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Ann Thorac Surg 2005;80:1381-1387
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Low Hematocrit During Cardiopulmonary Bypass is Associated With Increased Risk of Perioperative Stroke in Cardiac Surgery

^a Department of Anesthesia, University Health Network
^c Division of Cardiovascular Surgery, University Health Network
^b Department of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada

Accepted for publication March 28, 2005.

^_* Address reprint requests to Dr Karkouti, Department of Anesthesia, 3 Eaton North, Toronto General Hospital, University Health Network, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4 (Email: keyvan.karkouti{at}uhn.on.ca).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: The relationship between degree of hemodilution during cardiopulmonary bypass (CPB) and perioperative stroke has not been fully elucidated. The objective of this observational study was to evaluate the relationship between nadir hematocrit during CPB and perioperative stroke while adjusting for variables known to have an association with stroke and anemia.

METHODS: Perioperative data were prospectively collected on 10,949 consecutive patients who underwent cardiac surgery with CPB from 1999 to 2004 at a quaternary care hospital. Stroke was defined as a persistent neurologic deficit, consistent with a central nervous system lesion, occurring within 30 days of operation. Stroke was classified as perioperative if patients awoke from anesthesia with neurologic symptoms and postoperative if patients awoke without symptoms. Multivariable logistic regression analysis was used to control for confounding variables to obtain the independent relationship between nadir hematocrit during CPB and perioperative stroke.

RESULTS: The prevalence of perioperative stroke was 1.0% (n = 110). An additional 50 patients had postoperative stroke. Nadir hematocrit during CPB was an independent predictor of perioperative stroke. After controlling for confounding variables, each percent decrease in hematocrit was associated with a 10% increase in the odds of suffering perioperative stroke (95% confidence interval, 4% to 18%; p = 0.002). The model was accurate (c-index = 0.85) and reliable (Hosmer-Lemeshow test p = 0.4).

CONCLUSIONS: There is an independent, direct association between degree of hemodilution during CPB and risk of perioperative stroke. Prospective randomized clinical trials comparing different degrees of hemodilution during CPB are required to determine whether this is a cause–effect relationship or a simple association.

	Introduction

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This article has been selected for the open discussion forum on the CTSNet Web Site: http://www.ctsnet.org.discuss

 

Cardiac surgery often necessitates the use of cardiopulmonary bypass (CPB). In the early days of cardiac surgery, CPB circuits were primed with whole blood to avoid hemodilution and the subsequent drop in hematocrit. This practice often resulted in patients receiving multiple units of allogeneic blood [1]. Concerns about the scarcity of allogeneic blood supplies as well as the risks of blood transfusion resulted in considerable modifications in CPB management. Currently, CPB prime is composed of crystalloid and colloid solutions that can result in marked hemodilution, often to hematocrit concentrations of 20% or less. Although this practice has been accepted for more than four decades, there is a renewed debate about the optimal degree of hemodilution during CPB [2]. Recent observational studies have found a direct association between severity of hemodilution during CPB and perioperative morbidity and mortality [3–5]. More specifically, there is a growing body of evidence linking low hematocrit concentrations during CPB with increased risk of stroke [5–9].

The risk of perioperative stroke has been reported in the range of 0.3% to 8% depending on the type of cardiac surgery performed [10–12]. Excessive hemodilution during CPB may increase the risk of stroke by causing inadequate oxygen delivery or by increasing embolic load to the brain [2, 13]. The relationship between stroke and severity of hemodilution has been examined by several observational studies with conflicting results [4, 5, 14–17]. These studies were limited by small sample sizes or inadequate adjustment for confounders. Our goal was to evaluate the effects of low hematocrit during CPB on perioperative stroke while adjusting for a large number of variables known to have a relationship with stroke or anemia.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
After institutional ethics approval, data on consecutive adult (18 years or older) patients undergoing cardiac surgery with CPB at the Toronto General Hospital from June 1999 to June 2004 were obtained from prospectively collected, validated, and accurate clinical databases. Details of the databases have been previously described [18, 19]. Research personnel blinded to the details of this study and to the intraoperative hematocrit data adjudicated all outcomes from patients' medical records.

Study Setting and Clinical Practice
The Toronto General Hospital is a quaternary care teaching hospital affiliated with the University of Toronto. A full range of adult cardiac surgery procedures, including congenital heart disease repair and heart transplantation, is performed at this hospital. Perioperative patient management followed standardized protocols.

Anesthetic Management
‘Fast-track' anesthesia with fentanyl (10 to 20 µg/kg), midazolam (0.1 mg/kg), pancuronium (0.15 to 0.20 mg/kg), isoflurane (0.5 to 1.5%), and propofol (0.5 to 4 mg·kg^–1 ·h^–1) was used. Patients were routinely monitored with pulmonary artery catheters. Transesophageal echocardiography was routinely used except for patients undergoing isolated coronary artery bypass grafting, in whom it was used only in selected, high-risk cases. Epiaortic scanning was used in patients who were thought to be at high risk of ascending aortic atherosclerosis (patients with multiple risk factors or palpable plaque). Tranexamic acid (50 to 100 mg/kg, intravenous bolus) was used routinely for antifibrinolysis, except in patients at very high risk of perioperative bleeding. Such patients received aprotinin (2 x 10⁶ U before sternotomy, 2 x 10⁶ U during CPB, and 2 x 10⁶ U infused for 4 hours).

Cardiopulmonary Bypass Management
Anticoagulation was achieved with heparin to maintain activated clotting time greater than 480 seconds. The CPB circuit was primed with 1.8 L of Ringer's lactate solution and 50 mL of 20% mannitol. Management of CPB included systemic temperature drift to 34°C, alpha-stat pH management, targeted mean perfusion pressure between 50 and 70 mm Hg, and pump flow rates of 2.0 to 2.4 L·min^–1 ·m^–2. Myocardial protection was achieved with intermittent antegrade and, occasionally, retrograde blood cardioplegia. Deep hypothermic circulatory arrest was achieved by cooling to 20°C with retrograde cerebral perfusion when required; ancillary therapies for brain protection were not routinely used during deep hypothermic circulatory arrest.

During CPB, red blood cell concentrate transfusion (leukoreduced blood products) was aimed at maintaining a hematocrit concentration of greater than 17% or a mixed venous saturation of greater than 55%. Pericardial blood was salvaged into the cardiotomy suction reservoir and was reinfused by means of the CPB circuit for as long as patients were anticoagulated. After separation from CPB, heparin was neutralized with protamine sulphate, 1 mg per 100 U of heparin, to achieve an activated clotting time within 10% of baseline. After CPB, red blood cells were transfused to maintain a hematocrit of at least 24% in stable patients and 27% in bleeding or unstable patients.

Dependent Variable
Perioperative stroke was defined as any new persistent postoperative neurologic deficit consistent with a central nervous system lesion that was present on emergence from anesthesia. Neurologic deficits were diagnosed by the intensivists and were confirmed by computed tomography or magnetic resonance imaging, as well as by an attending neurologist. In patients with a previous history of stroke or transient ischemic attack, a new stroke was diagnosed if they developed new neurologic radiologic findings as well as marked, prolonged worsening of their preexisting neurologic deficits.

Patients who emerged from anesthesia without any neurologic deficits but later developed neurologic deficits while hospitalized were classified as having had a postoperative stroke and were analyzed separately from those who had perioperative strokes.

Independent Variables
The primary variable of interest was nadir hematocrit during CPB, which was measured every 15 minutes during CPB. Variables related to perioperative stroke, anemia, or perioperative blood loss were considered for inclusion in the multivariable analysis as confounding variables.

Statistical Analysis
Statistical analyses were performed using SAS version 8.2 (SAS Institute, Inc, Cary, NC). Whenever possible, missing values were completed from patients' records; otherwise, patients with missing values were excluded if a categorical variable or nadir hematocrit was missing. For continuous variables other than nadir hematocrit, missing values were imputed based on the mean for the entire sample, according to stroke status.

The bivariate association between the independent variables and perioperative stroke was assessed by the Student's t test, Mann-Whitney U test, ² test, Fisher's exact test, or Mantel-Haenszel test where appropriate. The bivariate association between nadir hematocrit and other independent variables was assessed by the Pearson correlation test. Variables associated with perioperative stroke (p < 0.1 in the bivariate analyses) as well as with nadir hematocrit (p < 0.1 in the correlation analysis) were included in the logistic regression analysis.

The mathematical relationships between the continuous independent variables and the probability of perioperative stroke were assessed using cubic spline functions [20, 21]. Variables that were not linearly related were either mathematically transformed, categorized along appropriate cut points, or were converted into multiple dichotomous variables for the logistic regression analyses [22]. A Pearson correlation matrix of variables was used to identify collinear independent variables [22].

To determine the independent relationship between nadir hematocrit during CPB and perioperative stroke, a logistic regression model was constructed with perioperative stroke as the dependent variable and nadir hematocrit and all identified confounders (including significant two-way interaction terms) as independent variables. For sensitivity analyses, four additional models were constructed that (1) excluded patients with nadir hematocrit below 18% or above 29%; (2) excluded patients who underwent deep hypothermic circulatory arrest; (3) excluded all complex cases; and (4) included both perioperative stroke and postoperative stroke as the dependent variable.

All models were constructed using backward stepwise variable selection and a p value less than 0.05 as the criterion for variable retention. The models' fit was assessed by the Hosmer-Lemeshow test (larger p value means better fit or reliability), and predictive accuracy was assessed by the c-index (which is equivalent to the area under the receiver-operating characteristic curve) [22]. The validity of the relationship between hematocrit and stroke was assessed by the bootstrap technique [23], for which 50 computer-generated samples, each including 10,000 patients, were derived from the study population by random selection with replacement. For each bootstrap sample, the primary model was refitted and the average odds ratio for nadir hematocrit during CPB was obtained.

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
A total of 10,949 patients who underwent cardiac surgery with CPB were included in the analyses. For those patients who underwent more than one operation requiring CPB during the study period, only data from their first operation was used. Less than 1% of patients had missing data—all missing nadir hematocrit data were obtained from patients' records. Mortality rate was 1.9% (n = 204) and perioperative stroke rate was 1.0% (n = 110). An additional 50 patients experienced postoperative strokes; thus, the total stroke rate was 1.5%. The average nadir hematocrit in the entire population was 22.9% ± 3.5%; in 25% of patients the nadir hematocrit was 20% or less. The unadjusted relationship between nadir hematocrit, categorized into six categories, and stroke is shown in Figure 1. The unadjusted relationships between stroke and selected independent variables, including nadir hematocrit as a continuous variable, are shown in Table 1. Figure 2 shows the spline function graph of the relationship between nadir hematocrit and stroke. Because this relationship was linear, nadir hematocrit was analyzed as a continuous variable. No two variables had a correlation coefficient greater than 0.6; thus, multicollinearity was not an issue in the modeling.

View larger version (14K): [in this window] [in a new window]   Fig 1. Bivariate relationship between nadir hematocrit during cardiopulmonary bypass (CPB) and perioperative stroke. Bars represent confidence intervals.

View larger version (15K): [in this window] [in a new window]   Fig 2. Spline function graph of the unadjusted relationship between nadir cardiopulmonary bypass (CPB) hematocrit and logit probability (Prob.) of perioperative stroke. The probability of event P(X) can be calculated from the logit probability of stroke using the formula: P(X) = 1 / [1 + e–logit P(X)]. Upper and lower lines represent the 95% confidence interval of the relationship.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

Three large observational studies that investigated the relationship between nadir hematocrit and perioperative morbidity had conflicting results with respect to stroke. DeFoe and associates [4] found no association between hematocrit concentration during CPB and stroke after isolated coronary artery bypass grafting in their multicenter series of 6,980 patients (116 strokes). Similarly, van Wermeskerken and colleagues [14] did not find an association between nadir hematocrit and stroke in their study of 2,862 coronary artery bypass graft patients (36 strokes). Most recently, in a series of 5,000 consecutive cardiac surgery patients (95 strokes), low hematocrit during CPB was strongly associated with stroke (p < 0.001), but confounders were not controlled for [5].

In this study, several steps were taken to ensure that the results represented a valid estimate of the relationship between nadir hematocrit during CPB and perioperative stroke. First, an accurate database that included detailed information on consecutive cardiac surgery patients was used. The data were prospectively collected and outcome adjudication was blinded. Second, important confounders were identified and appropriately adjusted for using a large sample size and proper modeling techniques, including sensitivity analysis [22]. Third, several confounding variables that could have occurred before or after the onset of perioperative strokes (eg, reexploration, perioperative atrial fibrillation) were nevertheless included in the analysis to ensure that their confounding effects were accounted for. Fourth, nadir hematocrit during CPB was analyzed as a continuous variable (rather than as a categorical variable based on arbitrary cutoff points) and the linearity assumption of logistic regression was confirmed [22]. Finally, this study included the entire cardiac surgery case mix of a single large quaternary referral center in which patient management was highly standardized. This increases the generalizability of the results and minimizes the chance that the observed association is related to variations in clinical practice that occur across different institutions. Of note, the composition of the model in this study, with the exception of nadir hematocrit, is very similar to other cardiac surgery perioperative stroke prediction models [10–12], which supports the validity of our results.

The observed association between degree of hemodilution during CPB and stroke is biologically plausible. One possibility is that excessive hemodilution during CPB may lead to stroke by increasing the embolic load to the brain [2, 13]. There is ample evidence that macroemboli and microemboli occur in virtually 100% of patients undergoing CPB and that these emboli are a significant cause of cerebral injury [10, 24–28]. Hemodilution may increase embolic load to the brain by increasing cerebral blood flow (which is two to three times higher at a hematocrit of 15% than at 25%) [13].

Another possible mechanism pertains to the effects of hemodilution on oxygen delivery. Under normal conditions, oxygen delivery to the brain is maintained even during periods of severe hemodilution by increased cerebral blood flow and increased cellular oxygen extraction. These compensatory mechanisms, however, may not apply to ischemic brain cells. It has been shown that cellular oxygen consumption in the normal brain is maintained to hematocrit concentrations as low as 18% [29]. In ischemic areas of the brain, however, oxygen extraction reaches its limits at a hematocrit concentration of approximately 30%, and oxygen uptake decreases with lower hematocrits [30]. Thus, cells in ischemic areas of the brain may not receive adequate supplies of oxygen with severe hemodilution to levels that are commonly used during CPB. It is important to note that this study was not designed to address the mechanism of injury.

This study has several other limitations. It is an observational study and therefore causality cannot be inferred from the observed associations. In addition, the effects of unmeasured confounding variables or complex interactions between covariates on the observed association cannot be ruled out. Finally, the databases used were created before this study was conceived, and therefore subtle errors in recording of perioperative variables are possible. Previous quality assurance reviews, however, have revealed a data error rate of less than 2%.

Until the results of this study are confirmed by randomized controlled trials or other large observational studies, it would be inappropriate to recommend that the practice of CPB be modified to maintain higher hematocrit concentrations. This is particularly important given that some of the options for maintaining higher hematocrit concentrations have their own risks. For example, limiting hemodilution during CPB by red blood cell transfusion may do more harm than good (as was recently demonstrated by a randomized trial comparing different degrees of hemodilution during CPB that was terminated early because both the high and low hematocrit groups had a higher adverse event rate than the control group [personal communication, G. Djaiani]). Other options, such as retrograde priming of the CPB circuit with autologous blood, reducing the prime volume by using smaller circuits, and ultrafiltration during CPB, may not be appropriate in all cardiac operations and may increase costs.

In conclusion, this study found an independent, direct relationship between degree of hemodilution during CPB and perioperative stroke. Before any modifications in CPB management can be recommended, however, carefully designed prospective randomized clinical trials comparing the safety of different degrees of hemodilution during CPB are required to determine whether this is a cause–effect relationship or a simple association.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Dr Karkouti is supported in part by the Canadian Institutes of Health Research and Canadian Blood Services. Dr Beattie is the R. Frasier Elliot Chair of Cardiac Anesthesia. No third-party funding was used for this study.

	References

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