Cognitive Deficit After Aortic Valve Replacement

Transcription

1 Cognitive Deficit After Aortic Valve Replacement Daniel Zimpfer, MS, Martin Czerny, MD, Juliane Kilo, MD, Marie-Theres Kasimir, MD, Christian Madl, MD, Ludwig Kramer, MD, Georg M. Wieselthaler, MD, Ernst Wolner, MD, and Michael Grimm, MD Departments of Cardio-Thoracic Surgery and Internal Medicine, Vienna General Hospital, University of Vienna, Vienna, Austria Background. Impairment of cognitive brain function after coronary artery bypass grafting (CABG) is well known. In contrast the potential neurocognitive damage related to aortic valve replacement (AVR) is uncertain. Methods. In this contemporary case-matched control study we followed 30 patients (mean age 70 years) receiving isolated AVR with a biological prosthesis. A cohort of sex-and age-matched patients (n 30, mean age 70 years) receiving CABG with cardiopulmonary bypass served as controls. Cognitive brain function was measured by means of auditory evoked P300 potentials (peak latencies, ms) before the operation and 7 days and 4 months after the operation. Additionally, two standard psychometric tests (Mini-Mental State Examination and the Trailmaking Test A) were performed. Results. In preoperative measures there was no difference between patients undergoing AVR and patients undergoing CABG (AVR ms, CABG ms, p 0.629). One week after surgery P300 peak latencies were prolonged (impaired) in both groups compared with preoperative values (AVR ms, p 0.001; CABG ms, p 0.004). At this point of follow-up there was no difference between the groups (p 0.607). Finally, 4 months after surgery P300 auditory evoked potentials returned to normal in the CABG group ( ms, p 0.940) while in contrast in the valve group they continued to become prolonged (worsened) compared with preoperative values ( ms, p 0.005). At this time of follow-up P300 peak latencies were prolonged in AVR patients as compared with CABG patients (p 0.032). The Trailmaking Test A and Mini- Mental State Examination failed to discriminate any difference. Conclusions. Four-month impairment of cognitive brain function is more pronounced in patients undergoing biological AVR as compared with age-matched control patients undergoing CABG. Further studies are needed to clarify the potential pathologic mechanisms causing an ongoing cognitive impairment in patients with biological aortic valve prostheses. (Ann Thorac Surg 2002;74:407 12) 2002 by The Society of Thoracic Surgeons Accepted for publication March 28, Address reprint requests to Dr Grimm, Department of Cardio-Thoracic Surgery, University of Vienna, Waehriger Guertel 18-20, A-1090 Vienna, Austria; michael.grimm@akh-wien.ac.at. Cognitive brain dysfunction after open heart surgery with cardiopulmonary bypass (CPB) has tremendous social and economical impact. It affects quality of life and has profound implications because neurocognitive impairment prolongs in hospital stay and increases use of resources [1, 2]. Despite technical improvement of CPB circuits resulting in less systemic activation and consecutively less systemic inflammatory response cognitive dysfunction appears in 30% to 70% of patients undergoing open heart surgery with CPB [3, 4]. Evoked potential measurements detected by cortical leads, representing stable sequences of negative and positive electroencephalogram peaks within a period of several hundred milliseconds, are a highly sensitive and reproducible tool for evaluation of cognitive and neuronal brain dysfunction caused by various disorders [5 9]. Cognitive P300 auditory evoked potentials elicited by a tone discrimination paradigm are objective measures related to information and cognitive processing which therefore allow a quantification of cognitive brain dysfunction [9, 10]. Furthermore the low coefficient of intraindividual test-retest variation of below 2% in cognitive P300 auditory evoked potential measurement, which is of particular importance in follow-up assessments, demonstrates its usefulness in patients after cardiac surgery [7, 17, 29] The aim of this study was to compare postoperative cognitive deficit by objective P300 auditory evoked potentials and standard psychometric tests in patients undergoing aortic valve replacement (AVR) with an biological prosthesis and coronary artery bypass grafting (CABG). Patients and Methods Patients After approval was obtained by the Ethics Committee of the University of Vienna 30 consecutive survivors (mean age years) undergoing aortic valve replacement with a biological prosthesis were enrolled in this prospective study. Thirty patients undergoing standard CABG with CPB (mean age 70 7 years) served as ageand sex-matched controls. Exclusion criteria included a hemodynamically relevant carotid artery stenosis (of more than 75%) and a history of one of the following medical conditions: prior stroke with residual deficit, 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 408 ZIMPFER ET AL Ann Thorac Surg COGNITIVE DEFICIT AFTER AORTIC VALVE REPLACEMENT 2002;74: uncontrolled hypertension, psychiatric illness requiring treatment, alcoholism, renal disease (defined as a creatinine more than 2.0 mg/dl), active liver disease or presence of significant aortic sclerosis in routinely performed intraoperative transesophageal echocardiography (TEE). Narcotics for pain relieve were restricted to the time of chest tube drainage. Chest tubes were removed on postoperative day 2. All investigations were performed by the same investigator who was blinded to the group classification (single blind, prospective design). Preoperative Risk Stratification Preoperative risk stratification was performed using the EuroSCORE (European System for Cardiac Operative Risk Evaluation). The EuroSCORE is a risk stratification system to help in the assessment of quality of cardiac surgical care. The score consists of patient-, cardiac-, and operation-related factors [11]. Neuropsychological Testing Neuropsychological testing and physical examinations were completed preoperatively and 7 days and 4 months after surgery. The investigator performing the preoperative and postoperative assessments was blinded to the group classification of each patient. Neuropsychological testing consisted of auditory P300 evoked potentials, Mini-Mental State Examination (MMSE), and Trailmaking Test A. AUDITORY P300 EVOKED POTENTIALS. Cognitive P300 auditory evoked potentials were recorded with Ag/AgCl electrodes on a Nicolet 2000 (Nicolet, Madison, WI). P300 evoked potentials were generated after a binaurally presented tone discrimination paradigm (odd-ball paradigm) with frequent (80%) tones of 1000 Hz and rare (20%) target-tones of 2000 Hz at 75 db HL. Filter bandpass was 0.01 to 30 Hz. Active electrodes were placed at Cz (vertex) and Fz (frontal) and referenced to linked earlobe A12 electrodes (10/20 international system). During the paradigm the subjects were instructed to keep a running mental count of the rare 2000 Hz target tones. To verify attention, P300 recordings with a discrepancy of more than 10% between the actual number of stimuli and the number counted by the subjects were rejected and repeated. P300 evoked potential recording resulted in a stable sequence of positive and negative peaks. Latencies (ms) of the cognitive P300 peak were assessed. To confirm reproducibility two sets of P300 measurements were recorded in all patients. To avoid any influence of biorhythm alteration all study measurements were performed in the afternoon under comparable conditions by the same physician. Special care was taken that studied patients were free from narcotics or sedatives for at least 48 hours. PSYCHOMETRIC TESTS. Immediately after P300 recording, the standard psychometric tests Trailmaking Test A and MMSE were performed to test cognitive impairment and psychometric performance. To minimize learning effects, five different Trailmaking Tables were randomly used. The Trail Making Test (Trails; part A) requires subjects to connect, by drawing a line, a series of numbers and letters in sequence (ie, 1-2 3) as quickly as possible [12]. The MMSE is a widely used method for assessing cognitive mental status. It assesses orientation, attention, immediate and short-term recall, language, and the ability to follow simple verbal and written commands. Furthermore it provides a total score that places the subject on a scale of cognitive function [13]. Anticoagulation Regimen AVR PATIENTS. Perioperative IE/d Dalteparin- Natrium (Fragmin; Pharmacia and Upjohn GmbH; Vienna, Austria) was started on day 5 with Phenoprocoumon (Marcumar; Roche Austria GmbH, Vienna, Austria) for 2 months (targeted international normalized ratio [INR] range: 2 to 3; targeted INR: 2.5). In case of persistent atrial fibrillation (AF) Phenoprocoumon was continued (targeted INR range: 2 to 3; targeted INR: 2.5). In case of sinus rhythm patients were switched to low-dose aspirin (Thrombo Ass; Lannacher Heilmittel GmbH, Lannach, Austria). CABG PATIENTS. Perioperative IE/d low-molecularweight heparin Dalteparin-Natrium (Fragmin), and in case of AF IE Dalteparin-Natrium, and aspirin (Thrombo Ass) was started on postoperative day 1 life long. In case of persistent AF Phenoprocoumon was continued (targeted INR range: 2 to 3; targeted INR: 2.5). Follow-up In addition to the neuropsychological testing patients were studied by means of echocardiography, electrocardiography, blood tests, and clinical investigation at all points of follow-up. Anesthesia and Surgical Procedure Patients were premedicated with midazolam. Additionally midazolam in 1 mg increments was administered intravenously as needed for general anesthesia with midazolam, ethmidate, fentanyl, and pancuronium. Patients were ventilated with oxygen in air; ventilation was set to a tidal volume of 8 ml/kg and a respiratory rate of 12/min, PEEP 5. The TEE probe was placed after anesthetic induction in all patients. The TEE views used to assess regional wall motion abnormalities included the transesophageal four- and two-chamber views and the transgastric short- and long-axis views. Surgical access in both groups was gained through a median sternotomy. All patients underwent normothermic CPB with intermittent cold blood cardioplegia with a hot shot before opening the cross clamp. The CPB circuit consisted of a hollow-fiber oxygenator (Bard HF 5701; C.R. Bard, Havorhill, MA) and a lining system primed with ringer lactate, mannitol, heparine, and apoproteine. Flow during CPV was maintained at 2.5 l min 1 m 2. Blood cardioplegia was maintained at 4:1 ratio. Hematocrit was kept above 20% with packed red blood cells if necessary. Perfusion pressure during CPB was kept above 50 mm Hg with phenylephrine if necessary. Before

3 Ann Thorac Surg ZIMPFER ET AL 2002;74: COGNITIVE DEFICIT AFTER AORTIC VALVE REPLACEMENT 409 Table 1. Patient Characteristics Variable AVR CABG p Value Number Age Ejection fraction (%) Diseased vessels (n) Peak gradient (mm Hg) EuroSCORE Data are reported as mean SD. AVR aortic valve replacement; graft surgery. opening of cross-clamp as well as weaning from cardiopulmonary bypass careful deairing was performed through the apex of the heart and the ascending aorta under continuous inflation of the lungs. This was vigorously controlled by TEE monitoring. Heparin was antagonized with protamine sulfate until preoperative activated clotting time was achieved. Mean arterial pressure after CPB was kept above 60 mm Hg with volume and vasoactive drugs as appropriate. Intensive care unit treatment was performed according to institutional standards. Statistical Analysis Data are reported as mean SD. Comparison of P300 auditory evoked potentials and standard psychometric tests were performed using two-way analysis of variance (ANOVA) after testing for normality of distribution. Categoric variables were compared using the 2 test or Fisher s exact test as appropriate. Values of p less than 0.05 were considered as significant, two sided. The study was analyzed using SAS software, version 8 (SAS Institute, Cary, NC). Results CABG coronary artery bypass Thirty elective patients receiving aortic valve replacement at our institution were prospectively observed. These patients were age and sex matched with a cohort of patients receiving elective CABG with CPB. Preoperative risk measured with EuroSCORE (AVR versus CABG , p ) as was higher in the valve group. Patient characteristics are given in Table 1. Clinical Outcome As only survivors entered this prospective study, operative mortality was 0%. In the period of follow-up there was no death in either group. Although operation time was higher in the CABG group (AVR 193 minutes versus CABG 227 minutes, p 0.043) CPB times were comparable (AVR 92 minutes versus CABG 88 minutes, p 0.677). One patients in the CABG group had a postoperative myocardial infarction (defined as any new Q wave or loss of R in the electrocardiogram, significant creatinine kinase-mb elevation [ 40 U/L]). There was no postoperative stroke. A total of 27 patients developed postoperative atrial fibrillation (AVR n 10 versus CABG n 7, p 0.344). Reexploration for bleeding was performed in 1 patient in the AVR group. On the first postoperative day, 2 patients in the CABG group had transitory psychotic syndrome (defined as preserved wakefulness with affective liability and disorientation, which completely resolved with 24 hours) [37]. Clinical outcome is shown in Table 2. Objective P300 Auditory Evoked Potentials In preoperative measures there was no difference between patients undergoing aortic valve replacement (AVR) and patients undergoing CABG (AVR ms versus CABG ms, p 0.629). One week after surgery P300 peak latencies were prolonged (impaired) in both groups compared with preoperative values (AVR ms versus ms preoperative, p 0.001; CABG ms versus ms preoperative, p 0.004). At this point of follow-up there was no difference between the groups (p 0.607). Finally, 4 months after surgery P300 auditory evoked potentials returned to normal in the CABG group ( ms versus ms preoperative, p 0.940) whereas in contrast in the AVR group they continued to become prolonged (worsened) compared with preoperative values ( ms versus ms preoperative, p 0.005). At 4 months of follow-up P300 measures were worse in AVR patients as compared with CABG patients (p 0.032; Fig 1). Standard Psychometric Tests To detect clinically overt changes of cognitive brain function we used the MMSE and Trailmaking Test A. Both tests showed no statistically significant changes throughout the study period. This finding only suggests that all patients were without clinical neurologic problems. Results of Trailmaking Test A and MMSE are given in Table 3. Table 2. Clinical Outcome Variable AVR CABG p Value Operative data Operation time (min, mean SD) Cardiopulmonary bypass time (min, mean SD) Grafts (n, mean SD) Major adverse events Death (n) 0 0 NS Myocardial infarction (n) 0 1 NS Stroke (n) 0 0 NS Bleeding (n) 1 0 NS Minor adverse events Transitory psychotic syndrome (n) Atrial fibrillation (postoperative) Atrial fibrillation (4 months) Infection (n) AVR aortic valve replacement; graft surgery. CABG coronary artery bypass

4 410 ZIMPFER ET AL Ann Thorac Surg COGNITIVE DEFICIT AFTER AORTIC VALVE REPLACEMENT 2002;74: Fig 1. P300 auditory evoked potentials: graph shows serial assessments of cognitive brain function by P300 auditory evoked potentials. The solid line represents coronary artery bypass graft surgery patients, the dotted line aortic valve replacement patients. *p 0.05 compared with preoperative values. p 0.05 within the two groups. Comment In this prospective series we found by objective P300 auditory evoked potentials that patients undergoing AVR with a biological prosthesis and CABG have markedly decreased cognitive brain function in postoperative measures (7 days). Most important, in 4-month follow-up cognitive brain dysfunction returns to normal in patients undergoing CABG, whereas it persists or even worsens in patients after AVR. Postoperative cognitive dysfunction has been reported to occur in 30% to 70% of patients undergoing open heart surgery with CPB [2 4, 15]. The most frequently reported deficits related to surgery with CPB are those of concentration, memory, and learning, and speed of visual-motor response [16]. We have to keep in mind that neurologic and neuropsychological impairments related to CPB are not only disconcerting and demoralizing and therefore affect the daily life of patients but also have tremendous social and economic implications [4]. In 7-day postoperative investigations we found that both patient groups exhibited a similar extent of impaired cognitive processing. It is generally suspected that postoperative cognitive decline may be caused by impaired cerebral perfusion during CPB and postoperative systemic inflammatory response as well as microembolism and macroembolism [2, 15]. Comparing two different types of operative procedures AVR versus CABG we speculate now that perioperative cognitive decline seems to reflect primarily extensive operative trauma (eg, tissue trauma, use of CPB, and potential systemic inflammation) mimicking the potential impact of factors particularly related to the type of operative procedure (eg, air embolism, particulate matter, blood-valve prosthesis interaction in AVR versus, for example, partial crossclamping in CABG). Most interestingly, from 7-day through 4-month follow-up cognitive processing takes different courses. In CABG patients cognitive brain function normalizes again whereas in AVR patients (with biological valve prostheses) cognitive impairment continues. The reasons for this remain unclear and may only be for the moment subject to speculation. It seems likely that more extensive injury occurs during operation in the open heart AVR patients owing to potential particulate matter and air emboli. One might speculate now that in AVR patients this intraoperative damage may result in neurocognitive changes that persist or even worsen over time. This speculation is supported by data from Braekken and associates [17] who report that AVR leads to a higher number of intraoperative microemboli as compared with CABG. Another potential explanation may be the fact that the biological valve itself serves as a possible source of microemboli. Whereas cavitation phenomena do not seem likely in biological prostheses, disturbances at the blood valve-surface interface may be speculated (eg, subclinical insufficiency of anticoagulation regimen). Recently postoperative AF has been found to affect cognitive brain function [31]. We have found no difference in the occurrence of AF between CABG and AVR patients at 7-day and 4-month follow-up. Therefore the impact of AF on the diverging development of cognitive brain function in this study seems to be limited. To compare cognitive function between patients we used P300 auditory evoked potentials and standard psychometric tests. P300 peak latencies of auditory evoked Table 3. Scores on Tests of Neurocognitive Function Test a AVR p Value b CABG p Value b p Value c Mini-Mental State Examination Preoperative Seven-day follow-up Four-month follow-up Trialmaking Test A Preoperative Seven-day follow-up Four-month follow-up Data are reported as mean SD. a Higher scores indicate better cognitive brain function, with the exception of scores on the Trailmaking Test A for which lower scores indicate better cognitive function. b Versus preoperative. c Within the two groups.

5 Ann Thorac Surg ZIMPFER ET AL 2002;74: COGNITIVE DEFICIT AFTER AORTIC VALVE REPLACEMENT 411 potentials have widely been used to evaluate cognitive brain function in different diseases and have been proven in their usefulness for measuring cognitive brain function in patients undergoing open heart surgery [5 8, 18, 19]. In our series psychometric tests failed to reveal any subtle cognitive decline. This only suggests that all patients were without any overt neurologic disorders throughout the study period. It is generally accepted that psychometric tests are not without bias, eg, in part because of long performance times (stressing attention), visual impairment, influence of psychomotor function, level of education, or learning effects [19 21]. The latter are of particular interest for follow-up studies [22]. Cognitive P300 evoked potentials elicited by a tone discrimination paradigm represent an objective and valid measure of cognitive brain function. P300 peak latencies, which increase with age in healthy subjects, are related to cognitive impairment rating, rapid evaluation of cognitive function test, orientation, stimulus evaluation, selective attention, visual pattern recognition, and digit span and were shown to be much more sensitive in detecting metabolically induced cognitive brain dysfunction than psychometric tests or electroencephalograms [6, 8, 18, 23 29]. Moreover the P300 technique has a very low intraindividual test-retest variability with a coefficient of variation of 2%, which further stresses its usefulness for cognitive follow-up studies [5]. Limitations It has to be taken into account that cognitive brain function can be influenced by various biases in 4-month follow-up and that there might be confounding factors we did not list in this study. In the present study selected CABG-patients served as age-matched controls to patients after aortic valve surgery. Therefore the presented measures of P300 potentials are only valid for CABG patients in the mean age range of 70 years undergoing normothermic cardiopulmonary bypass. These data can not be extrapolated to other age ranges, different comorbidities (eg, diabetes mellitus, significant carotid artery stenosis), and perfusion protocols. From the present data we are also unable to totally exclude that 4-month cognitive impairment in AVR patients is only a result of extremely delayed return to normal values. Still, the major limitation of the present paper is that we are only able to show that a patient carrying a biological aortic valve prosthesis has a more pronounced cognitive deficit as compared with an age-matched CABG patient. As to potential pathologic mechanisms, we can only speculate and proceed with further studies. Taking these limitations into account we conclude that after a 4-month follow-up impairment of cognitive brain function is more pronounced in patients undergoing biological AVR as compared with sex- and age-matched CABG patients who served as controls. The underlying mechanisms of this particular ongoing cognitive damage need to be elucidated by further studies. We thank Daniela Dunkler, MS (Stat), for the statistical analysis of the work. References 1. Weintraub WS, Jones EL, Craver J, Guyton R, Cohen C. Determinants of prolonged length of hospital stay after coronary bypass surgery. Circulation 1989;80: Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996;335: Sotaniemi KA. Long-term neurologic outcome after cardiac operations. 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6 412 ZIMPFER ET AL Ann Thorac Surg COGNITIVE DEFICIT AFTER AORTIC VALVE REPLACEMENT 2002;74: impairment on neuropsychological test performance. J Clin Exp Neuropsych 1994;16: Rossini ED, Karl MA. The Trail Making Test A and B: a technical note on structural nonequivalence. Percept Mot Skills 1994;78: Conn HO, Lieberthal M. The hepatic coma syndromes and lactulose. Baltimore, MD: Williams and Wilkins, 1979: Gil R, Neau JP, Toullat G, Rivasseau-Jonveaux T, Lefevre JP. Maladie de Parkinson et potentiels évoqués cognitifs. Rev Neurol (Paris) 1989;145: Courchnesne E, Hillyard SA, Galambos R. Stimulus novelty, task relevance, and the visual potential in man. Electroencephalogr Clin Neurophysiol 1975;39: McCarthy G, Douchin E. A metric for thought: a comparison of P300 latency and reaction time. Science 1981;211: Hansen JC, Hillyard SA. Endogenous brain potentials associated with selective auditory attention. Electroencephalogr Clin Neurophysiol 1980;49: Ritter W, Simson R, Vaughan HG Jr, Macht M. Manipulation of event related potential manifestations of information processing stages. Science 1982;218: De Feo P, Gallai V, Mazzota G, et al. Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal men. J Clin Invest 1988;82: Ginn HE. Neurobehavioral dysfunction in uremia. Kidney Int 1975;7(suppl 2):S Kilo J, Czerny M, Gorlitzer M, et al. Cardiopulmonary bypass affects cognitive brain function after coronary artery bypass grafting. Ann Thorac Surg. 2001;72: Stanley TO, Mackensen GB, Grocott HP, et al. The impact of postoperative atrial fibrillation on neurocognitive outcome after coronary artery bypass graft surgery. Anesth Analg 2002;94: INVITED COMMENTARY The vulnerability of the brain during operations on the heart has always been recognized. In the 50 years of open heart surgery multiple etiologies of cerebral injury have been identified, both procedure-related and patientrelated, and mitigating strategies continue to occupy the attention of surgeons, anesthesiologists, and perfusionsists. Diagnosis and the audit of major neurological events present little difficulty. More problematic is the measurement of cognitive impairment. As doctors we recognize the central importance of cognitive function on the quality of life and its influence on survival. But the complexity of the human brain and the massive diversity of its functions and compensatory mechanisms has confounded numerous attempts to devise measures reliable and sensitive enough to guide the selection of therapeutic interventions. Measurement of auditory-evoked potentials has the superficial appeal of apparent simplicity, objectivity, and reproducibility, and therefore suitability for studying patients undergoing cardiac operations. Nevertheless, like neuropyschological tests, the results are heavily dependent on patient concentration and performance, and may also be influenced by electrode number and placement, and the physical condition of the patient, together with metabolic and pharmacological variables. Although auditory evoked potentials are known to be abnormal in overt clinical syndromes of neurological, hematological, metabolic, and toxic disorders, the significance of abnormal auditory potentials in subjects without such overt disorders remains unknown and speculative. The embolic potential of prosthetic heart valves is well known, and ultrasound Doppler studies of the middle cerebral artery in prosthetic valve recipients suggest ongoing asymptomatic microemboli events. Just as we do not really know what the cumulative effect of these microemboli adds up to in the longer term, we do not really know the long-term clinical or social cost of isolated deficits in neuropsychological tests or more specific measures like auditory-evoked potential after cardiac surgery. However, we are not surprised when another group of researchers informs us that aortic valve replacement has a greater effect on the brain in the short term than coronary bypass surgery. A major advantage of both cranial Doppler and auditory-evoked potential studies is their relative independence of the learning effects which reduce the reliability of multiple repeat neuropsychological tests. This advantage would best be explored in longitudinal studies over several years including comparison groups of patients undergoing nonvascular major surgery, and patients having percutaneous cardiological interventions. Longer-term data correlated to survival and quality of life scores might eventually identify the significance of these measures. Christopher I. Blauth, FRCS Cardiothoracic Centre Guy s & St. Thomas Hospital London SE1 7EH, England ciblauth@aol.com 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)