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Ann Thorac Surg 1999;68:2082-2088
© 1999 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Brain SPECT imaging and neuropsychological testing in coronary artery bypass patients

^a Department of Physical Medicine and Rehabilitation,, Virginia Mason Medical Center, Seattle, Washington, USA and Section of Nuclear Medicine
^b Department of Radiology, Virginia Mason Medical Center, Seattle, Washington, USA

Address reprint requests to Dr Hall, Section of Cardiothoracic Surgery, Virginia Mason Clinic, X3-CAR, 1100 Ninth Ave, Seattle, WA 98111
e-mail: r.alanhall{at}vmmc.org

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Patients and materials Results Comment References

 
Background. Cognitive deficits appear frequently after cardiac operation. While the etiology remains unclear, alterations in cerebral perfusion during cardiopulmonary bypass may be causative. Single photon emission computed tomography (SPECT) scanning utilizes a radiopharmaceutical to provide images of cerebral perfusion. We proposed to study the cerebral circulation of patients during coronary artery bypass operation employing cardiopulmonary bypass.

Methods. Thirty-five neurologically normal patients underwent preoperative SPECT brain scanning and neuropsychological testing. A second SPECT brain perfusion scan was obtained by administering the radioisotope during cardiopulmonary bypass, with subsequent scanning upon completion of the procedure. Postoperative neuropsychological testing was performed prior to discharge.

Results. Fourteen (40%) of patients demonstrated significant neuropsychological decline. Patients who suffered cognitive impairment were no different in demographic, general health, or surgical variables. Patients who demonstrated neuropsychological decline had significantly poorer cerebral perfusion both at baseline and during operation.

Conclusions. Impaired cerebral perfusion at baseline may identify patients at risk for cognitive injury after cardiac operation. Alterations in cerebral perfusion during cardiopulmonary bypass is common, and may be a factor in neuropsychological deficits seen after cardiac operation.

	Introduction

Top Abstract Introduction Patients and materials Results Comment References

 
Multiple authors have described the cognitive deficits which frequently appear after cardiac operation [1–8]. Such deficits, documented by repetitive neuropsychological testing, have been consistently noted in such domains as short-term memory, reasoning abilities, and fine motor function. While such deficits have been repeatedly demonstrated, their etiology remains unclear. While criticisms over the methodology employed in studies of neuropsychological deficits have recently been presented [9, 10], repetitive neuropsychological testing remains a reliable, and frequently utilized, method to assess cognitive and adaptive abilities. Successive neuropsychological testing can quantify cognitive change after medical or surgical intervention [11].

Single photon emission computed tomography (SPECT) occupies a prominent place in the realm of functional brain imaging, studies that evaluate metabolic or neurochemical processes of the central nervous system. A relatively new technology, SPECT utilizes technetium-based radioisotopes, attached to ligands, which are actively bound to cerebral endothelial membranes. The binding characteristics and prolonged half-life allow examiners to capture regional cerebral blood flow images by administering the radiopharmaceutical during the time to be studied (cardiopulmonary bypass) with subsequent brain scanning hours later.

This pilot study utilizes SPECT as a new technique in the study of cerebral perfusion in patients undergoing coronary artery bypass operation (CABG) employing cardiopulmonary bypass (CPB). We hypothesized that cerebral perfusion, as measured by SPECT brain scanning, is altered during CPB, as compared to the resting state. Furthermore, we hypothesized that those patients with the most compromised cerebral circulations will be prone to greater neurologic injury, as measured by serial neuropsychologic testing.

	Patients and materials

Top Abstract Introduction Patients and materials Results Comment References

 
Forty-one neurologically normal patients were enrolled after providing informed consent in an Institutional Review Board approved study (approved on February 20, 1997 and February 20, 1998). Patients had no history of stroke, transient ischemic attack, head injury, degenerative neurologic disease, or carotid artery disease, as identified by preoperative carotid ultrasound. All patients were in need of isolated CABG and all were classified as elective or urgent. Patient demographics are provided in Table 1.

SPECT brain perfusion scanning
All patients were imaged supine with an ADAC Dual Head Genesys Gamma Camera linked to a Pegasys computer system (ADAC Laboratories, Milpitas, CA). The SPECT tracer employed, ^99mTc Bicisate (Neurolite, DuPont Pharma, Wilmington, DE) is a technetium-based Federal Drug Administration (FDA) approved radioisotope, and has been shown comparable to ¹³³Xe and ^99mTc HMPAO in cerebral SPECT studies [12, 13]. Acceptability within subject reproducibility of technetium SPECT scans has been demonstrated, supporting its use in same subject repetitive scan studies [14]. 99mTc-Bicisate forms a stable lipophilic complex, crosses the blood-brain barrier, and is passively diffused across intact cell membranes. The radioisotope is stable within the brain, can be scanned up to 6 hours after injection, and yields a snapshot image of cerebral perfusion at the time the isotope was administered.

All patients were injected with 99mTc-Bicisate preoperatively and scanned 3 hours after radioisotope injection. Preoperative scans were performed 1 to 3 days prior to operation. Intraoperatively, the radioisotope was administered approximately 30 minutes after institution of CPB. Patients were scanned 3 hours after intraoperative injection; each injection consisting of 30 millicuries of 99mTc-Bicisate, a FDA approved dosage.

SPECT brain images are divided into 12 regions: (right and left) inferior and superior frontal lobes, medial and lateral temporal, and anterior and posterior parietal lobes. A Functional Brain Threshold Analysis program (ADAC Laboratories, Milpitas, CA) was utilized for scan analysis. This software program consists of a visual quantitation program based upon percentage thresholding to the mean pixel value in the visually normal cerebellar hemisphere(s). Perfusion abnormalities were defined as pixel counts equal to 80% or less as compared to the cerebellum. Cerebral perfusion scan results were also analyzed by neuroradiologists blinded to outcomes of cognitive testing. A total number of abnormal zones of cerebral perfusion was identified (range 0 to 12) for each patient.

Cardiopulmonary bypass and anesthesia
Induction was accomplished with midazolam (0.2 to 0.3 mg/kg). Fentanyl was utilized as indicated, subject to the judgment of the attending anesthesiologist. Intubation was facilitated with pancuronium (10 cc). Bolus or constant infusion of midazolam and fentanyl combinations were used as indicated, with supplementary pancuronium to provide adequate muscle relaxation. Isoflurane up to a maximum of 0.5% (end-tidal) was utilized to supplement anesthesia, as needed, throughout the case.

CPB was performed, following standard institutional protocol, with systemic cooling to 32°C. Perfusion pressures were maintained between 45 and 60 mm Hg with vasopressor (neosynephrine) or vasodilator (nitroglycerin) administered when necessary. Systemic flow rates were maintained between 2.0 and 2.4 L/min/m² and pH maintained by the alpha-stat method.

Neuropsychologic testing
Patients underwent a brief battery of neuropsychological tests assessing general cognitive functioning. The tests chosen were standardized neuropsychological instruments with well established clinical success in detecting brain impairment, and have been utilized in previous studies of cognitive injury after heart operation. The test battery consisted of parts A and B of the Trail Making Test [15], Digit Span Forward and Digit Span Backward Tests [16], and the Controlled Oral Word Association Test [17]. To measure current levels of depression, the Beck Depression Inventory [18] was also administered. All testing was performed by trained psychometricians, blinded to subject SPECT outcomes. Preoperative testing was typically done on an outpatient basis, 1 day prior to operation. Postoperative testing took place in either the subject’s hospital room prior to discharge or in a clinic room at the postoperative examination (mean = 5.74 days postoperatively, standard deviation = 4.09).

Statistical analysis
Preoperative, postoperative, and change scores on uncorrected raw test data for Digit Span Forward, Digit Span Reverse, Word Association, and time to complete Trail Making parts A and B, were calculated. Raw scores were subsequently converted to standard scores (Z-scores) by subtracting the sample mean and dividing by the standard deviation. Standardized Z-scores for all five tests were then summed to yield a single metric of preoperative neuropsychological test performance for each patient. The same methods were undertaken to standardize postoperative neuropsychological test scores and change scores. Patients were considered to have suffered a significant decline on neuropsychological testing if their total standardized change score was -1.0 or less. The resulting two groups (no deterioration versus deterioration) were then compared (Table 2).

	Results

Top Abstract Introduction Patients and materials Results Comment References

 
Complete data was available on 35 subjects. All patients survived operation and there were no obvious neurologic injuries. The typical patient was 66 years of age (8 women, 27 men) and had a preoperative ejection fraction of 57%. The average operation consisted of 3.4 bypass grafts with a bypass time of 82 minutes, cross-clamp time of 48 minutes, and mean perfusion pressure of 54 mm Hg (Table 1).

Forty percent (n = 14) of the subjects demonstrated neuropsychological decline in the early postoperative recovery period, as defined by a change in Z-score of -1.0 or less. Statistically significant group differences were demonstrated in standardized postoperative neuropsychological test scores (p = 0.012) and in standardized change scores (p = 0.0001), confirming the basis upon which the subjects were initially divided.

Comparing patients whose neuropsychological test scores deteriorated with the remaining subjects (Table 2), no significant differences were found in age, sex, or preoperative neuropsychological test performance. There was no evidence of depression as assessed by the Beck Depression Inventory in either group nor was there significant group differences in Beck scores either before or after operation. There were no significant differences between groups in general health variables (diabetes, hypertension, tobacco use), surgical variables (bypass time, cross-clamp time, perfusion pressure, ejection fraction), or preoperative medications (nitrates, calcium channel blockers, beta-blockers).

For all patients, preoperative baseline SPECT scans yielded an average of 5 areas of abnormal cerebral perfusion per subject (range 0 to 12, Figs 1–3). Similarly, the average number of perfusion abnormalities on intraoperative scan was 5 (range 0 to 12). Patients whose neuropsychological test performance deteriorated had significantly poorer cerebral perfusion on both preoperative baseline SPECT (p = 0.015) and intraoperative SPECT scans (p = 0.012).

View larger version (54K): [in this window] [in a new window]   Fig 1. (A) Preoperative baseline SPECT perfusion scan revealing moderate left frontal lobe abnormality. (B) Intraoperative scan (during cardiopulmonary bypass) of same patient showing severe frontal and temporal hypoperfusion.

View larger version (42K): [in this window] [in a new window]   Fig 2. (A) Midtransverse preoperative SPECT scan image showing near normal cerebral perfusion at baseline. (B) Intraoperative SPECT scan during cardiopulmonary bypass demonstrating severe bilateral frontal lobe hypoperfusion.

View larger version (114K): [in this window] [in a new window]   Fig 3. Preoperative baseline SPECT scan showing bilateral frontal and parietal hypoperfusion in a patient who suffered marked deterioration on serial neuropsychologic testing.

To further understand the relationships between neuropsychological, SPECT, and demographic variables, correlational analyses were performed. Preoperative SPECT results were negatively correlated with neuropsychological change (r = -0.32, p = 0.05), such that worse presurgical perfusion implied greater neuropsychological deterioration. Preoperative and intraoperative SPECT results were also highly correlated (r = 0.66, p = 0.001). Patients who demonstrated worse presurgical cerebral perfusion tended to do worse intraoperatively. Preoperative SPECT results were unrelated to age, but there was a nonsignificant trend for higher educational level to be associated with better preoperative perfusion (r = -0.29, p = 0.08). As expected, age was negatively correlated with both preoperative (r = -0.36, p = 0.03) and postoperative (r = -0.43, p = 0.009) neuropsychological test performance. Age was unrelated to neuropsychological change or to either preoperative or postoperative SPECT data. There was a nonsignificant trend for educational level to be correlated with neuropsychological change (r = 0.29, p = 0.08). Patients with higher educational levels tended to deteriorate less on test scores after CABG.

A stepwise regression analysis was utilized to isolate which variables might best predict postsurgical neuropsychological test scores. Presurgical test scores, presurgical SPECT data, intraoperative SPECT data, age, and education comprised the domain of possible independent variables. Variables were added in the order of accounting for the greatest amounts of variance (or residual variance) in postsurgical neuropsychological test scores. Variables were added only if their contribution to the final regression model was significant at the 0.05 level. Presurgical neuropsychological test scores and education were accepted into the model and accounted for 69% of the variance in postoperative test scores (r = 0.83, p = 0.0001).

The methodology of the current study has several limitations relating to both the neuropsychologic testing and SPECT imaging. As with many neuropsychologic test studies on CABG patients, a control group is lacking. As such, the influence on neuropsychological test scores of test-retest effects, normal test variability, and the effects of other factors, such as general anesthesia or medications, could not be determined. Such nonexperimental effects are distributed across all subjects and do not preclude detecting valid trends, or the association between cerebral perfusion as assessed by SPECT and neuropsychological impairment. Defining significant cognitive decline also proved problematic. Other authors, faced with the same limitations, have used a variety of techniques to identify which patients suffered meaningful cognitive injury after CABG. These have included dividing the subject population around the mean level of cognitive decline, or designating those subjects, who suffered a test decline of one standard deviation on one or more tests, to be significantly injured. Employing different definitions of significant impairment will yield different rates of injury, and may partially explain the confusion that exists regarding the incidence of neurologic injury after CABG. We have chosen to identify patients who have suffered serious short-term cognitive decline as those whose standardized change score is one or more standard deviation below the mean. Patients could thus be considered impaired after CABG, if there was at least a minimal general trend to do worse across most tests, or significant impairment on one or two. While imperfect, we believe this is a conservative measure of impairment. Many subjects assigned to the nonimpaired group demonstrated the expected improvement upon repeat neuropsychological testing. In the present study, some patients may have had postoperative cognitive decline of insufficient magnitude to overcome practice effects, and would have been included in the unchanged group.

In addition, long-term neuropsychological follow-up would have been helpful. Such data would help to discriminate the influence of early general perioperative effects from more permanent neurologic injury. Testing in this study was confined to the early postoperative period, and generalization to longer time intervals will require further study.

Employing SPECT to study the cerebral circulation during CPB is a novel method of looking at possible neurotoxic events. Much work remains to identify the parameters and characteristics of SPECT in such circumstances. SPECT test-retest reliability (stability) has been established for patients tested under similar environmental and hemodynamic conditions [14]. SPECT has been employed in the functional imaging of cognitive processes, and has been shown to be responsive to the internal cognitive state [19]. In our study, subjects first underwent SPECT evaluation awake in a nuclear radiology suite, and secondly under anesthesia in the operating room. Such dramatically different environmental conditions may render comparisons of preoperative and intraoperative SPECT results difficult [19, 20]. Yet, nearly 60% of subjects had no significant change in cerebral perfusion during CPB, as compared to baseline. We believe such consistency lends credibility to the use of SPECT in the study of cerebral perfusion during CPB. Additionally, lacking an established normative data base, defining abnormalities on SPECT imaging remains subjective.

Finally, there is an inherent selection bias in the patients enrolled in this study. Given the physical layout of our medical center, with operating rooms, intensive care units, and the department of neuroradiology all occupying separate floors, we selected patients we believed would most likely tolerate transportation and brain scanning immediately after operation. As these subjects constituted our healthiest patients, it seems unlikely that sicker individuals would have better cerebral perfusion, or would do better on serial cognitive testing.

	Comment

Top Abstract Introduction Patients and materials Results Comment References

 
We were surprised that many low-risk, neurologically intact patients would have such prevalent cerebral perfusion abnormalities in the resting state. Perhaps such regional perfusion abnormalities reflect the same vascular process that led to their coronary disease. Despite this finding, there was no observed relationship between presurgical SPECT abnormalities and presurgical neuropsychological status, suggesting that at baseline, patients are able to compensate for cerebral perfusion abnormalities. Over 40% of patients suffered worsening of cerebral perfusion during CPB as compared to the resting state, and while not attaining significance, there was a trend for these patients to do poorer on repetitive cognitive testing. This diminution of cerebral perfusion during CPB occurred in our healthiest patients, despite maintenance of traditionally accepted perfusion pressures and systemic flow rates.

Relatively preoperative hypoperfused patients were at greater risk for cognitive decline following CPB, and perfusion abnormalities preoperatively were correlated with poorer intraoperative perfusion. It has been suggested that cognitive decline in a number of neurologic conditions may not be manifest until a certain threshold for neuronal loss or impairment is reached [21]. Pathologic changes in such neurologic conditions as Parkinson’s disease, Alzheimer’s disease and multiinfarct dementia are present long before clinical symptoms are noted. Patients with a pathologic process affecting cortical neuronal reserve may appear neuropsychologically and clinically normal until some other challenge, such as CPB, is presented. Preoperative SPECT may identify patients with compromised cerebral perfusion, and although they are able to function normally, these individuals with minimal cortical reserve, have little tolerance for further neurologic injury. The insult of CPB, on an already compromised central nervous system, may result in clinical decompensation as documented by neuropsychologic testing.

Presurgical neuropsychological status and education explained the majority of the variance in postsurgical test scores during regression analysis. SPECT results were not entered into the model, though remain correlated with neuropsychological change scores. Educational level has been shown to be significantly related to the prevalence of neurologic conditions, such as Alzheimer’s disease, and may also reflect underlying cerebral reserve [22]. Patients who are most vulnerable to the deleterious effects of CPB may be those with preexisting vulnerability, as reflected in low education and/or altered cerebral perfusion.

While this small study suffers methodological limitations, we believe it supports the continued use of SPECT as a research tool in cardiovascular surgery. We have found that patients who suffer the greatest deterioration on serial cognitive testing have diminished cerebral perfusion, both at baseline and during CPB. If validated, SPECT may be a technique to study pharmacologic or other interventions, to favorably affect cerebral perfusion, attempting to maintain baseline cortical blood flow during CPB.

	Acknowledgments

 
This work was supported by a grant from the Washington American Heart Association.

	References

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