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CARDIOVASCULAR ANESTHESIA

The Rewarming Rate and Increased Peak Temperature Alter Neurocognitive Outcome After Cardiac Surgery

Alina M. Grigore, MD^*, Hilary P. Grocott, MD FRCP^*, Joseph P. Mathew, MD^*, Barbara Phillips-Bute, PhD^*, Timothy O. Stanley, MD^*, Aimee Butler, MS^*, Kevin P. Landolfo, MD, Joseph G. Reves, MD^*, James A. Blumenthal, PhD, and Mark F. Newman, MD^* the Neurologic Outcome Research Group of the Duke Heart Center

Departments of *Anesthesiology, Surgery, and Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina

Address correspondence to Joseph P. Mathew, MD, and reprint requests to Mark F. Newman, MD, Division of Cardiothoracic Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to mathe014{at}mc.duke.edu

	Abstract

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Neurocognitive dysfunction is a common complication after cardiac surgery. We evaluated in this prospective study the effect of rewarming rate on neurocognitive outcome after hypothermic cardiopulmonary bypass (CPB). After IRB approval and informed consent, 165 coronary artery bypass graft surgery patients were studied. Patients received similar surgical and anesthetic management until rewarming from hypothermic (28°–32°C) CPB. Group 1 (control; n = 100) was warmed in a conventional manner (4°–6°C gradient between nasopharyngeal and CPB perfusate temperature) whereas Group 2 (slow rewarm; n = 65) was warmed at a slower rate, maintaining no more than 2°C difference between nasopharyngeal and CPB perfusate temperature. Neurocognitive function was assessed at baseline and 6 wk after coronary artery bypass graft surgery. Univariable analysis revealed no significant differences between the Control and Slow Rewarming groups in the stroke rate. Multivariable linear regression analysis, examining treatment group, diabetes, baseline cognitive function, and cross-clamp time revealed a significant association between change in cognitive function and rate of rewarming (P = 0.05).

IMPLICATIONS: Slower rewarming during cardiopulmonary bypass (CPB) was associated with better cognitive performance at 6 wk. These results suggest that a slower rewarming rate with lower peak temperatures during CPB may be an important factor in the prevention of neurocognitive decline after hypothermic CPB.

	Introduction

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Cardiopulmonary bypass (CPB) for coronary artery bypass graft (CABG) surgery is associated with a substantial incidence of postoperative neurocognitive complications such as deficits in memory, attention, concentration, and learning (1,2). The etiology of these neurologic and neurocognitive complications is most likely multifactorial (3). The seemingly increased risk of stroke and neurocognitive dysfunction seen in patients undergoing CABG surgery in recent years has been associated with the increasing proportion of elderly patients presenting for this surgery (4,5). Although mortality related to adverse cardiac events has decreased, the percentage of deaths related to neurologic deficits has increased (6). Despite continued improvements in surgical and anesthetic techniques, the frequent incidence of postoperative neurocognitive dysfunction remains a concern, because of its associated morbidity (2), impaired quality of life (7), and increased perioperative cost (8).

Hypothermia improves myocardial and cerebral tolerance to ischemia (9–12). Nonetheless, hypothermia necessitates rewarming to normothermic temperatures, with the rate and duration of rewarming dependent on the extent of hypothermia. Rewarming speed has been directly related to jugular bulb (SjvO₂) desaturation (13), which in turn has been associated with poorer neurologic outcome (14). Therefore, our prospective study tested the hypothesis that slow rewarming would result in improved neurologic and neurocognitive outcome after CABG surgery.

	Methods

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After IRB approval and written informed consent, 165 patients undergoing elective CABG surgery were studied. Patients with a history of symptomatic cerebrovascular disease with residual deficits, uncontrolled hypertension, alcoholism, psychiatric illness requiring treatment, renal disease (creatinine >2.0 mg/dL), and active liver disease were excluded. Pregnant women and subjects with less than a seventh-grade education were also excluded from this investigation. A total of 65 patients (Slow Rewarm group) were warmed slowly before separation from CPB (see CPB methodology). These 65 subjects were compared with a group of 100 patients (Control group) who were warmed in a conventional manner as part of a large trial investigating the effect of hypothermic versus normothermic CPB on cerebral outcome after CABG surgery (15). Control patients were selected to coincide with the same enrollment period as the treatment group. Investigators performing the pre- and postoperative assessments were blinded to the rewarming protocol of each patient (single blind, prospective design). Only the clinicians involved in intraoperative care of these patients were aware of the treatment group.

Neuropsychological Testing
A neurocognitive test battery was administered the day before surgery, and 6 wk postoperatively. Assessment of neurocognitive function was done by investigators who were blinded to the rewarming protocol of each patient. Five instruments resulting in 10 measures, consistent with the statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery, were used (16):

1. The Short Story module of the Randt Memory Test requires subjects to recall the details of a short story immediately after it has been read to them (immediate) and after a 30-min delay (delay).

2. The Digit Span subtest of the Wechsler Adult Intelligence Scale—Revised Test requires subjects to repeat a series of digits that have been orally presented to them both forward and, in an independent test, in reverse order.

3. The Modified Visual Reproduction Test from the Wechsler Memory Scale measures short- and long-term figural memory and requires subjects to reproduce from memory several geometric shapes both immediately and after a 30-min delay (17).

4. The Digit Symbol subtest of the Wechsler Adult Intelligence Scale—Revised is a paper and pencil task that requires subjects to reproduce, within 90 s, as many coded symbols as possible in blank boxes beneath randomly generated digits according to a coding scheme for pairing digits with symbols.

5. The Trail Making Test (Trails) (part B) requires subjects to connect, by drawing a line, a series of numbers and letters in sequence (i.e., 1-A-2-B) as quickly as possible.

Neurologic Testing
Neurologic history and physical examinations were completed preoperatively, and on day 3–5 postoperatively. Investigators performing the pre- and postoperative assessments were blinded to the rewarming protocol of each patient. Neurologic outcome was primarily defined by using the Western Perioperative Neurologic Scale (WPNS)—a scale that is designed to detect and quantify anatomically discrete neurologic abnormalities and that has previously been used in randomized clinical trials (18,19). It consists of the following domains: mentation, speech, memory, cranial nerve assessment, motor function, and sensation and cerebellum. Patients were assessed and scored on a scale from 0 to 3 for a total possible score of 42 points. Our primary neurologic outcome variable was defined as a decrease from baseline in the WPNS of individual elements totaling two or more points, representing either mild decrease in performance in two areas or significant decrease in one area. Stroke was defined as fulfillment of any of the following criteria: 1) new worsened motor or sensory deficits of the face or upper and lower extremities (not attributable to peripheral lesions), 2) impaired speech, 3) visual disturbances (gaze palsy, visual loss), or 4) altered level of consciousness or confusion (not attributable to pharmacologic or metabolic causes).

Anesthesia and Perfusion Technique
Patients were premedicated with diazepam 0.1 mg/kg and methadone 0.1 mg/kg per os, 90 min before induction. Catheters were placed in the radial artery and right internal jugular vein before induction of anesthesia. Anesthesia was induced with 75–100 µg/kg midazolam and 5–10 µg/kg fentanyl IV. Supplemental isoflurane (0.5%–1.0%) was used as required to maintain heart rate and mean blood pressure within 25% of the preinduction values. Pancuronium was used to achieve and maintain neuromuscular blockade. The perfusion apparatus consisted of a Cobe CML membrane oxygenator^TM (COBE Chem Labs, Lakewood, CO), a Sarns 7000 MDX pump^TM (Sarns Inc., 3M Inc., Ann Arbor, MI), and a 40-µm Pall SP 3840^TM arterial line filter (Pall Biomedical Products Co., Glen Cove, NY). Nonpulsatile perfusion was maintained at 2–2.4 L/min/m². The pump was primed with crystalloid solution (lactated Ringer) with packed red cells added as necessary to maintain a hematocrit of 0.18. All patients were perfused during CPB through an ascending aortic cannula. Arterial CO₂ tension was maintained throughout CPB at 35 to 40 mm Hg (uncorrected for temperature), and PaO₂ was kept at 150 to 250 mm Hg. Mean arterial pressure was maintained between 50 and 90 mm Hg during CPB. All patients were cooled to a hypothermic temperature between 28° and 32°C. Myocardial protection was achieved in both groups with blood cardioplegia, prepared by mixing oxygenated blood with crystalloid additive in a 4:1 mixture, and delivered at 8°C in both groups. Myocardial temperature was kept 20°C during the period of aortic cross-clamping. During rewarming, a 2°C difference between nasopharyngeal (NP)-CPB perfusate temperature was maintained for patients enrolled in the Slow Rewarm group. The subjects in the Control group were conventionally warmed at NP-CPB perfusate temperature gradients of 4°–6°C. NP temperature and radial mean arterial pressure were measured each minute during CPB and recorded automatically by using the Arkive Information Management System (Arkive IMS Inc., San Diego, CA). These NP temperature measurements were summarized as: 1) maximal per minute temperature rate increase over 5 min (maximal rewarm rate), 2) area under the curve for temperature >37°C, 3) minimal rewarm temperature, and 4) maximal rewarm temperature.

Statistical Methods
To assess neurocognitive decline over time while minimizing the potential for redundancy in the neurocognitive measures, a factor analysis with orthogonal rotation was first performed on the 10 individual baseline neurocognitive test scores. This analysis included the entire baseline population of 165 patients. Factor analysis was used as a variable reduction technique to reduce the larger number of correlated dependent variables to a smaller number of uncorrelated outcome variables to be used in the final analysis. A factor analysis on 10 baseline neurocognitive test scores suggests that 4 factors accounted for 86% of the variance present in our test battery at baseline. The four factors represent the cognitive domains of: 1) verbal memory and language comprehension—short-term and delayed, 2) attention, psychomotor processing speed, and concentration, 3) abstraction and visuospatial orientation, and 4) figural memory. The factor loadings (weights), based on patients’ preoperative test scores, were used to construct domain scores at the 6-wk follow-up time period. In this manner, the domains were identified at baseline and remained consistent at follow-up. Because the factors are uncorrelated with each other, Type 1 errors attributed to multiple comparisons are minimized, and analysis can be done on each of the factors as a separate outcome. Using factors as outcomes instead of the individual test scores in subsequent analyses also eliminates the concern about redundancy of tests and the possibility of over-representing a single domain of cognitive functioning.

To assess overall cognitive function and severity of cognitive decline, a composite cognitive index score was calculated by adding together the four factor scores for each person. A patient missing up to 2 of 10 baseline scores was included in the factor analysis by using the mean test score as an imputed value. Missing follow-up scores were imputed by using the patient’s baseline test score plus the mean change score of the test cohort. A cognitive change score (continuous outcome measure) was calculated by subtracting baseline factor cognitive index scores from 6-wk cognitive index scores. In addition, a change score for each of the individual factors was calculated by subtracting baseline factor scores from the follow-up scores. A dichotomous outcome representing cognitive deficit was defined as a standard deviation decline on at least one of the four factors (domains). Whereas the analysis of neurocognitive deficit as a dichotomous measure captures only serious decline, the analysis of neurocognitive performance as a continuous measure is more sensitive to improvement. We investigated the effect of rewarm rate, defined as the fastest per minute rewarm rate over any 5 consecutive min, on both continuous and dichotomous measures to detect the presence of any significant neurocognitive changes in these areas.

Predictors of cognitive decline (as a continuous measure) were investigated with multivariable linear regression. Predictors of cognitive deficit (as a dichotomous measure) were evaluated with multivariable logistic regression.

To investigate the relationship between the Rewarm group and neurologic outcome, change in WPNS scores (calculated for each patient as postoperative score minus preoperative score) was examined as a continuous outcome in a multivariable linear regression model. Covariates included in all models were baseline cognitive index, cross-clamp time, and diabetes. P < 0.05 was considered significant.

	Results

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A total of 165 patients undergoing elective CABG were enrolled in this study. Table 1 shows that both Slow and conventional (Control) Rewarm groups were similar in most of the preoperative characteristics. Despite our efforts to achieve two rigorously matched groups, a significantly larger percentage of patients in the Slow Rewarm group had diabetes.

Baseline neurocognitive tests were performed in 65 patients in the Slow Rewarm group and 100 patients in the Control group. There were 15 patients in the Slow Rewarm group and 21 patients in the Control group who missed the 6-wk neurocognitive assessment after CABG. The reasons for the lack of follow-up included: 8, lack of interest; 12, nonneurologic health-related problems; 8, lack of transportation; 5, unable to contact; and 3, deceased (not related to neurologic cause). One patient each in the Control and Slow Rewarm group did not complete testing at 6 wk and therefore had unusable data. There were 6 imputed scores at baseline, and 4 imputed scores at follow-up, out of more than 2754 scores representing <0.04% of values. The raw test scores for both groups at baseline and 6 wk are presented in Table 2. The overall stroke rate was 2.4%, the neurocognitive deficit rate (dichotomous measure) was 45%, and the cognitive change score (continuous measure) was 0.51 ± 0.97. Univariable analysis revealed no significant differences between the Control and Slow Rewarming groups in the stroke rate, neurocognitive deficit rate, or cognitive change score.

The change in WPNS score for the Slow Rewarm group was -0.57, with a standard deviation of 1.3. Mean change for the Control group was -0.57, with a standard deviation of 1.7. In the multivariable linear regression, the Rewarm group was not significantly related to changes on WPNS scores (P = 0.81). The presence of covariates in the model did not significantly affect the results, and none of the covariates was a significant predictor of change in WPNS scores.

	Discussion

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This study confirmed our hypothesis that a slower rewarming rate with lower peak temperatures results in significantly better cognitive performance after cardiac surgery. Because rapid rewarming using available technology is inevitably associated with overshoot of targeted temperatures, failure to minimize the temperature gradient will result in increased exposure to hyperthermic temperatures and thus an increased potential for neurocognitive decline.

Hypothermia is often used as a presumptive strategy to protect the brain during cardiac surgery (10–12,20). However, hypothermia has been associated with decreased oxygen off-loading (21,22), rewarming oxygen imbalance and hyperthermia (23–26), and temperature redistribution producing recurrent hypothermia, bleeding, and shivering (27). Studies have reported a significant reduction in SjvO₂ associated with rewarming from hypothermic CPB (13,24,28–30). von Knobelsdorff et al. (28) noticed that during cooling and stable hypothermia, the ratio of SjvO₂/middle cerebral artery mean blood flow velocity (V_mean) was comparable to that before CPB. With rewarming, despite an increase in V_mean by 65%, SjvO₂ decreased by 25%, indicating a mismatch of cerebral blood flow and the cerebral metabolic rate for oxygen (CBF/CMRO₂). A decrease in SjvO₂ with rewarming has also been associated with poorer neurologic outcome. Andrews and Colquhoun (29) demonstrated that all patients with SjvO₂ <40% during rewarming experienced a reduction in median frequency and power in the higher frequency component of the electroencephalogram. Furthermore, Croughwell et al. (14) found evidence of impaired neurocognitive performance with cerebral venous desaturation.

The effect of rewarming rate on markers of cerebral metabolism has been studied before. Chen et al. (13), investigating 11 patients, found that SjvO₂ was directly related to the rewarming speed and inversely correlated with NP temperature change, and concluded that the magnitude and speed of temperature change are the major determinants of CBF/CMRO₂ balance during rewarming. Similar results were found by Nakajima et al. (30) in a small study involving 12 patients, indicating that rewarming speed is a critical factor responsible for an appropriate balance of oxygen supply/demand during CPB. More recently, in a nonrandomized, unblinded study performed on 28 patients, researchers reported SjvO₂ variations with respect to different rates of change of perfusate temperature (31). The degree of SjvO₂ reduction was not dependent on the rewarming rate, but only on jugular bulb temperature, with a maximal effect occurring just before reaching normothermia of the brain. Unfortunately, the small sample size (n = 28) did not provide enough statistical power to support their conclusions. Moreover, the authors did not differentiate diabetic patients who have altered autoregulation during rewarming (32). Also, the use of a continuous infusion of etomidate, known to cause cerebral vasoconstriction independent of its effect on cerebral metabolism (33), could have influenced the incidence of desaturation during rewarming.

Our study is the first prospective, blinded study investigating in a controlled manner the impact of patient rewarming rate on postoperative neurologic and neurocognitive performance in patients undergoing CABG surgery. Potential mechanisms for this neuroprotection include an improvement in the CBF/CMRO₂ balance and a decreased incidence of central nervous system hyperthermia. Because diabetic patients have impaired cerebral autoregulation during CPB, they may especially benefit from the use of slow rewarming rates.

Limitations to our study include the lack of true randomization resulting in the Slow Rewarm group having a larger percentage of diabetic patients. Therefore, in all statistical analyses, we controlled for the effect of diabetes on neurocognitive performance. A second limitation is that we found an effect on the continuous but not on the dichotomous neurocognitive outcome, similar to that demonstrated by Arrowsmith et al. (34) for neuroprotection with remacemide. The explanation for these seemingly inconsistent findings is that the continuous measure is more sensitive to improvement, whereas the dichotomous measure of impairment does not include measurement of a preserved learning effect. Third, some patients in the Slow Rewarm group achieved NP temperatures >37°C, although at lower peak temperatures and for shorter periods. These patients could have masked an increased benefit to slower rewarming rates.

In conclusion, our data suggest that slower rewarming rates are better than standard rewarming techniques in improving neurocognitive outcome. We believe that our report brings new and important information to the vital field of central nervous system protection during CPB. However, further prospective, randomized trials are necessary to clarify the optimal speed and peak temperature for rewarming from hypothermic CPB.

Appendix 1. Neurologic Outcome Research Group of the Duke Heart Center
Director: Mark F. Newman, MD; Co-director: James A. Blumenthal, PhD.

Anesthesiology: Fiona M. Clements, MD, Norbert de Bruijn, MD, Katherine Grichnik, MD, Hilary P. Grocott, MD, Steven E. Hill, MD, Andrew K. Hilton, MD, Joseph P. Mathew, MD, J. G. Reves, MD, Debra A. Schwinn, MD, Mark Stafford Smith, MD, David Warner, MD, Alina M. Grigore, MD, G. Burkhard Mackensen, MD, Timothy Stanley, MD, Jerry L. Kirchner, BS, Aimee M. Butler, MS, Vincent E. Gaver, BA, Wayne Cohen, MPH, Bonita L. Funk, RN, E. D. Derilus, BS, Deborah Manning, BS, Scott Lee, BS, Jonathan Williams, BS, Melanie Tirronen, BS, Erich Lauff, BA, Chonna Campbell, BS, Keinya Lee, BS, William D. White, MPH, and Barbara Phillips-Bute, PhD.

Behavioral Medicine: James A. Blumenthal, PhD, Michael A. Babyak, PhD, and Parinda Khatri, PhD.

Neurology: Carmelo Graffagnino, MD, Daniel T. Laskowitz, MD, Ann M. Saunders, PhD, and Warren J. Strittmatter, MD.

Surgery: Robert W. Anderson, MD, Thomas A. D’Amico, MD, R. Duane Davis, MD, Donald D. Glower, MD, David H. Harpole, MD, James Jaggers, MD, Robert H. Jones, MD, Kevin P. Landolfo, MD, Carmelo Milano, MD, Peter K. Smith, MD, and Walter G. Wolfe, MD.

	Acknowledgments

 
This work was supported by NIH Grant RO1-AG09663-4, GM08600-02; National Center for Research Resources, Clinical Research Centers Program, NIH MO1-RR-30; and American Heart Association Patient Care and Outcomes Research Program 9970128N, HL54316-04.

	Footnotes

 
The members of the Neurological Outcome Research Group (N.O.R.G.) of the Duke Heart Center are listed in Appendix 1.

	References

Top Abstract Introduction Methods Results Discussion References

 

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