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Ann Thorac Surg 1996;61:1423-1427
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Cardiopulmonary Bypass, Rewarming, and Central Nervous System Dysfunction

Department of Anaesthesia, Clinical Epidemiology Unit and Department of Medicine, Department of Psychology, Division of Neurology, Department of Medicine, and Division of Cardiovascular Surgery, Department of Surgery, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada

Accepted for publication February 3, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. During cardiopulmonary bypass a nasopharyngeal temperature greater than 38°C at the end of rewarming may indicate cerebral hyperthermia. This could exacerbate an ischemic brain injury incurred during cardiopulmonary bypass.

Methods. In a cohort of 150 aortocoronary bypass patients neuropsychologic test scores of 66 patients whose rewarming temperature exceeded 38°C were compared with those who did not. There were no differences between groups with respect to demographic and intraoperative variables.

Results. A trend was seen for hyperthermic patients to do worse on all neuropsychologic tests in the early postoperative period but not at 3-month follow-up. By analysis of covariance hyperthermic patients did worse on the visual reproduction subtest of the Weschler memory scale at 3 months (p = 0.02), but this difference was not found by linear regression (p = 0.10).

Conclusions. We were unable to demonstrate any significant deterioration in patients rewarmed to greater than 38°C in the early postoperative period. The poorer performance in the visual reproduction subtest of the Wechsler memory scale at 3 months in the group rewarmed to more than 38°C is interesting but far from conclusive. Caution with rewarming is still advised pending more in-depth study of this issue.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Central nervous system dysfunction after cardiopulmonary bypass (CPB) is an important cause of morbidity and mortality after cardiac operations. Although cardiac causes of death after CPB have decreased, the incidence of neurologic complications has not. As a result, neurologic events are responsible for up to 20% of perioperative deaths in cardiac surgery [1, 2]. The incidence of neuropsychologic impairment after CPB is reported to be as high as 79% [1].

Brain temperature during CPB may influence the extent or severity of neurologic injury. Although there is an extensive body of evidence showing that hypothermia is neuroprotective in ischemic brain injury [3, 4], in a randomized trial comparing normothermic with hypothermic CPB we were unable to demonstrate a neuroprotective effect of moderate hypothermia [5]. In addition, a large retrospective analysis comparing 2,585 normothermic CPB patients with 1,605 hypothermic CPB patients found no difference in the incidence of overt neurologic injuries [6].

It is possible that a neuroprotective effect of hypothermic bypass was not demonstrated because of inappropriate cerebral hyperthermia during rewarming. Animal studies demonstrate increased cerebral infarct volume after focal ischemia in mildly hyperthermic animals com-pared with hypothermic ones [7]. Cerebral hyperthermia could be damaging in itself or it could exacerbate injury that occurred before rewarming, thereby abolishing any protective effects of hypothermia.

An elevated nasopharyngeal temperature (NT) at the end of rewarming may indicate that inappropriate cerebral hyperthermia is present. Using this indicator we have attempted to determine if cerebral hyperthermia during rewarming influences the degree of neuropsychologic dysfunction after CPB.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In a randomized, prospective trial comparing normothermic CPB (NT >34°C) with hypothermic CPB (NT 28°C) [5] (methods described in the following paragraphs), we found no difference in the severity of neuropsychologic dysfunction after CPB. The frequency of a final rewarming NT greater than 38°C was the same in both groups. For these reasons, to analyze the influence of cerebral hyperthermia on neuropsychologic dysfunction, a post-hoc analysis of the pooled neurologic outcome data from both groups was performed.

Patient Population
Patients undergoing isolated myocardial revascularization, urgent or elective, were eligible for entry in the study with the following exclusion criteria: (1) need for concomitant valvular operation, aneurysmectomy, atrial septal defect/ventricular septal defect repair, or other complicating procedure; (2) lack of consent for randomization; (3) factors precluding proper preoperative assessments such as emergency operation, unstable cardiac disease, and lack of fluency in English; (4) inability to arrange follow-up assessment; and (5) history of stroke. There were no educational level exclusions. Randomization was stratified by urgent versus elective cases and by surgeon. A sealed-envelope method was used, with treatment assignment determined when the perfusionist opened the envelope in the operating room.

Data Collection
Preoperative data was recorded regarding age, sex, left ventricular function as assessed by angiography or echocardiography, and educational achievement. Perioperative data collection included lowest NT during CPB, final NT after rewarming, cross-clamp duration, and CPB duration. Mean arterial pressure, central venous pressure, nasopharyngeal temperature, and pump flow were recorded every 5 minutes during CPB. Cerebral perfusion pressure was defined as mean arterial pressure minus central venous pressure. To quantitate the degree of hypotension a modification of the TM<50 score developed by Stockard and associates [8] was used. The TM<50 was calculated by summing the product of (50 - cerebral perfusion pressure) x time (minutes) for each period that the cerebral perfusion pressure was less than 50 mm Hg. The use of inotropes for separation from CPB was recorded. Glucose level was recorded before CPB, every 20 minutes during CPB, and after CPB.

Anesthetic, Surgical, and Cardiopulmonary Bypass Management
The anesthetic protocol consisted of premedication with diazepam (0.1 mg/kg orally) or lorazepam (0.03 mg/kg sublingually), and morphine sulfate (0.15 mg/kg intramuscularly) with perphenazine (0.05 mg/kg intramuscularly). Anesthesia was induced with intravenous fentanyl citrate (10 to 15 µg/kg), midazolam, or diazepam, with or without titrated doses of thiopental sodium (<3 mg/kg) and pancuronium bromide (0.15 mg/kg). After tracheal intubation, anesthesia was maintained with halothane in oxygen, with additional doses of fentanyl, diazepam/midazolam, and pancuronium, or with both. Anesthesia during CPB was maintained with supplemental doses of diazepam/midazolam, fentanyl, or both. In addition, isoflurane at a minimum concentration of 0.5% (turned off 10 minutes before separating from CPB) was used. No attempt was made to standardize the administration of opioid or sedative agents in the postoperative period.

Surgical exposure was via a median sternotomy with extracorporeal circulation lines consisting of ascending aortic and right atrial (two-stage) cannulas. Patients were anticoagulated with heparin sodium (300 U/kg), supplemented as needed to maintain an activated clotting time of more than 400 seconds (Hemotec). A Cobe heart-lung machine (Cobe Cardiovascular, Arvada, CO) with Bentley tubing and reservoirs (Baxter Healthcare Corp, Irvine, CA) was used for CPB, including membrane oxygenators and in-line arterial line filters. A crystalloid, non-glucose-containing priming solution was precirculated through a 5-µm prebypass filter (Bentley) before cannulation. Hematocrit was maintained greater than 0.20 on CPB with the addition of blood as necessary. Nonpulsatile flows of 2.4 L•min^-1•m^-2 were used at normothermia and were no less than 1.8 L•min^-1•m^-2 at 28°C. Mean arterial pressure was maintained at more than 50 mm Hg (with phenylephrine if necessary), and hypertension (mean arterial pressure >90 mm Hg) was treated first with additional isoflurane, then with nitroprusside if necessary. Oxygen inflow of 2 to 5 L/min was adjusted for normal oxygenation and alpha-stat acid-base balance. Rewarming was initiated at the surgeon's request, usually before unclamping of the aorta. At their discretion, perfusionists would set the water bath temperature at 39° to 42°C in an attempt to stabilize nasopharyngeal temperatures at 37° to 38°C.

Cardioplegia was delivered in an antegrade manner. Distal graft anastomoses were constructed during complete aortic cross-clamping. After declamping and reapplication of a partial occluding clamp the proximal anastomoses were performed.

Neuropsychologic Assessment
Neuropsychologic assessment was performed preoperatively, at 4 to 5 days after operation (when the patient was ambulatory and no longer receiving parenteral narcotics), and at 3-month follow-up. Neuropsychologic assessment was performed by a nurse (trained by the study neuropsychologist) who was blinded to CPB treatment. A brief neuropsychological test battery, including measures of nonverbal memory, psychomotor speed, constructional praxis and manual dexterity was utilized. The tests used included (1) the Wechsler memory scale-revised visual reproduction subtest (WMS-RVRS), a commonly used measure of visual memory; (2) the trail-making test (parts A and B), a simple two-part measure of psychomotor speed; (3) the Wechsler adult intelligence scale-revised digit symbol subtest, a measure of concentration and psychomotor speed; and (4) the grooved pegboard test, a measure of dexterity and motor speed.

Statistical Analysis
Cerebral hyperthermia was defined as a final rewarming NT greater than 38°C. This temperature was chosen as the cutoff point because temperatures greater than 38°C overshot the intended rewarming objective, and have been demonstrated in animal studies to reduce ischemia tolerance [7, 9, 10]. Subsequent statistical analysis was performed using the SAS statistical software package (SAS, Cary, NC). When comparing continuous data, unpaired t tests were used. Proportions were analyzed using the ² test. Analysis of covariance procedures to control for individual preoperative test scores as well as other potential confounding variables (age, left ventricular function, educational level, and hypotension score) were used to compare neuropsychologic test scores between groups. Data from the analysis of covariance are presented as adjusted means ± standard deviation.

To eliminate any random threshold effects resulting from the choice of the 38°C cutoff point, multiple linear regression techniques were also used. Neuropsychologic test scores were regressed against temperature under two conditions: first, with the preoperative test score results as covariates, and second, with preoperative test score results, age, left ventricular function, education, and hypotension score as covariates.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Two hundred one patients were enrolled in the study. Twenty-nine patients had incomplete data, 17 refused to continue in the study, and 3 had intraoperative changes in their management. Focal deficits were detected in 6 patients. Four of these patients had final nasopharyngeal temperatures greater than 38°C, and 2 were 38°C or less (not significant). Of these 6 patients, 1 died and 1 was unable to complete subsequent neuropsychologic assessment. This left 150 patients with complete temperature and neuropsychologic data for analysis. The mean final rewarming NT was 37.9 ± 0.06°C, with a range of 35.3° to 39.4°C. The distribution of temperatures is shown in Figure 1.

View larger version (23K): [in this window] [in a new window]   Fig 1. . Histogram showing the distribution of final rewarming nasopharyngeal temperatures (NT). X-axis is temperature in 0.5°C increments. Y-axis is number of patients in each group.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The aim of this study was to determine if there are any adverse neurologic effects of inappropriate cerebral hyperthermia during the rewarming phase of CPB. This inappropriate cerebral hyperthermia could exacerbate an ischemic brain injury due to embolism or hypoperfusion incurred at any time during CPB regardless of what temperature the body was lowered to during CPB. During early rewarming it is not uncommon to have blood returning to the patient in excess of 39°C. The brain with its high blood flow rewarms rapidly and could be hyperthermic for a significant period.

Several animal studies demonstrate that even mild hyperthermia reduces the ability of the brain to tolerate ischemic injury. In rats, cerebral infarct volume after reversible occlusion of the middle cerebral artery was larger in hyperthermic (39°C) compared with normothermic and hypothermic rats [7]. Histopathologic findings confirm increased severity of brain injury in rats when forebrain ischemia was induced during hyperthermia (39°C) [9]. Animal studies also suggest some mechanisms by which hyperthermia exacerbates ischemic brain injury. Blood-brain barrier permeability after forebrain ischemia is exacerbated by normothermic (36°C) or hyperthermic (39°C) intraischemic brain temperatures [10]. Excitotoxic mechanisms may also play a role. Intraischemic hyperthermia (39°C) increases extracellular levels of glutamate compared with normothermic levels [11].

Although these studies elegantly demonstrate that hyperthermic intraischemic temperatures increase brain injury, there are no studies to date that specifically examine the effect of hyperthermia after an ischemic injury incurred during a period of hypothermia or normothermia. This would resemble the clinical scenario where cerebral hyperthermia caused by rewarming follows an ischemic injury incurred during hypothermic or normothermic CPB.

We believe pooling the data from patients undergoing normothermic CPB with those undergoing hypothermic CPB is valid. Previous analysis of these patient groups found no difference with respect to postoperative neurologic outcome [5]. Thus we believe that it is not a factor. In addition, separating out the groups would greatly reduce our ability to detect any differences due to rewarming technique.

We found no difference between the two groups in the postoperative period. The differences observed in the follow-up WMS-RVRS scores should be interpreted with caution for a variety of reasons: this is a post-hoc look at data collected with a different question in mind, p values are less meaningful given the multiple comparisons performed, linear regression did not consistently confirm the results, and finally the differences seen are not large enough to be clinically meaningful.

It is possible that our inability to demonstrate a significant difference between the two groups is due to a number of factors. First, the perfusionists attempted to rewarm to a target NT of between 37°C and 38°C. Consequently the range of final rewarming temperatures was small. In fact, 70% of the final temperatures were between 37.6°C and 38.3°C. This central clustering of data could obscure any adverse effects on test scores of the more excessive but relatively less frequent extreme rewarming temperatures. Second, subjects repeating the same neuropsychologic test battery over and over may improve their test scores solely by a ``practice effect,'' again potentially obscuring an adverse effect due to excessive rewarming. Third, nasopharyngeal temperatures may not accurately reflect cerebral temperature, therefore resulting in an underestimation or overestimation of the degree of cerebral hyperthermia [12]. Nasopharyngeal temperature does correlate with cerebral temperature, and it seems likely that at worst we were underestimating the degree of cerebral hyperthermia, something that should not have affected the sensitivity of our linear regression analysis. Fourth, the time that the brain is actually hyperthermic, if at all, may be very brief and significant injury may not occur. Unfortunately we did not record the duration of temperature elevation and are unable to address this issue. It would, however, seem logical to assume that a higher final temperature would be associated with a greater duration of hyperthermia. Fifth, the rate and homogeneity of brain rewarming may be more important than the final temperature reached. Finally, in humans hyperthermic potentiation of brain injury may require more extreme temperature elevations than the temperatures noted to have exacerbated injury in the animal studies. The highest NT measured in this study was 39.4°C.

In summary, we were unable to demonstrate any clearly deleterious effects of excessive rewarming after CPB for coronary artery operation in this patient population. We would, however, continue to recommend caution with rewarming. It is possible given the numbers studied and the technical challenges of applying consistent neuropsychologic test batteries that a statistically significant trend was missed. Because of these uncertainties and concerns raised by findings in animal studies, we have modified our rewarming technique to reduce the risk of inappropriate cerebral hyperthermia occurring. During the initial phase of rewarming water heat exchanger is set at 40° to 42°C until NT is 37°C, at which point the heater temperature is reduced to 38°C until the end of CPB.

The use of a more accurate measure of intracerebral temperature and further refinements in techniques to measure the subtle manifestations of neuropsychologic dysfunction should be pursued in future studies. Ideally a sensitive biochemical marker of cerebral injury that could be simply measured in a person's serum would obviate the need for tedious and potentially insensitive neuropsychologic testing. A candidate for this is the S-100 glial protein that is released by ischemic injury. Increases in serum levels of this protein can be detected by radioimmunoassay after CPB and correlate with the extent of neurologic injury [13, 14].

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Erluo Chen, MB, MPH, for performing the statistical analysis.

This study was supported by a grant from the Medical Research Council of Canada (MA-1178).

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr McLean, Department of Anaesthesia, Sunnybrook Health Science Centre, 2075 Bayview Ave, Toronto, Ont, Canada M4N 3M5.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Shaw PJ, Bates D, Carlidge NEF, et al. Neurologic and neuropsychological morbidity following major surgery: comparison of coronary artery bypass and peripheral vascular surgery. Stroke 1987;18:700–7.
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3. Ginsberg MD, Sternau LL, Globus MY, Deitrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to brain injury. Cerebrovasc Brain Metab Rev 1992;4:190–225.
4. Deitrich WD. The importance of temperature in cerebral injury. J Neurotrauma 1992;9(Suppl 2):S475–84.
5. McLean RF, Wong BI, Naylor CD, et al. Cardiopulmonary bypass, temperature, and central nervous system dysfunction. Circulation 1994;90(Suppl 2):250–5.
6. Singh AK, Bert AA, Feng WC, Rotenberg FA. Stroke during coronary artery bypass grafting using hypothermic versus normothermic perfusion. Ann Thorac Surg 1995;59:84–9.[Abstract/Free Full Text]
7. Morikawa E, Ginsberg MD, Dietrich WD, et al. The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1992;12:380–9.[Medline]
8. Stockard JJ, Bickford RG, Schauble JF. Pressure dependent cerebral ischemia during cardiopulmonary bypass. Neurology 1973;23:521–9.[Free Full Text]
9. Minamisawa H, Smith M, Saisjo BK. The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol 1990;28:26–33.[Medline]
10. Dietrich WD, Busto R, Halley M, Valdes I. The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990;49:486–97.[Medline]
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12. Van der Linden J. Cerebral hemodynamics after low-flow versus no-flow procedures. Ann Thorac Surg 1995;59:1321–5.[Abstract/Free Full Text]
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