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Anesth Analg 2008; 107:1356-1370
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318184cfe9
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NEUROSURGICAL ANESTHESIOLOGY

Anemia and Cerebral Outcomes: Many Questions, Fewer Answers

Gregory M. T. Hare, MD, PhD*{dagger}, Albert K. Y. Tsui, BSc*{dagger}, Anya T. McLaren, MSc*{dagger}, Tenille E. Ragoonanan, BSc*{dagger}, Julie Yu*, and C. David Mazer, MD*{dagger}

From the *Department of Anesthesia, Cara Phelan Trauma Research Centre, Keenan Research Centre in the Li Ka Shing Knowledge Institute, University of Toronto, St. Michael’s Hospital, Toronto, Ontario; and {dagger}Department of Physiology, University of Toronto, Toronto, Ontario.

Address correspondence and reprint requests to Gregory M.T. Hare, MD, PhD, Departments of Anesthesia and Physiology, University of Toronto, St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Address e-mail to hareg{at}smh.toronto.on.ca.

Abstract

A number of clinical studies have associated acute anemia with cerebral injury in perioperative patients. Evidence of such injury has been observed near the currently accepted transfusion threshold (hemoglobin [Hb] concentration, 7–8 g/dL), and well above the threshold for cerebral tissue hypoxia (Hb 3–4 g/dL). However, hypoxic and nonhypoxic mechanisms of anemia-induced cerebral injury have not been clearly elucidated. In addition, protective mechanisms which may minimize cerebral injury during acute anemia have not been well defined. Vasodilatory mechanisms, including nitric oxide (NO), may help to maintain cerebral oxygen delivery during anemia as all three NO synthase (NOS) isoforms (neuronal, endothelial, and inducible NOS) have been shown to be up-regulated in different experimental models of acute hemodilutional anemia. Recent experimental evidence has also demonstrated an increase in an important transcription factor, hypoxia inducible factor (HIF)-1{alpha}, in the cerebral cortex of anemic rodents at clinically relevant Hb concentrations (Hb 6–7 g/dL). This suggests that cerebral oxygen homeostasis may be in jeopardy during acute anemia. Under hypoxic conditions, cytoplasmic HIF-1{alpha} degradation is inhibited, thereby allowing it to accumulate, dimerize, and translocate into the nucleus to promote transcription of a number of hypoxic molecules. Many of these molecules, including erythropoietin, vascular endothelial growth factor, and inducible NOS have also been shown to be up-regulated in the anemic brain. In addition, HIF-1{alpha} transcription can be increased by nonhypoxic mediators including cytokines and vascular hormones. Furthermore, NOS-derived NO may also stabilize HIF-1{alpha} in the absence of tissue hypoxia. Thus, during anemia, HIF-1{alpha} has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions. Experimental studies have demonstrated that HIF-1{alpha} may have either neuroprotective or neurotoxic capacity depending on the cell type in which it is up-regulated. In the current review, we characterize these cellular processes to promote a clearer understanding of anemia-induced cerebral injury and protection. Potential mechanisms of anemia-induced injury include cerebral emboli, tissue hypoxia, inflammation, reactive oxygen species generation, and excitotoxicity. Potential mechanisms of cerebral protection include NOS/NO-dependent optimization of cerebral oxygen delivery and cytoprotective mechanisms including HIF-1{alpha}, erythropoietin, and vascular endothelial growth factor. The overall balance of these activated cellular mechanisms may dictate whether or not their up-regulation leads to cytoprotection or cellular injury during anemia. A clearer understanding of these mechanisms may help us target therapies that will minimize anemia-induced cerebral injury in perioperative patients.

Anemia has been associated with cardiac,1,2 renal,3,4 and cerebral morbidity5–7 and an increase in perioperative mortality.8–14 However, the risks associated with allogeneic blood transfusions and recent randomized clinical trials have influenced current clinical practice to reduce transfusion thresholds toward a hemoglobin (Hb) concentration of 7 g/dL in adult and pediatric patients.15–18 This threshold is in keeping with current transfusion guidelines.19,20 It remains controversial whether a Hb transfusion threshold of 7 g/dL is appropriate for patients with unstable cardiac syndromes or neurotrauma.1,21,22 Furthermore, minimal acceptable Hb thresholds have not been established for patients at risk of cerebral injury, such as those undergoing neurosurgical procedures. In these settings, the high metabolic requirements of the brain may render it more susceptible to injury at a low Hb concentration or hematocrit (Hct).5,22–24 However, mechanisms of cerebral injury and the specific Hb threshold at which injury occurs have not been clearly established. The current review 1) summarizes the risk of cerebral injury associated with acute anemia, 2) describes potential cellular mechanism by which cerebral injury may occur, and 3) explores possible physiological and cellular mechanisms which may ameliorate cerebral injury associated with acute anemia. This review will focus on the potential impact of acute perioperative anemia. Although many patients will have a background of chronic anemia which could impact clinical outcomes, the responses to chronic anemia will not be reviewed. The threshold Hb concentrations for activation of cellular mechanisms will be discussed. However, these thresholds should not be interpreted as transfusion triggers because the activated cellular mechanisms may have either protective or detrimental effects. The risks of anemia outlined in this review must always be balanced with the risk of harm from allogeneic transfusions. Characterizing the risk of acute perioperative anemia, and potential cellular mechanisms of injury is a prerequisite to determining if preoperative treatment of anemia and/or the transfusion of banked blood can reduce anemia-induced cerebral injury in perioperative patients.

ANEMIA AND NEUROLOGICAL OUTCOMES

The Risk of Preoperative Anemia
The severity of preoperative anemia has been shown to be an independent risk factor for perioperative mortality.8–12,14 In addition, two recent large observational studies have demonstrated that the incidence of adverse composite cardiovascular outcomes, including stroke, increases in anemic cardiac surgical patients when the preoperative Hb level decreases below 12 g/dL.6,25 A progressive increase in the incidence of stroke with declining preoperative Hb concentration below 12 g/dL was reported in one study.6 Low preoperative Hb would predispose towards a lower intraoperative Hb level which has also been associated with neurological injury.5,7

The Risk of Lowest Hct on Cardiopulmonary Bypass
The association between low Hb concentration and increased stroke incidence has been most clearly illustrated in cardiac surgical patients exposed to cardiopulmonary bypass (CPB).5,7 In two large observational studies, the incidence of stroke increased progressively below a nadir Hct of about 20% (Hb approximately 7 g/dL) on CPB.5,7 In an analysis of 10,949 adult patients undergoing CPB, Karkouti et al.5 demonstrated a 10% increase in stroke risk for every 1% decrease in lowest Hct on CPB from 29% to 17%. Similarly, a retrospective analysis of 5000 cardiac surgery patients demonstrated that the incidence of stroke and coma increased progressively as Hct values decreased on CPB.7 The only randomized controlled trial which has assessed the effect of hemodilution during CPB was performed in pediatric patients. This study demonstrated that moderate hemodilution to a Hct value near 22% resulted in impairment in psychomotor development in infants 1 yr after cardiac surgery, relative to those maintained at a higher Hct value near 28%.26 These results suggest that there may be a linear relationship between the degree of intraoperative anemia and the incidence of neurological injury in cardiac surgical patients.

The Risk of Anemia in Nonsurgical Patients
Anemic patients with cardiovascular disease who are not exposed to surgery or CPB may also be at risk of increased mortality27 and neurological injury.23,24,28 Analysis of patients undergoing coronary intervention (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications Trial) demonstrated that anemic patients (Hct approximately 36%) had up to a fivefold increase in the incidence of stroke relative to nonanemic patients (Hct approximately 44%).24 Specifically, the incidence of disabling stroke increased from 0.1% vs 0.8% at 30 days and from 0.4% to 2.1% at 1 yr (control versus anemic) in anemic patients undergoing coronary angioplasty.

Patients with sickle cell anemia may have an increased risk of neurological injury at reduced Hb concentrations. In these patients, increased cerebral blood flow (CBF),29–31 and reduced cerebral oxygen tension may contribute to cerebral injury.32,33 Similar to patients with hemodilutional anemia, the increase in CBF may be a compensatory response, activated to maintain adequate cerebral oxygen delivery when the blood oxygen content is reduced. Furthermore, correction of anemia with blood transfusions reduced the CBF velocity and the incidence of stroke in these patients, providing evidence that augmentation of cerebral oxygen delivery limits neurological injury.30,33 In addition, iron deficiency anemia has been associated with stroke in pediatric patients and anemia has been suggested to be a risk factor for cerebral venous thrombosis.34,35

Defining the Hb Threshold for Cerebral Injury
Experimental studies have demonstrated that the threshold for secondary neurological injury in animals is near the currently accepted transfusion threshold in humans (Hb 6–7 g/dL, Hct approximately 20%).36,37 In humans with cardiovascular disease, the risk of stroke increases at Hb concentration near 12 g/dL.24,28 Similarly, a preoperative Hb concentration near or below 12 g/dL has been associated with an increased incidence of neurological injury in patients undergoing cardiac surgery.6,25 In addition, the incidence of stroke increases progressively below a nadir Hct near 20% (Hb 7 g/dL) in patients exposed to CPB.5,7 These studies suggest that the threshold for treatment of anemia would be near 12 g/dL preoperatively and 7 g/dL intraoperatively. However, a recent large observational study has demonstrated an increase in adverse composite cardiovascular outcomes, including stroke, when the Hb concentration is acutely reduced by more than 50% from baseline. This suggests that some patients undergoing cardiac surgery may experience adverse outcomes at even higher intraoperative Hb concentrations.38

Limitations of Current Studies
The majority of clinical studies which have demonstrated an association between anemia and neurological injury are retrospective or nonrandomized prospective observational studies in patients undergoing cardiac surgery. Therefore, the association between acute anemia and neurological injury cannot be defined as causal as the interpretation of these studies is subject to bias and the potential influence of undefined confounding variables.5,7 A single randomized blinded study supports the outcomes of the observational studies.26 However, the lack of prospective blinded randomized trials defines a great need to perform such studies to more fully assess the risk of acute anemia on neurological outcomes and to define the potential benefit of specific anemia treatment strategies. The collective body of experimental and clinical evidence supports the hypothesis that acute anemia causes neurological injury in perioperative patients. However, this hypothesis requires further testing before the threshold Hb concentrations for specific interventions can be defined.

Development of Hypotheses
To develop novel hypotheses regarding the effect of acute anemia on cerebral outcomes, two requirements must be met: 1) appropriately powered randomized, controlled, clinical trials must be performed in anemic surgical patients and 2) a clearer understanding of the physiological and cellular mechanisms responsible for anemia-induced cerebral injury must be obtained in experimental models.

ANEMIA-INDUCED CEREBRAL SUBSTRATE LIMITATION

The following review makes the following assumptions: 1) activation of compensatory physiological mechanisms, such as the increase in CBF, and up-regulation of cytoprotective molecules may represent an attempt to maintain cerebral homeostasis; and 2) evidence of organ dysfunction does not necessarily correlate with organ injury, but it likely reflects a condition of substrate limitation which might predispose to organ injury. For example, the finding that healthy anemic human volunteers demonstrate impairment in central neuronal processing and cognitive function at Hb concentrations near 5–6 g/dL (Hct approximately 15%) suggests that cerebral oxygen delivery may be inadequate to maintain normal neuronal and synaptic transmission at these Hb concentrations.39,40 Concurrent exposure to additional risk factors such as surgical stress, drugs which limit cardiovascular compensatory responses, hemodynamic instability, cardiovascular co-morbidities, and advanced age could increase the risk of brain injury in patients exposed to these Hb concentrations.

REGULATION OF GLOBAL OXYGEN HOMEOSTASIS

An estimated half-billion years ago, metazoic organisms evolved and proliferated by virtue of their ability to use oxygen and efficiently generate adenosine triphosphate via oxidative phosphorylation in the mitochondrion.41 The importance of oxygen as a substrate for mitochondrial function is exemplified by their capacity to sense oxygen.42,43 Subsequently, vertebrates have developed unique methods of maintaining oxygen homeostasis and surviving oxygen deprivation. For example, the crucian carp can exist for several months in anoxic environments by converting lactate to ethanol which is excreted by the gills. This mechanism maintains brain adenosine triphosphate levels in the absence of oxygen.44 Although mammals are not as adept at surviving in anoxia, multiple regulatory physiological mechanisms have been developed to compensate for significant reductions in tissue oxygen delivery including adaptation of glycolytic enzymes, angiogenesis, increased Hct and blood volume, and augmentation of tissue oxygen delivery.45 During acute anemia, there is an increase in aortic chemoreceptor activation46 and sympathetic activity,47 resulting in an increase in cardiac index,48–50 heart rate, and stroke volume.49,51 Concurrently, mean arterial blood pressure and systemic vascular resistance are reduced,48–50 whereas oxygen extraction is increased.50,51 These adaptations optimize global tissue oxygen delivery. In addition, there is a disproportional increase in CBF which ensures that the brain receives preferential perfusion during acute anemia.50,51 This optimization of tissue perfusion is complemented by a compensatory reduction in overall metabolic requirement which reduces oxygen demand.45,52 In addition to these rapid changes, slower adaptations which include promotion of angiogenesis and an increase in Hb concentration, also serve to optimize tissue oxygen delivery.45,53–55 Despite these physiological adaptations, severe reduction in blood oxygen content eventually leads to inadequate tissue oxygen delivery, anaerobic metabolism, and lactic acidosis.47,48,56 Such changes occur experimentally at Hb concentrations near 3–4 g/dL.47,48,57 Many of these adaptations, including the increased cardiac index, increased CBF, and increased oxygen extraction, have been observed in normal human subjects.49,58–62 However, despite these compensatory changes, clinical evidence of increased morbidity and mortality occurs in anemic patients at much higher Hb concentrations near 6–8 g/dL.1–12,14,25,26

REGULATION OF CEREBRAL TISSUE OXYGEN DELIVERY

The importance of increased blood flow as a means of augmenting tissue oxygen delivery is emphasized in a recently published study in which forearm blood flow was assessed in Tibetans living at high altitude. This study demonstrated that the Tibetans’ stimulated forearm blood flow and oxygen delivery were up to 10-fold higher than controls who live at sea level, as were systemic nitric oxide (NO) metabolite levels.63 Similarly, the increase in CBF in response to hypoxia has long been identified as a means of maintaining cerebral oxygen delivery in hypoxic conditions.64 Such augmentation of CBF is also activated during acute anemia. The well characterized increase in CBF which occurs during anemia is proportional to the reduction in blood oxygen content in both experimental50,65–67 and clinical studies.58–61 This response also occurs with extracorporeal circulation during CPB, suggesting that specific regulation of cerebral vascular resistance contributes to maintaining cerebral perfusion during hemodilution.62,68,69 The robust nature of the anemia-induced increase in CBF is illustrated by its use as a transfusion trigger for the treatment of prenatal fetal anemia.70,71 The observation that brain blood flow is preferentially increased, to a greater degree than blood flow to other less vital organs, provides additional evidence of specific cerebral vasodilation during acute anemia.50,51This could be achieved through the activation of central and peripheral chemo- and baro-receptors46 that send afferent signals to the vasoregulatory centers of the brain and trigger efferent signals, which result in augmented cerebral vasodilation72 (Fig. 1). Experimental models demonstrate that the anemia-induced increase in CBF occurs in part by NO and β2 adrenergic mechanisms.69,72,73 The importance of active cerebral vasodilation in maintaining cerebral tissue oxygen tension has been shown in an experimental study in which inhibition of β2 adrenergic receptors attenuated the CBF response and reduced cerebral cortical tissue oxygen tension after hemodilution.72 Thus, the increases in CBF associated with anemia may be regarded as a necessary response to optimize cerebral oxygen delivery and minimize tissue hypoxia. To achieve this goal, cerebral vascular tone is regulated at multiple levels including: 1) perivascular innervation of cerebral arteries and arterioles; 2) the vascular smooth muscle (VSM); 3) endothelial derived vasoactive mechanisms; and 4) intravascular stimuli such as changes in blood viscosity and production of NO by NO synthase (NOS). The current review will focus on NOS/NO-mediated vasodilation as all three known NOS isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), have been shown to be up-regulated during acute hemodilutional anemia.74–76


Figure 146
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  		Figure 1. Autonomic pathways and cellular mechanisms which regulate cardiovascular and cerebral responses during anemia. Central and peripheral receptors within the aorta, carotid body, and tissue sense changes in oxygen tension, oxygen content, and arterial blood pressure and send afferent signals to the cardiovascular control centers in the brainstem. The efferent responses are carried by parasympathetic and sympathetic nerves to the heart and blood vessels. These efferent responses regulate cardiac output, cerebral and systemic vascular resistance to optimize global and cerebral perfusion and tissue oxygen homeostasis. Panel A, Intrinsic mechanisms which augment cerebral perfusion during anemia include increased sympathetic activation of β2 adrenergic receptors (β2r) on neuronal nitric oxide synthase (nNOS) positive perivascular neurons which promote vasodilation by releasing nitric oxide (NO) in the region of arteriolar vascular smooth muscle (VSM). Adaptive cerebral cellular responses also include an increase expression of nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS). Within the blood vessel, NO produced by all NOS isoforms can activate soluble guanlyl cyclase (sGC) within endothelial and VSM cells. This could lead to a decrease in platelet aggregation and promotion of cerebral vasodilation. In addition, NO could act to stabilize hypoxia inducible factor (HIF)-{alpha} in normoxic cerebral tissue. Panel B, Within the vasculature, as oxygen is off-loaded to the tissue, deoxyhemoglobin can change from the relaxed (R)- to the taut (T)-state. This conformational change facilitates the release of NO from S-nitroso-hemoglobin (SNO-Hb). Soluble S-nitrosothiol groups (SNO) can then interact with other small molecules such as glutathione to stimulate ventilation or diffuse to the endothelium and VSM to promote vasodilation. Thus, SNO-Hb may improve tissue oxygen delivery by increasing blood flow and minute ventilation during anemia.

 

Peri-Vascular Cerebral Neurons
The cerebral vasculature is richly supplied by a variety of peri-vascular neurons that contain a number of different vasoactive neurotransmitters.77,78 The importance of NO as a vasodilating mediator is emphasized by the fact that the hyperemic response to both hypoxia and acute hemodilution is blunted by systemic NOS inhibitors.73,79 nNOS positive "nitroxidergic" perivascular neurons have been identified on cerebral blood vessels and may initiate NO-mediated cerebral vasodilation in vitro and in vivo.80–85 One clinical study has demonstrated that NOS helps to maintain baseline CBF in humans.86 Experimental studies suggested that nNOS-mediated NO production contributes to maintaining baseline CBF86–88 and results in a regulated increase in CBF under a variety of physiological and pathophysiological conditions including ischemia,89–91 hypoxia,79,92 hypercarbia,93–95 acidosis,82 increased cerebral functional activity,96 and anemia.73,74 NO is released from peri-vascular cerebral neurons by activation of presynaptic β2 adrenergic receptors resulting in cerebral vasodilation and a regulated increase in CBF83,97 (Fig. 1A). Acute hemodilution increased the expression of nNOS in cerebral cortical neurons which project to small cerebral blood vessels that contain VSM.75 Similar up-regulation of nNOS positive neurons has been observed in response to hypoxia.98,99 Defining the physiological role of nNOS-mediated cerebral vasodilation will help to define its potentially protective role in optimizing cerebral oxygen delivery.

Vascular Smooth Muscle Regulation of Vascular Tone
Regulation of vascular tone by VSM is influenced by muscle stretch, endothelial cell interactions, and intracellular signaling leading to depolarization and ion channel activation.100 These responses lead to activation of second messengers and changes in intracellular calcium which influence VSM tone and responsiveness. There are few studies which assess the myogenic response to acute anemia or hemodilution. Tomiyama et al.101 concluded that K-ATP channels do not contribute to the increase in CBF after hemodilution. Although the influence of NOS has not been studied in VSM during anemia, hypoxia has been shown to up-regulate VSM nNOS and influence the vascular responsiveness of blood vessels to vasoconstrictors in vitro99 (Fig. 1B). Systemic NOS inhibition also interferes with CBF autoregulation, possibly by disrupting the normal myogenic response to altered cerebral perfusion pressures.102 In addition, the influence of other systemic mediators, such as erythropoietin (EPO), may affect VSM responsiveness during anemia by up-regulating angiotensin II receptors and endothelin-induced calcium mobilization103,104 and promoting cell proliferation105 (Fig. 2).


Figure 246
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  		Figure 2. Potential cytoprotective (white boxes) or cytotoxic cellular mechanisms (black boxes) activated by acute anemia in the brain. Hypoxia inducible factor (HIF)-1{alpha} is increased in the neurons and astrocytes of acutely anemic animals by either hypoxic or nonhypoxic mechanisms. During tissue hypoxia, inhibition of PHDs results in increased HIF-{alpha} levels. During tissue normoxia, increased nitric oxide (NO) from all NO synthase (NOS) isoforms can also stabilize HIF by limiting its degradation. In both cases, increased HIF-{alpha} levels could activate HIF-dependent protective mechanisms including glycolysis, angiogenesis, neuroprotection, and stem cell proliferation. In the astrocytes, HIF-2{alpha} accumulation increases transcription of both vascular endothelial growth factor (VEGF) and erythropoietin (EPO). Paradoxically, these molecules can have both cytoprotective and cytotoxic properties which are initiated via specific receptors (EPOr, VEGFr). EPO binds to the EPOr which can activate neuroprotective mechanisms via the Janus kinase 2 (JAK) including signal transducer and activator of transcription 5 (STAT5), phosphoinositol 3 kinase (PI3K), mitogen-activated protein kinase (MAPK), and nuclear factor kappa b (NF-KB). In the vascular lumen, increased shear stress activates endothelial NOS (eNOS) in the endothelium. Increased eNOS-derived NO decreases platelet adhesion and regulates vasodilation. Increased neuronal NOS (nNOS) expression in vascular smooth muscle cells also results in vasodilation via soluble guanyl cyclase (sGC)-dependent mechanism. NO may also contribute to harmful effects, including reactive oxygen species (ROS) production and excitotoxicity. Anemia leads to increased adhesion molecule expression and leukocyte adhesion. This may lead to transmigration of leukocytes into neural tissue. Cellular injury can occur as a result of the tissue inflammatory responses.

 

Endothelial Responses to Acute Anemia
The endothelium plays a central role in mediating vascular responses to hemodynamic stresses. eNOS is up-regulated by shear stress and has been shown to be neuroprotective in models of focal ischemia possibly because of its ability to optimize cerebral vasodilation and reduce vascular platelet adhesion106–109 (Figs. 1B and 2). eNOS may also mediate vascular endothelial growth factor (VEGF)-dependent angiogenesis and neurogenesis after focal ischemia.110 In an experimental model of acute anemia, hemodilution with high, but not low, viscosity solutions increased functional capillary density and peri-aortic eNOS expression.76 In another study, hemodilution with low viscosity solutions increased eNOS expression in the ileum and lung, but not in the kidney, liver, or heart.111 Finally, the combination of hemodilution and CPB resulted in increased renal eNOS expression, suggesting that it may be important in regulating kidney perfusion in conditions of laminar flow and altered shear stress.112 However, acute hemodilution with low viscosity solutions did not increase eNOS mRNA or protein levels in cerebral cortical tissue.74,75 Given the potential cerebral-protective influence of eNOS, further characterization of the eNOS response to anemia is warranted.107

Hb and NO Biology
In addition to its role in transporting oxygen and carbon dioxide, Hb may influence tissue blood flow by the regulated release of bound NO. Although there are conflicting hypotheses,113 evidence suggests that S-nitroso-Hb (SNO-Hb) may release NO in a regulated manner.114 Under physiological conditions, NO can bind with the heme pockets of deoxyhemoglobin to form iron-nitrosyl-hemoglobin. NO can also interact with the thiol group cysteine within the β-globin chain of Hb (Cysβ93) to form SNO-Hb. The formation of SNO-Hb involves the transfer of NO from the heme to thiol (Cysβ93) within the β-globin chain, and is favored in the relaxed (R)-state of oxygenated Hb.114 In the R-state, the S-nitrosothiol moiety (SNO) is buried within the Hb and is not accessible. As oxygen is unloaded in the peripheral tissues, the allosteric structural transitions of Hb switches from R-state to the taut (T)-state in deoxyhemoglobin. This exposes SNO to cytoplasmic elements allowing for transfer of SNO into the plasma or onto other thiols, such as glutathione and anion exchange protein 1115 (Fig. 1). NO groups released in this manner may promote vasodilation in hypoxic tissue, thus regulating local blood flow and oxygen delivery to maintain oxygen homeostasis.116 Under the same conditions, S-nitrosylation of small molecules such as glutathione may contribute to the increase in ventilation observed during acute anemia.52,117 Increased NO binding to the heme within oxyhemoglobin results in the generation of methemoglobin and nitrite molecules and may be responsible for the increased concentration of methemoglobin observed after hemodilution.75 The potential application of SNO-Hb biology has been recently demonstrated in an experimental study in which renitrosylation of banked blood augmented SNO-Hb levels and restored its ability to produce oxygen-dependent vasoreactivity in vitro.118

Angiogenesis as a Mechanism to Improve Oxygen Delivery
Cerebral vascular angiogenesis is a dynamic process which can augment cerebral oxygen delivery. For example, exposure to varying levels of oxygen exposure can cause dynamic changes in cerebral cortical vascular density.54,119 VEGF is an important mediator of angiogenesis which is up-regulated during hypoxia preconditioning and anemia.75,119 An association between lower Hb concentrations and increased systemic VEGF levels was observed in anemic patients. Correction of anemia resulted in a subsequent reduction in measured VEGF levels.53 During anemia, VEGF may support the development of new blood vessels and an increase in capillary density, as has been demonstrated in the myocardium of anemic animals55 and placental tissue of anemic women.120

POTENTIAL MECHANISMS OF CELLULAR INJURY IN ACUTE ANEMIA

Although experimental studies have demonstrated that acute hemodilution may increase the degree of neurological injury after neurotrauma,36 CPB,121 and circulatory arrest,122 few studies have identified the physiological and cellular mechanisms involved. Although none of the cellular mechanisms have been identified in humans, preclinical experimental studies in mammals may help to identify mechanisms which contribute to neurological injury in perioperative patients (Table 1).


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  		Table 1. Summary of Cellular Mechanisms and Mediators Activated During Anemia

 

Anemic Cerebral Hyperemia
The well-defined proportional relationship between reduced blood oxygen content and increased CBF has been established for over 30 yrs.65,123 This response occurs in humans under general anesthesia and during CPB,61,62 in part due to active cerebral vasodilation.69,73 Paradoxically, the increased incidence of neurological injury in anemic patients during CPB5,7 occurs in the setting of acute cerebral hyperemia. The increase in CBF augments tissue oxygen delivery but at the cost of a potential increase in the number of cerebral embolic events. Such emboli may contribute to the observed increase in the incidence of ischemic injury in patients undergoing CPB.124,125

Tissue Hypoxia
Although cerebral oxygen tension is tightly regulated and maintained during acute anemia, inhibition of cerebral vasodilation has been shown to reduce cerebral tissue oxygen tension in anemic rats.72 In addition, experimental studies have demonstrated that anemia accentuates the degree of cerebral injury during CPB or after cerebral trauma.36,37 The increase in cerebral injury which occurred during transient ischemia and CPB in anemic rats was located primarily in gray matter, but not white matter, suggesting that areas of high metabolic oxygen requirements were at increased risk of hypoxic cell death.37 After unilateral traumatic brain injury, anemia accentuated the degree of cerebral tissue hypoxia and caused a threefold increase in cerebral infarction volume within the contused cerebral hemisphere.36 Relatively small reductions in cerebral tissue oxygen tension resulted in dramatic increases in cerebral tissue injury.36 Similarly, relatively minor changes in cerebral oximetry were associated with impaired neurological function in humans.126 These findings suggest that under conditions of impaired cerebral vascular function (neurotrauma) or nonphysiological blood flow (CPB) the brain may be more susceptible to anemia-induced cerebral injury. The role of supplemental oxygen delivery as a means of minimizing morbidity and mortality in these conditions must be explored further.53 Careful attention to optimizing cerebral oxygen delivery may minimize neurological morbidity in perioperative patients.

Reactive Oxygen Species, Excitotoxicity, and Apoptosis
The early observation of reduced cerebral infarction volumes in nNOS deficient mice suggests a neurotoxic role for nNOS in models of focal cerebral ischemia.127 Such toxicity has been attributed to glutamate-mediated activation of N-methyl-d-aspartate receptors leading to excessive calcium influx, nNOS activation, NO production, and generation of reactive oxygen species.128 Increased cerebral NO may mediate neuronal injury by a number of mechanisms including excitotoxicity,107,127,129 oxidative neuronal injury,130,131 and neuronal apoptosis.132 Furthermore, eNOS may contribute to reperfusion injury after transient focal cerebral ischemia,133 and both eNOS and nNOS may modulate ischemic preconditioning.134 Interestingly, the observed neurotoxic effect of nNOS during cerebral ischemia is sexually dimorphic and does not occur in female mice.135 Therefore, the adaptive and maladaptive roles played by nNOS and eNOS during anemia require further characterization.

Inflammation
A number of studies have demonstrated an increase in inflammatory mediators in association with acute hemodilution.111,136,137 Duebener et al.136 demonstrated a significantly lower functional capillary density in the brain on early reperfusion and increased leukocyte adhesion in piglets maintained at a Hct of 10%, compared with animals maintained at a Hct of 30%. The increase in leukocyte adhesion and migration may have been due to enhanced endothelial adhesion molecule expression associated with hemodilution (Fig. 2).111 Hemodilution increased expression of E- and P-selectin, primarily in the lung and ileum, whereas E-selectin was increased in the kidney.111 Increased leukocyte migration may occur as a result of inflammatory cell activation and increased adhesion molecule expression resulting in transmigration of activated leukocytes into specific organs, including the brain.136 Enhanced systemic inflammation may also contribute to the increased neuronal injury associated with hemodilution after neurotrauma.36,138 Acute anemia also up-regulated cerebral cortical iNOS and CXCR4 expression.75 Both molecules have been associated with neuronal injury, suggesting that they may play a cytotoxic role in the anemic cerebral cortex.139,140 Thus, inflammation may play an important role in mediating anemia-induced cerebral injury (Fig. 2).

Other Mechanisms of Injury
Up-regulation of hypoxia inducible factor (HIF)-1{alpha} and HIF-responsive molecules have all been associated with cytoprotective mechanisms, as outlined below. Paradoxically, increased expression of these molecules may also have cytotoxic effects.141 For example, VEGF can cause increased vascular permeability and disruption of blood-brain barrier function142–144; HIF-{alpha} can promote neuronal injury via increased brain natriuretic peptide levels145 and EPO can promote vascular thrombosis. Therefore, further understanding of the physiological and pathophysiological mechanisms of these molecules must be gained to assess their roles in anemia.

POTENTIAL CELLULAR MECHANISMS OF CEREBRAL PROTECTION IN ACUTE ANEMIA

Hypoxic, ischemic, and anesthetic preconditioning are preconditioning stimuli which demonstrated cerebral-protective capacity in part by up-regulating HIF.146–148 Recently, McLaren et al.75 have demonstrated an increase in HIF-1{alpha} protein levels and an increase in mRNA levels of a number of HIF-responsive molecules, including EPO, VEGF, and iNOS within the cerebral cortex of anemic rats. The potential neuroprotective role of these molecules will be discussed below (Fig. 2, Table 1).

Hypoxia Inducible Factor
HIF has been described as the master regulator of oxygen homeostasis149 and plays an important role in brain oxygen sensing.42,150 HIF can be stabilized in hypoxic tissue by inhibition of prolyl hydroxylase enzymes (PHDs). In addition, HIF can be increased by nonhypoxic mediators of HIF transcription, including angiotensin II and thrombin.151 In normoxic tissue, NO inhibits HIF degradation, promoting activation of HIF-dependent mechanisms.152–154 HIF has been implicated as an important cerebral-protective molecule in models of hypoxic, ischemic, and anesthetic preconditioning148,155 and may play a role in neuronal and glial stem cell proliferation.156,157 HIF is a heterodimer which consists of two distinct components.158 HIF-1{alpha} and HIF-1β are the prototypic HIF molecules present in many cell types. HIF-1β is constitutively expressed and does not respond to changes in oxygen tension. HIF-1{alpha} protein levels increase in response to tissue hypoxia by inhibition of PHDs, which normally degrade HIF-1{alpha} in normoxic conditions. Stabilization of HIF-1{alpha} during hypoxia leads to its accumulation and dimerization with HIF-1β. The HIF-1{alpha}β dimer then enters the nucleus, binds to HIF-response elements on deoxyribonucleic acid, and promotes transcription of a number of HIF-responsive molecules. These include molecules involved in regulating cellular energy metabolism, vasoreactivity, angiogenesis, erythropoeisis, cell proliferation, and inflammation.150,158

HIF has been demonstrated to reduce cerebral injury in models of hypoxic preconditioning.159 The complexity of the HIF system within the brain is outlined by the finding that HIF-1{alpha} and HIF-2{alpha} are differentially expressed in specific brain cells. Whereas HIF-1{alpha} is expressed in neurons, astrocytes, and endothelial cells, HIF-2{alpha} appears to be restricted to astrocytes and endothelial cells.150 Neuron-specific HIF-1{alpha} deficient mice experience increased neurological injury in response to middle cerebral artery occlusion demonstrating the cell-specific nature of HIF-protective mechanisms.160 Specific up-regulation of HIF-2{alpha} in astrocytes is responsible for increasing EPO and VEGF transcription and secretion in a paracrine fashion, which may contribute to neuroprotection within the central nervous system.160 However, a recent experimental study has demonstrated that up-regulation of HIF-1{alpha} in neurons is protective but its up-regulation in astrocytes may be neurotoxic, suggesting that the biological significance of HIF regulation is complex and incompletely understood.161 The recent finding that HIF-1{alpha} is up-regulated in both cerebral cortical neurons and astrocytes of anemic rats suggests that HIF may be an important regulator of cerebral protection or injury during anemia.75

Increased nNOS/NO Stabilizes HIF in Anemic Cerebral Tissue
The increase in cerebral cortical nNOS expression is a robust cellular finding in anemic rodents.74,75 However, the physiological role of nNOS in the anemic brain remains to be defined. The finding that both HIF-1{alpha} and nNOS are up-regulated within neurons in the cerebral cortex of anemic rats raises the possibility of an important interaction between these molecules.75 Clues toward defining this relationship lie in the finding that NO may influence HIF-1{alpha} levels differentially under normoxic and hypoxic conditions.162,163 Under hypoxic conditions, NO can increase HIF-1{alpha} degradation, leading to relative reduction in HIF levels.164–166 Conversely, under normoxic conditions, NO can stabilize HIF-1{alpha} by inhibiting its degradation.152–154 Therefore, in the anemic cerebral cortex, NOS/NO-mediated HIF-1{alpha} stabilization may contribute to the observed increase in cytoprotective elements including EPO.

Erythropoietin
EPO is the prototypic HIF-responsive molecule which has neuroprotective potential.167 EPO is produced by both astrocytes and neurons and acts as an autocrine and paracrine hormone via EPO receptors (EPOr), which have been identified on neurons, astrocytes, endothelial cells, and VSM cells.168,169 EPO protects neurons via Janus kinase 2 (JAK) which then activates a number of intracellular mediators including signal transducer and activator of transcription 5, phosphoinositol 3 kinase, mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor kappa b (Fig. 2). These molecules down-regulate apoptotic mediators and promote neuronal survival.168–170 In addition to activating neuronal protective mechanisms, EPO also acts on EPOr on VSM and endothelial cells to promote cell proliferation, angiogenesis, and vasodilation via eNOS-dependent mechanisms171–173 (Fig. 2). EPO may also protect against the increased blood-brain barrier permeability associated with VEGF.174 Evidence of increased EPO mRNA in the cerebral cortex of anemic animals provides preliminary indication that it may play a cytoprotective role during anemia. Despite abundant experimental evidence that EPO is neuroprotective, few clinical studies have assessed its efficacy in patients. In one clinical study, EPO improved outcomes after acute stroke, demonstrating the potential clinical utility of EPO therapy to minimize brain injury.175 An additional clinical trial in critically ill patients demonstrated that EPO therapy reduced mortality in trauma patients, independent of its effect on Hb concentration.176 In addition to its ability to reduce perioperative anemia and allogeneic blood transfusions,177 assessment of EPO’s capacity as a preconditioning stimulus for cerebral protection would be an exciting next step in perioperative medicine. The use of PHD inhibitors to stabilize HIF may provide another potential neuroprotective strategy.178,179

VEGF-Mediated Angiogenesis, Vascular Repair, and Neuroprotection
HIF, EPO, and VEGF may mediate stem cell proliferation and migration which promote vascular repair.156,157,173,180 In anemia, increased VEGF levels have been associated with promotion of angiogenesis and increased capillary density.181 These changes may provide an important long-term mechanism for optimizing tissue oxygen delivery. VEGF may also be beneficial to neurons by promoting neurogenesis182 and by mediating mechanisms of hypoxic preconditioning.183

Inducible NOS
iNOS has also been implicated as an important mediator of cerebral ischemic preconditioning.140,184,185 In an experimental study, lipopolysaccharide administration reduced the degree of cerebral ischemia in wildtype, but not iNOS-deficient mice.186 iNOS induced ischemia preconditioning may be mediated by mitochondrial protection.184 iNOS also appears to be important in mediating anesthetic-induced cerebral preconditioning.187 The significance of the increase in iNOS mRNA identified in the cerebral cortex of anemic rats remains to be defined.75

SUMMARY OF CLINICAL KNOWLEDGE AND POTENTIAL FUTURE THERAPUTIC INTERVENTIONS

In summary, a growing body of evidence suggests that anemia is an independent risk for neurological injury in perioperative patients. Observational clinical studies have demonstrated that preoperative anemia is associated with increased neurological injury in cardiac surgical patients with preoperative Hb concentrations <12 g/dL,6,25 whereas neurological injury increases in proportion to reduced blood oxygen content below an intraoperative Hb concentration of 7 g/dL (Hct approximately 21%).5,7 Although clinical evidence of increased neurological injury in anemic patients with acute cerebral trauma is lacking,22 experimental evidence supports the hypothesis that anemia is a risk factor for secondary cerebral injury after neurotrauma.36,37 However, the lack of prospective, randomized, blinded, clinical trials to assess neurological outcomes at different Hb levels severely restricts the ability to make sound clinical recommendations on how to manage anemic patients in the perioperative setting. Characterization of complex hypoxic cellular mechanisms, including HIF, nNOS, and EPO, which are activated in the brain of anemic animals, may provide valuable preclinical information which will help clinicians to develop treatment strategies to minimize cerebral injury associated with anemia in perioperative patients. For example, clinical studies have suggested that EPO therapy may reduce cerebral injury and improve survival in stroke and trauma patients, respectively.175,176 Application of such protective strategies may also benefit anemic surgical patients. Finally, transient preoperative exposure to mild anemia may provide a protective cerebral preconditioning stimulus which activates protective cellular mechanisms. Such preconditioning could be performed preoperatively in anesthesia blood-conservation clinics using current autologous blood donation protocols. Concomitant treatment with EPO could restore baseline Hb levels, thereby avoiding the risk of preoperative anemia and adding an additional cytoprotective element. Characterization of cerebral-protective mechanisms induced by anemia may improve clinical outcomes for anemic perioperative patients.

Footnotes

Accepted for publication June 5, 2008.

Supported by the Department of Anesthesia, St. Michael’s Hospital, Canadian Anesthesiologists’ Society, Physicians’ Services Incorporated Foundation, St. Michael’s Hospital (Toronto, Canada). Dr. Hare is the recipient of the Bristol-Myers Squibb-CAS Career Scientist Award.

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