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Anesth Analg 2004;99:974-981
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000131504.90754.D0

CARDIOVASCULAR ANESTHESIA

Hemodilution During Cardiopulmonary Bypass Increases Cerebral Infarct Volume After Middle Cerebral Artery Occlusion in Rats

H. Mayumi Homi, MD*, Hong Yang, MD*, Robert D. Pearlstein, PhD*, and Hilary P. Grocott, MD{dagger}

Departments of *Surgery and {dagger}Anesthesiology (Multidisciplinary Neuroprotection Laboratories), Duke University Medical Center, Durham, North Carolina

Address correspondence and reprint requests to Hilary P. Grocott, MD, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to h.grocott{at}duke.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Although the optimal hematocrit during cardiopulmonary bypass (CPB) is not defined, excessive hemodilution may lead to organ ischemia via a reduction in oxygen-carrying capacity uncompensated by autoregulatory and/or rheologic increases in organ blood flow. As a result, the consequences of hemodilution in patients at risk for cerebral ischemia are not clearly understood. We designed this study to evaluate the effects of hemodilution in the setting of focal cerebral ischemia during CPB. Wistar rats surgically prepared for CPB were randomized to either hemodilution (hemoglobin (Hb), 6 g/dL; n = 9) or control (Hb, 11 g/dL; n = 8) groups and subsequently exposed to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Immediately after the onset of MCAO (maintained for 90 min), 65 min of hypothermic (28°C) CPB was initiated. Twenty-four hours later, functional neurological outcome and cerebral infarct volume were determined. Compared with controls, the hemodilution group had worse neurological performance (new score = 8 [2], hemodilution; versus 10 [2], control; P = 0.030) and larger total cerebral infarct volumes (182 ± 84 mm3, hemodilution; versus 103 ± 58 mm3, control; P = 0.043). In this experimental model of CPB with reversible MCAO-induced focal cerebral ischemia, hemodilution worsened neurological function and increased cerebral infarct volume.

IMPLICATIONS: Hemodilution (hemoglobin, 6 g/dL) increased cerebral infarct volume and worsened outcome after focal cerebral ischemia during cardiopulmonary bypass in rats; this suggests that excessive hemodilution may increase the risk of cardiac surgery-related stroke.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Hemodilution, occurring either spontaneously or as a result of intentional acute normovolemic hemodilution, manifests often during cardiopulmonary bypass (CPB). The optimal hemoglobin/hematocrit level (Hb/Hct) during CPB is not defined; however, excessive hemodilution may lead to organ ischemia via a reduction in oxygen-carrying capacity uncompensated by autoregulatory and/or rheologic increases in organ blood flow. This issue is of particular importance for the patient considered at risk for neurologic complications (stroke). Neurologic injury and neurocognitive dysfunction remain frequent problems in cardiac surgical patients (1,2). Physiologic perturbations induced by CPB may affect the initiation and propagation of various forms of neurologic injury. One physiologic variable that is frequently manipulated during CPB is Hb concentration.

Moderate hemodilution is thought to be generally well tolerated during CPB, and it offers the advantage of reducing the need for blood transfusion and its associated risks. A lower Hct changes the rheological characteristics of blood by decreasing its viscosity, with resultant increases in microcirculatory blood flow. Anemia does, however, carry some risks. The optimal Hct to meet tissue oxygen demand during CPB is not known. Experimental investigations of hemodilution during CPB have been performed, but their results have not examined issues related to the brain at risk for ischemia (3–6).

Previous investigations of the effects of hemodilution on the brain have used isolated cerebral ischemia models (7–12). The applicability of these to the setting of CPB is not clear. In addition, although the effects of hemodilution on systemic responses during CPB have been studied extensively (13,14), the specific effects of hemodilution on cerebral ischemia during CPB have not been studied. The purpose of this study was to evaluate the effects of hemodilution in the setting of focal cerebral ischemia during CPB in an experimental model in rats.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by the Duke University Animal Care and Use Committee, and all procedures met the National Institutes of Health guidelines for animal care (15). Male Wistar rats (12–14 wk of age; body weight, 290–340 g; Harlan, Indianapolis, IN) were fasted 12 h overnight but were allowed free access to water before experiments. The animals were anesthetized in a chamber with 3% isoflurane in 50% oxygen/balance nitrogen. The trachea was intubated (14-gauge catheter), and the lungs were mechanically ventilated (Harvard Rodent Respirator; Boston, MA). The isoflurane concentration was reduced (1.5%–2.0%). The ventilatory variables were adjusted to produce an arterial carbon dioxide tension of 36–42 mm Hg. A needle thermistor was inserted in the left temporal muscle adjacent to the skull, and this pericranial temperature (16) was servo-controlled (YSI 400 series thermistor and 73 ATA Indicating Controller; YSI, Yellow Springs, OH) with both forced-air and surface heating systems to the target temperature defined at each phase of the experiment (37.5°C before and after CPB; 28°C during CPB). The rectal temperature (core temperature) was also monitored.

The animals were then prepared for CPB. The right superficial caudal epigastric artery was cannulated (polyethylene-10 Intramedic tubing; Becton-Dickinson, Sparks, MD) for continuous monitoring of the mean arterial blood pressure (MAP), as well as arterial blood gas analysis (IL-1306 blood gas analyzer; Instrumentation Laboratories Inc., Lexington, MA). The ventral tail artery was dissected, cannulated (20-gauge; 1.16-in. IV catheter; Insyte-WTM; Becton-Dickinson, Sandy, UT), and used for the arterial inflow in the CPB circuit. By using a polyethylene-50 catheter (Intramedic polyethylene tubing), the tail vein was cannulated for anesthetic drug infusion during CPB. A cervical anterior midline incision was then performed, and the right external jugular vein was identified and isolated for later cannulation. The right carotid artery was then surgically prepared for middle cerebral artery occlusion (MCAO) (17). By using blunt dissection, its branches were identified and isolated with 5-0 silk. The external carotid artery was ligated remote from its origin, and the proximal end was temporarily occluded with a microsurgical aneurysm clip, thereby allowing subsequent intraluminal filament insertion (4-0 nylon monofilament; the tip was heat-blunted and coated with silicone). The jugular vein was incised, and a modified multiorifice cannula (4.5F Desilets-Hoffman Pediatric Introducer; Cook Inc., Bloomington, IN) was inserted and advanced into the right heart for use as the venous return cannula in the CPB circuit.

The CPB circuit consisted of a venous reservoir (Bubble Chamber; Radnoti Glass Technology, Monrovia, CA) that collected the venous blood from the external jugular vein and was located 12 cm below the heart level, creating a gravity drainage gradient. The venous blood collected in the reservoir drained to a peristaltic pump (Masterflex®; Cole-Parmer Instrument Co., Vernon Hills, IL) via tubing (1.6-mm internal diameter; Tycon®; Cole-Parmer Instrument Co.) and pumped through a membrane oxygenator (modified from a Cobe Micro® neonatal oxygenator; Cobe Cardiovascular Inc., Arvada, CO). Sequentially, in line with the membrane oxygenator, the blood was directed by water-jacketed inflow tubing to the tail arterial inflow cannula. The CPB flow was continuously monitored with a flowprobe located within the circuit (2N806 flowprobe and T208 volume flowmeter; Transonics System Inc., Ithaca, NY).

The CPB circuit was primed with whole blood obtained from two heparinized donor rats (100 IU of heparin IV per animal). The blood was collected from the donor animals under isoflurane anesthesia through a silicone catheter inserted in a right external jugular vein. The Hb concentration in the blood used for priming the CPB circuit was adjusted as necessary in each experimental protocol (6 g/dL for the hemodilution group and 11 g/dL for the control group) by using colloid solution (6% hydroxyethyl starch solution; Hextend®; Abbott Laboratories, North Chicago, IL). In the hemodilution group, the circuit was primed with 20 mL of whole blood, and in the control group the circuit was primed with 40 mL of whole blood.

Figure 1 shows the time course for the experimental protocol. Blood samples were collected throughout the experiment to follow the changes in physiologic variables at each protocol stage. After surgical preparation, the animals were randomized to one of two groups: hemodilution or control. Normovolemic hemodilution was performed by withdrawing of arterial blood coupled with IV infusion of Hextend® until the target Hb concentration (6 g/dL) was achieved. The hemodilution was induced just before the start of CPB. In the control group, the Hb concentration was maintained at approximately 11 g/dL (slightly less than the normal rat Hb of 15 g/dL).


Figure 1
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  		Figure 1. An overall time course for the experimental protocol. MCA = middle cerebral artery; CPB = cardiopulmonary bypass for 65 min; • = blood samples.

 
The animals were then allowed to stabilize for 15 min, after which MCAO was performed by insertion of the filament through the external carotid artery stump. The filament was advanced until resistance was felt as the tip occluded the circle of Willis at the origin of the middle cerebral artery. After MCAO, the mechanical ventilation was stopped, and hypothermic (28°C) CPB was initiated. Isoflurane anesthesia (1.2% inspired) was maintained during CPB, and atracurium (0.3 mg/kg IV, repeated every 25 min) was administered (after establishing in unparalyzed pilot experiments that the animals did not exhibit escape behavior in response to noxious stimuli with a similar isoflurane anesthetic) (18) to prevent shivering.

CPB (flow rate, 120–170 mL · kg–1 · min–1; adjusted to maintain a minimal venous reservoir blood level) was maintained for 65 min, including 30 min of rewarming to 37.5°C. If normothermia was not achieved at the end of CPB, warming was continued in the post-CPB period. After the cessation of CPB, the hemodilution group received a whole-blood transfusion to restore the Hb concentration to 11g/dL. The MCAO filament was then withdrawn (after 90 min of focal cerebral ischemia), and the animals remained anesthetized and ventilated for an additional 120 min after CPB was discontinued. No vasopressors were used in the study. After this, all catheters were removed, and the wounds were infiltrated with local anesthetic (1% lidocaine) and closed. The heparin effect was allowed to dissipate spontaneously without the addition of protamine. The rats were allowed to recover in a chamber (fraction of inspired oxygen, 0.5) with a controlled environmental temperature (25°C) for 24 h.

After 24 h, the rats underwent functional neurological evaluation (18 points as the maximum neuroscore; normal behavior) (19) by an observer blinded to the group assignments. This functional testing assesses spontaneous activity—no movement (0 points) to normal behavior (3 points); motor symmetry in all limbs—no movement at the left side (0 points) to normal behavior (3 points); motor symmetry in the forelimbs—no movement (0 points) to normal motor symmetry (3 points); climbing—falls trying to climb (1 point) to normal climbing (3 points); body proprioception—no response at left side (1 point) to symmetrical response (3 points); and response to vibrissae touch—no response on the left side (1 point) to symmetrical response (3 points).

After neurological testing, the animals were anesthetized (5% isoflurane) and killed by decapitation. The brain was immediately removed and freshly cut in 2-mm coronal section intervals. The brain sections were immersed in 2% 2,3,5-triphenyltetrazolium chloride in phosphate buffer for 30 min at 37.5°C (20). The brain sections were then photographed, and the digitized images were subsequently analyzed, by an investigator (HMH) blinded to group assignment, by using a computer program (Image J; National Institutes of Health Processing System) to determine the infarcted areas (pale areas failing to stain with 2,3,5-triphenyltetrazolium chloride). These brain regions were independently outlined for both cortical and subcortical infarcts. The infarct volume was calculated for each section by multiplying the drawn areas by the section thickness (2 mm). The total brain infarct volume was obtained by the sum of all calculated values for the cortex and subcortex.

Statistical analysis was performed with StatView (Version 5; SAS Institute, Cary, NC). Results are expressed as mean ± SD for the physiological values and brain infarct volumes and as median [interquartile range] for the neuroscore values. Physiologic values were compared among groups by using analysis of variance followed by the Scheffé test for post hoc analysis when indicated by a significant F ratio. Neurological scores and infarct volume were compared by using analysis of variance followed by the Kruskal-Wallis test followed by the Mann-Whitney U-test, as appropriate. Statistical significance was considered when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The Hb concentrations for the two experimental groups are outlined in Table 1. The differences in Hb concentration between groups were present only during the CPB phase. Animals in both groups were otherwise managed identically, except where indicated by group assignment, and had few statistical differences in the physiological variables or blood analysis values (Table 2). Three rats from the hemodilution group died before the 24-h end-point because of a severe cerebral infarct that was confirmed by autopsy. In the control group, one animal was excluded because of a nonfatal cerebral hemorrhage. These animals were replaced; thereby, 17 animals completed the experimental protocol (hemodilution group, n = 9; control group, n = 8).


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  		Table 1. Hemoglobin Concentration for Rats Submitted to MCAO During CPB
 

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  		Table 2. Physiologic Variables
 
Twenty-four hours after CPB, the functional neurological performance was worse in the hemodilution animals when compared with controls (Table 3). With respect to the histologic results, the control group had a significantly smaller total cerebral infarct volume compared with the hemodilution group (103 ± 58 mm3, control; versus 182 ± 84 mm3, hemodilution; P = 0.043; Fig. 2); this was largely attributable to a significantly smaller cortical infarct volume (77 ± 43 mm3, control; versus 171 ± 26 mm3, hemodilution; P = 0.004). There was no difference in subcortical infarct volume between groups (45 ± 12 mm3, control; versus 49 ± 14 mm3, hemodilution; Table 3, Fig. 2).


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  		Table 3. Neurologic Outcome and Brain Infarct Volume in Animals Submitted to Focal Cerebral Ischemia During Cardiopulmonary Bypass
 

Figure 2
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  		Figure 2. The cerebral infarct volumes in animals submitted to hypothermic cardiopulmonary bypass in addition to middle cerebral artery occlusion. The total infarct brain volume was significantly greater in the hemodilution group (P < 0.043) (A), as was cortical infarct volume (P < 0.004) (B). There was no significant difference between groups with respect to subcortical volumes (C).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Despite the surgical and anesthetic improvements in cardiac surgery, neurologic injury and neurocognitive dysfunction remain significant contributors to morbidity and mortality. The mechanism of cardiac surgery-associated cerebral injury is likely multifactorial. Cerebral injury can occur because of emboli (21,22), global cerebral hypoperfusion (23), inflammatory responses (24,25), cerebral edema (26), and hyperthermia (27), all of which may be superimposed on a background of possible genetic susceptibility (28,29). In addition, hemodilution has also been implicated in the etiology of this injury.

Of the above-stated etiologies, however, cerebral arterial microembolism, both gaseous and particulate, is thought to be one of the principal causes of neurological dysfunction after CPB (1,21,22,30). Although gaseous microemboli are unlikely to cause significant prolonged cerebral ischemia, particulate microemboli may obstruct cerebral vessels for prolonged periods (even permanently) leading to focal cerebral ischemic damage. In addition to microembolization, patients may experience macroemboli of large atheromatous plaques or thrombi that may result in even more significant cerebral ischemia, ultimately manifesting as stroke. Although patients are clearly at risk of experiencing focal cerebral ischemia during cardiac surgery, variable amounts of hemodilution often also occur during CPB at the same time. The interaction between focal cerebral ischemia and CPB-related hemodilution has not been investigated. In this study, by using an experimental model that combines both of these CPB-related occurrences, we found that reducing the Hb from 11 to 6 g/dL significantly increased cerebral infarct volume and worsened neurological outcome in rats submitted to focal ischemia during CPB.

Some degree of hemodilution is standard practice in patients undergoing CPB. It is principally used to facilitate a reduction in the need for intraoperative and postoperative blood transfusions, as well as their associated risks (13). Previous studies of hemodilution in CPB have generally concluded that moderate hemodilution (to levels similar to those we used) is a safe procedure during hypothermic CPB (5,13,14,31,32). The principal reason supporting its use, and the widespread belief in its safety profile, relate to the blood rheological characteristics induced by hemodilution that allow for increased organ blood flow (31). It is thought that the increase in the organ blood flow—in this case, the cerebral blood flow—offsets the decrease in the oxygen-carrying capacity induced by the hemodilution. However, the critical Hct to maintain adequate arterial oxygen content and oxygen delivery—in our case, the cerebral oxygen delivery—is not defined. There is evidence both from experimental settings and limited clinical studies that the lower limit of acceptably tolerated hemodilution in these patients is an Hct of approximately 18%–20%. Data from a normothermic CPB experimental setting in dogs demonstrated that although an Hct of 25% was sufficient to match the whole-body oxygen consumption, an Hct <18% was unsafe (33). In a study of 20 adults undergoing cardiac surgery (without known cerebral vascular disease), an Hb of 6.2 g/dL during CPB at 27°C allowed for normal global cerebral oxygenation with the nitrous oxide saturation technique (31).

However, there is little uniformity in the degree of hemodilution that is practiced in the setting of cardiac surgery. Arguments have been made in favor of a minimum Hct of 20% in low-risk patients (34), but others believe that hemodilution to an Hct <28% is optimal (35). These arguments, as well as efforts to push the limits of hemodilution to further minimize transfusion, have led to questioning of the safety of a low Hct in cardiac surgery. A study involving 6980 patients undergoing coronary artery bypass graft surgery demonstrated that a Hct <19% was associated with a higher mortality rate; even a Hct as high as 23% had an adverse effect on mortality (36).

In our experiments, we investigated two ends of the hemodilution spectrum: a control group (that itself had a slightly lower Hb than baseline) and a moderate hemodilution group. The hemodilution was generally well tolerated by the animals, with few differences between groups in blood gas values or other physiological variables throughout the experiments. The hemodilution group did have a slightly lower temperature at the end of CPB compared with controls; however, the difference was transient and dissipated by the end of the first post-CPB hour. In addition, the hemodilution group had a slightly higher CPB flow rate, possibly secondary to hemodilution-induced vasodilation (Table 2). There was no difference in the time for weaning from or recovery after CPB. Overall, the hemodilution group had a significantly worse neurological performance and larger cortical infarct volumes after 24 hours of survival. Of note, we excluded from analysis three animals in the hemodilution group and one in the control group because of mortality before the final assessment. Had these animals been included, the adverse effects of hemodilution would have been even more exaggerated.

In contrast to the adverse effects of hemodilution on cerebral ischemia demonstrated in this study, it has been effectively used in other non-CPB experimental settings to reduce brain damage after focal ischemia. In non-CPB experimental models of transient or permanent focal brain ischemia, hemodilution has been associated with better perfusion at the boundaries of the infarcted brain areas, thus reducing damage in the ischemic penumbra (7–11). However, the data showing neurologic outcome improvement and decreased cerebral infarct size after focal cerebral ischemia occurred in studies that used hemodilution with Hct levels of 29%–33% (12)—theoretically optimal to provide oxygen delivery (37,38) and considerably higher than what we used and what is commonplace in cardiac surgery. In addition, most of these studies were performed with body temperature strictly controlled at 37°C–37.5°C, and some used hypervolemia in addition to mild hemodilution (39). In our study, we chose normovolemic hemodilution, and the MAP was kept in an otherwise normal range; we also emulated the hypothermia often seen during CPB.

Another reason why our hemodilution group faired worse may be related to an adverse interaction between hypothermia and hemodilution. It is possible that the expected increases in oxygen delivery due to rheologic and autoregulatory factors may have been offset by the hypothermia-related leftward shift in the oxyhemoglobin dissociation curve, such that oxygen unloading in the ischemic brain may have been impaired (40). This potential adverse effect of temperature on oxygen unloading, however, was likely overwhelmed by the generally robust and direct neuroprotective effects of hypothermia (40).

There were some limitations to these experiments. The wide differences in Hb concentration between groups did not allow us to examine any dose response to hemodilution. It is possible that an Hb concentration somewhere between the levels chosen may have been of benefit in this setting. Defining the optimal balance of oxygen-carrying capacity and rheology-related blood flow will require further experimental exploration. In addition, although the degrees of hemodilution that we studied often occur in the clinical arena, it is not known whether there are interspecies differences with respect to the threshold level of hemodilution beyond which detrimental neurologic effects may occur.

Another limitation is the relatively early end-point used in this study. Any differences in outcome may have been minimized had our recovery period been longer. During this time, other processes, including delayed neuronal necrosis (in the control group), may have had time to exert an effect, thereby decreasing differences between groups for both infarct volume and functional neurological outcome. However, the choice for an earlier survival time scheduled in this study is corroborated both by previous experience in our laboratory and by others. These studies showed no further neurological deterioration after the first day after brain reperfusion of an MCAO-induced injury (19,41). Accordingly, in previous reports of transient MCAO in the rat, the neurological score decreased 24 hours after ischemia and remained at the lowest values until Day 5, without additional worsening. After Day 5, the neurological score moderated with some motor improvement in the ischemic animals (19). In a similar way, our results with long-term survival (12 days) in rats exposed to normothermic CPB showed an initial (24-hour) neurological impairment that persisted throughout the study, thereby adding validity to our choice of a 24-hour recovery period in this model (41).

Neurologic injury during cardiac surgery occurs in many forms. Although cognitive dysfunction is more frequent and likely results, although not exclusively, from microembolic events (21,22), the model that we studied here may be more comparable to a macroembolic injury, whereby large cerebral vessels are occluded. Therefore, the effect of hemodilution discussed herein may be more applicable to stroke rather than cognitive dysfunction.

In conclusion, our data show that hemodilution during hypothermic CPB has a deleterious effect on functional and histologic outcome from transient focal cerebral ischemia after 24 hours. Although we are not advocating changing clinical practice on the basis of this single experimental study, it does question the rationale for exercising extremes of hemodilution in patients who may be at risk for cerebral ischemic injury.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 21, 2004.




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