 Increasing anesthetic depth progressively blunts the compensatory increase in cardiac output. 23,24 The same is observed in humans; the rise in cardiac output is significantly smaller in anesthetized than in awake patients. 14 In anesthetized patients, the increase in cardiac output is because of an increase in stroke volume, 14,15 whereas increases in stroke volume and heart rates are observed in awake persons undergoing ANH. 13,14,16 The lack of heart rate increase during ANH in anesthetized patients may be because of a depression of the autonomic nervous system by anesthetics. In addition, a central vagal stimulation by opioids may also contribute. CRITICAL HEMOGLOBIN Whole Organism Knowledge of the critical hemoglobin level is an important feature of ANH. Critical hemoglobin denotes the hemoglobin concentration where V O 2 becomes dependent on ḊO 2. Initially, V O 2 can be maintained by the above-mentioned compensatory mechanisms despite decreasing ḊO 2. When ḊO 2 decreases below a critical point, these compensatory mechanisms become insufficient and V O 2 decreases and lactate levels increase. Classically, the critical ḊO 2 is determined in a ḊO 2 -V O 2 plot with ḊO 2 on the x-axis and V O 2 (or lactate) on the y-axis. 25,26 To specifically determine the critical hemoglobin value, an analogous plot with the hemoglobin value on the x-axis and V O 2 (or lactate) in the y-axis may be used. 24 These critical values have been documented in animals. 24,27-34 In dogs, the critical systemic ḊO 2 varies between 4 and 10 ml of O 2 /kg/min depending on the type and depth of anesthesia used. 24,27,29 These ḊO 2 values corresponded to critical hemoglobin values of 2.5 to 4.1 g/dl or 18% to 26% of the baseline hemoglobin. 24,27,29 In pigs, the critical systemic ḊO 2 appears to be slightly higher (9-13 ml of O 2 /kg/min). 28,33,35-37 The corresponding critical hemoglobin values were between 3.0 and 4.6 g/dl or 29% to 54% of the baseline hemoglobin. 28,30,35-38 Anesthesia alone decreases V O 2 and in consequence might also reduce critical ḊO 2. However, anesthesia

3 ACUTE NORMOVOLEMIC HEMODILUTION 749 Fig 2. Relative changes of (A) O 2 consumption (V O 2, % of baseline) and (B) lactate levels (Lactate, % of baseline) during progressive ANH in dogs (}) and man ( ). Note that V O 2 is maintained even at very low hemoglobin levels. Only at extremely low hemoglobin values V O 2 decreases and blood lactate levels increase indicating insufficient oxygenation of the organism because of extreme ANH. (Modified according to Weiskopf et al 13 and van der Linden et al. 24 ) blunts the increase in cardiac output in response to ANH as well, and higher critical hemoglobin levels have recently been found at more profound anesthetic depths despite a progressive reduction in O 2 demand. 24 In humans, the critical hemoglobin concentration is not known, but attempts of defining critical ḊO 2 and critical hemoglobin concentration have been made. 13,34,39,40 In healthy, conscious, resting humans, a critical level was not reached at a hemoglobin concentration of 5 g/dl and a ḊO 2 of 10.7 ml of O 2 /kg/min. 13 In another study with conscious, healthy volunteers, at a hemoglobin level of 4.8 g/dl and a ḊO 2 of 9.9 ml of O 2 /kg/min, a further decrease in ḊO 2 (by the application of esmolol) to 7.3 ml of O 2 /kg/min did not produce any evidence of inadequate systemic oxygenation. 40 In a single case, a critical ḊO 2 value of 4.9 ml of O 2 /kg/min at a hemoglobin of 4.0 g/dl was found in an anesthetized 84-year-old. 34 Heart Tolerance to ANH has been investigated in patients with coronary and cardiac disease. Anesthetized, chronically -blocked patients with severe coronary artery disease tolerated ANH to a hemoglobin of g/dl without evidence of myocardial ischemia. 15 V O 2 was maintained by increases in cardiac output and oxygen extraction. Patients with 75% left main coronary artery stenosis may also tolerate limited intraoperative ANH without signs of myocardial ischemia. 41 Patients with mitral regurgitation have been shown to tolerate ANH to a hemoglobin of g/dl. 42 V O 2 was maintained by increases in cardiac output and oxygen extraction. 42 Patients with sinus rhythm and those with atrial fibrillation increased cardiac output and oxygen extraction in a similar manner. Thus, the former is not a prerequisite for adequate physiologic compensation during moderate ANH. To better define hemodilution tolerance of patients with cardiac disease, however, further studies are needed. In the context of ANH tolerance of the heart, a recent study of Wu et al 43 is often discussed. This study focused on a highly selected group of elderly patients (age 65 years) with acute myocardial infarction. The authors conclude that blood transfusions decrease short-term mortality if the hematocrit on admission is 30%. Although associations observed in retrospective studies cannot prove cause-and-effect relations, this study may be considered as an important piece of information justifying relatively high hemoglobin transfusion triggers of 30% or even 33% in elderly patients suffering from acute myocardial infarction. 44 What is the relevance of these findings in the perioperative period for patients with or at risks of coronary artery disease? First, the limitations of this study have to be discussed. It is a highly selected group of patients, only 33% of eligible patients were included, patients were treated 10 years ago, only 4% of the study population had an admission hematocrit of 30% (the population to may have benefited from a blood transfusion), and 5% of patients were transfused. In addition, the basic question asked was whether a blood transfusion anytime during hospitalization had an impact on short-term mortality in relation to admission hematocrit. It remains unclear what the nadir hematocrit was and why and when a blood transfusion was given. Also comorbidities, APACHE II scores, and cotreatment were highly different among the various admission hematocrit groups all in disfavor of patients admitted with a low admission hematocrit. Therefore, is it really so astonishing that elderly patients with an acute myocardial infarction treated less often by a cardiologist (19.7% v 33.2%), less often with beta-blockers (23.4% v 46.8%), less often by cardiac catheterization (9.7% v 29.4%), and having more frequent do-notresuscitate orders (22.1% v 8.8%) have a particularly high mortality? Whether all this was really adjusted for by multivariate statistical models remains an open question. In addition, the results of this retrospective analysis are in contradiction with the subgroup analysis on intensive care patients with preexisting cardiovascular disease treated in a prospective randomized study with hemoglobin transfusion triggers of 7.0 g/dl versus 10 g/dl where no difference in mortality was found. 45 In summary, these studies indicate that patients with or at risk of coronary artery disease do tolerate moderate ANH provided that normovolemia is maintained. They need to be carefully monitored and treated immediately when signs of inadequate myocardial oxygenation develop; it has been shown

4 750 JAMNICKI ET AL that early signs of ANH-induced myocardial ischemia can be easily treated by minimal transfusion. 46 Splanchnic Organs With regard to intestinal tissue oxygenation, a critical hematocrit of 15% was found in rats corresponding to 33% of baseline hematocrit. 22 Below this value, microvascular oxygen partial pressure could not be maintained at normal values despite a decrease in mesenteric venous partial oxygen pressure indicating an increased oxygen extraction. Microvascular oxygen partial pressure fell significantly from 54 mmhg (at 15% hematocrit) to 25 mmhg (at 9% hematocrit). At this point, V O 2 became dependent on ḊO 2. Interestingly, oxygen extraction still increased until a hematocrit of 6.2% (end of experiment), indicating that regulation of tissue oxygenation was still present, although insufficient. With advanced hemodilution below a hematocrit of 15%, intestinal oxygen partial pressure fell below venous partial oxygen pressure, indicating a shunt of oxygen away from the intestinal microcirculation. Mechanisms are not yet fully understood but may include direct anatomic shunting, altered microvascular architecture leading to vascular steal, or changes in oxygen-unloading capability of hemoglobin in the intestinal microcirculation. 47 In pigs, a critical hematocrit for the oxygenation of small intestine (mucosa) of 10% to 11% was found corresponding to 44% to 45% of baseline hematocrit. 35,36 In contrast, the critical hematocrit of the intestinal serosa appears to be higher at 17% to 20%, corresponding to 66% to 67% of baseline hematocrit. 35,48 This difference may be explained by a local redistribution of intestinal blood flow in favor of the mucosa, the dominant oxygen-consuming part of the intestinal wall. 35,49 In dogs, reducing hematocrit to 17%, corresponding to 49% of baseline hematocrit did not decrease splanchnic V O 2 or hepatic function. 50 Finally, in rabbits, progressive ANH to very low hematocrits (5%, corresponding to 15% of baseline hematocrit) was not associated with organ damage in liver or duodenum, although plasma lactate increased at a hematocrit of 5% in rabbits hemodiluted with albumin. 51 Central Nervous System One of the most obvious symptoms of acute and chronic anemia is fatigue. In patients with chronic anemia, lower hemoglobin levels are associated with more fatigue and less exercise tolerance than higher hemoglobin levels. 52,53 Several studies have tried to quantify subjective symptoms of wellbeing during ANH. 40,54,55 Self-scored energy level decreases with progressive hemodilution but reverts to baseline level after retransfusion of the autologous blood. 55 Cognitive function and memory decrease as well during ANH. Weiskopf et al 54 found no change in reaction time and error rate with verbal memory and standard computerized neuropsychological tests at a hemoglobin of 7 g/dl. 54 With a further decrease of hemoglobin to 5 g/dl, reaction time increased and immediate and delayed memory were compromised. After retransfusion to 7 g/dl, all tests but one returned to baseline. By the following day with retransfusion of the remaining autologous blood, all tests reverted to normal. Theoretically, because most of the signs and symptoms of ANH may be because of reduced ḊO 2 to different organ systems, applying more oxygen and increasing delivery through increased arterial oxygen content should reverse those very symptoms. In a recent study, Weiskopf et al 56 investigated the effects of higher inspired oxygen fraction on cognitive function in previously hemodiluted healthy volunteers. By breathing oxygen, applied through a mask with a flow of 15 L/min, PaO 2 increased to approximately 400 mmhg. At a hemoglobin level of 5.7 g/dl, previously increased reaction time and compromised memory returned to baseline with the higher PaO 2. Only self-assessed energy level remained low. Breathing oxygen thus can reverse some of the effects of acute anemia. A PaO 2 of 400 mmhg equals the amount of oxygen released by approximately 2.9 g/dl of hemoglobin. 56 A similar result was previously found in a dog study, but the hemoglobin equivalent of switching to pure oxygen ventilation (from room air) was found to be only 1.2 g/dl. 57 Increasing PaO 2 therefore has a similar effect to increasing oxygen-carrying capacity by increasing hemoglobin concentration via a blood transfusion. Although clinically relevant, 39 the magnitude of the effect of pure oxygen ventilation in mechanically ventilated patients is likely to be smaller because patients are generally ventilated with a fraction of inspired oxygen of 0.4 to 0.5. The increase in PaO 2 may therefore be limited when switching to pure oxygen ventilation. Elderly Patients Elderly patients tolerated ANH to a hemoglobin of g/dl well and maintained V O 2 by increases in cardiac output and oxygen extraction. 58 The autologous blood was retransfused at a median hemoglobin of 7.7 g/dl with 9 of 20 patients being transfused at a hemoglobin 7 g/dl. None of these patients was hemodynamically unstable or showed evidence of myocardial ischemia before retransfusion. Age per se therefore does not appear to limit tolerance to moderate ANH. This is in agreement with the results of a study on the individual effects of blood transfusions on O 2 dynamics in patients after cardiovascular surgery. 59 Age did not influence the individual effect of allogeneic blood transfusions on ḊO 2 and V O 2. EFFECTS ON COAGULATION Different in vitro and in vivo studies have shown various effects on blood coagulation during hemodilution, depending on the type of replacement fluid used and the degree of hemodilution. During moderate ANH with normal saline, a slight hypercoagulability is found in volunteers receiving normal saline. 60 Also in patients undergoing major hepatobiliary surgery, ANH of 30% of estimated blood volume with normal saline induced a slightly hypercoagulable state. 61 With more advanced hemodilution with hydroxyethyl starch, a compromised hemodilution has been found in vitro 62,63 and in healthy volunteers. 54,64 Interestingly, an isolated reduction of hematocrit with normal saline does not impair in vitro coagulation. 65 However, during advanced clinical hemodilution, coagulation factors and platelets may be diluted to a degree that would induce a disturbance of coagulation irrespective of the type of replacement fluid used. A recent mathematical model even suggests

5 ACUTE NORMOVOLEMIC HEMODILUTION 751 that the decrease in coagulation factors and platelets may be more limiting than low hemoglobin values during advanced hemodilution. 66 INDICATIONS OF ACUTE NORMOVOLEMIC HEMODILUTION Although ANH has been used with success in the therapy of different diseases, such as acute ischemic stroke, 67 peripheral arterial occlusive disease, 68 central retinal vein thrombosis, 69 sudden deafness, 70 subarachnoid bleed, 71 and acute pancreatitis, 72,73 the most important indication for ANH certainly is in the perioperative setting with the goal to save allogeneic blood transfusions. EFFICACY OF ANH TO AVOID ALLOGENEIC BLOOD TRANSFUSION For ANH, there is consensus that its most efficacious application is with high blood loss 5,74 and that a minimum blood loss is required for ANH to have any efficacy at all. 75,76 Several authors have developed equations to calculate efficacy of ANH as a function of surgical blood loss, initial hematocrit, amount of blood removed during ANH, target post-anh hematocrit, and hematocrit triggering a blood transfusion In this way, it was calculated that 50% of blood volume must be lost for ANH to be effective in terms of saving erythrocytes if a transfusion trigger of 7 g/dl is used, and an even greater blood loss is necessary, if a trigger of 6 g/dl is used. 78 Expressed as fraction of the patient s blood volume, 0.57 to 0.77 of total blood volume must be lost during surgery in order to achieve savings of at least 180 ml of red blood cells representing 1 standard unit. 78 Therefore, efficacy is greatest with a high initial hematocrit, a low post-anh hematocrit, a low hematocrit triggering a blood transfusion, and a high blood loss. These models are very helpful but have significant limitations; they do not take into account postoperative blood loss or a higher postoperative transfusion trigger. This is important because a variety of surgical procedures are regularly associated with progressive postoperative blood loss (eg, losses via drains). When relatively low hemoglobin values are reached at the end of surgery, the patient has no reserves for postoperative blood loss. In addition, postoperative transfusion triggers may be somewhat higher than those used intraoperatively because of a reduced oxygenation of the spontaneously breathing patient, less strictly controlled hemodynamics, and limited surveillance. Basing mathematical models solely on intraoperative transfusion triggers of 6 to 7 g/dl is thus not directly applicable in clinical practice, and such calculations therefore tend to overestimate the blood-saving potential of ANH. There has been controversy regarding efficacy of ANH for avoidance of allogeneic blood transfusions. 79 There are studies, in particular in which only small amounts of blood have been withdrawn during ANH, 80 in which no differences in blood transfusions were observed. 81 However, there are several prospective randomized studies in cardiac and orthopedic surgery indicating that patients undergoing ANH avoided allogeneic blood transfusions more often (63%; range: 50%-83%) than control patients (29%; range 0%- 48%). 41,82-84 Also in major liver surgery, the percentage of patients completely avoiding allogeneic blood transfusion was significantly higher in the ANH group compared with the control group. 85 In these studies, the difference in the amount of allogeneic blood transfusions administered was relatively modest (approximately 1 unit) but the difference in percentage of complete avoidance was significant. This is in keeping with the mathematical models mentioned earlier and supports the conclusion that ANH reduces transfusion needs in patients undergoing operations associated with significant perioperative blood loss. COSTS An important advantage of ANH is its comparably low cost and easy availability (no expensive equipment, no additional operator, no complicated planning). 86 In radical prostatectomy, ANH as compared to preoperative autologous donation resulted in similar allogeneic blood exposure rates, 87 but costs for ANH were significantly lower. Treatment with recombinant human erythropoietin conferred no additional advantage in avoiding allogeneic blood transfusions, but increased transfusion costs significantly. 87 PRACTICAL ASPECTS OF ANH Practical aspects are rarely described, probably because the principle appears so trivial. Although this may be so, its clinical implementation is not. Blood Harvesting Two intravenous catheters are needed, one to harvest the blood, the other one to administer the replacement fluid. Generally, only large-bore (14-gauge) catheters in a cubital or the external jugular vein drain well. Smaller, more distal, or central venous catheters do not drain well and thus may clot during blood harvesting. Anticipate 10 to 15 minutes per bag of 450 ml. It is rarely possible to harvest the blood much faster, and elderly patients or patients with concomitant cardiovascular diseases may not tolerate rapid ANH, even when normovolemia is maintained. The ANH blood is carefully labeled and stored in close proximity to the patient at room temperature to avoid erroneous retransfusion and to avoid compromising platelet function caused by storage in the refrigerator. Intraoperative Period During the operation normovolemia and normothermia must be meticulously maintained. Maintaining perioperative normovolemia is important to optimize cardiac function, to decrease postoperative morbidity and to shorten hospital stay. 7-9 Maintaining normothermia is crucial to minimize surgical blood loss, transfusion needs, and to avoid platelet dysfunction Maintaining normovolemia becomes the more important the lower the hemoglobin value declines. For maximum efficacy, ANH blood should be retransfused only after surgical hemostasis is achieved. This should result in a normovolemic patient at the end of the operation with ideally 2 to

6 752 JAMNICKI ET AL 4 units of ANH blood to be retransfused within 6 hours from harvesting. Postoperative Period Two to 4 units of ANH blood represents a considerable volume (900-1,800 ml). Thus, hypervolemia during reinfusion is of concern in order to avoid hypertension and disturbances in gas exchange in the early postoperative period. Forced diuresis is often used during retransfusion of the ANH blood by giving small doses of diuretics (eg, furosemide or mannitol). Excessive diuresis, however, must be avoided, not only to avoid hypovolemia but also to limit renal loss of potassium and magnesium, which may precipitate cardiac arrhythmias. Appropriate monitoring and repletion as necessary are therefore indicated in the early postoperative period. OUTLOOK In the future, artificial oxygen carriers may be introduced in clinical medicine. Their efficacy, in combination with ANH, has been proven so far in terms of reversing transfusion triggers in orthopedic surgery 92 and reducing transfusion needs in high-blood-loss noncardiac surgery. 93 The concept is that patients undergo ANH preoperatively, and during surgery, when hemoglobin concentration decreases further, receive an artificial oxygen carrier first (before receiving blood), which improves oxygen delivery and consequently tissue oxygenation. The autologous blood harvested during preoperative ANH is finally retransfused at the end of surgery. 93 SUMMARY Acute normovolemic hemodilution before major surgery is a relatively simple, cheap, and effective tool to avoid or reduce allogeneic blood transfusions. The anesthesiologist, however, must be familiar with the practical aspects of ANH. In addition, knowledge of the physiologic compensatory mechanisms that occur during ANH and their limits are mandatory for the safe use of this blood-saving technique. 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