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Eur J Cardiothorac Surg 2003;23:544-551
© 2003 Elsevier Science NL

Neurocognitive deficit following aortic valve replacement with biological/mechanical prosthesis

^a Department of Cardio-Thoracic Surgery, Vienna General Hospital, University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria
^b Department of Internal Medicine, Vienna General Hospital, University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria

Received 30 August 2002; received in revised form 20 November 2002; accepted 17 December 2002.

^* Corresponding author. Tel.: +43-1-40400-5620; fax: +43-1-40400-5640
e-mail: michael.grimm{at}akh-wien.ac.at

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

 
Objective: The aim of this study was to objectively measure neurocognitive deficit following aortic valve replacement with a mechanical or biological prosthesis. Materials and methods: In this prospective, contemporary study we followed 82 consecutive patients undergoing isolated aortic valve replacement with either a mechanical (n=29, mean age=52±7 years) or a biological (n=53, mean age=68±10 years) valve prosthesis. Neurocognitive function was measured by means of objective P300 auditory evoked potentials (peak latencies, ms) and two standard psychometric tests (Trailmaking Test A, Mini Mental State Examination) before the operation, 7 days and 4 months after the operation, respectively. Results: Since P300 peak latencies increase with age, preoperative P300 measures are lower in patients receiving mechanical valves (360±35 ms, mean 52 years) as compared to patients receiving biological valves (381±34 ms, 68 years, P=0.0001). Seven days after surgery, P300 peak latencies were prolonged (-worsened) in both groups as compared to preoperative values (mechanical valves: 384±36 ms; P=0.0001 and biological valves: 409±39 ms; P=0.0001). Although on a different level (-age-related), this development was comparable within both groups (P=0.800). Four months after surgery, P300 peak latencies normalized in the mechanical valve group (372±27 ms, P=0.857 versus preoperative), while in contrast in the biological valve group they remained prolonged (417±37 ms, P=0.0001). We found no difference within patients receiving different types of biological or mechanical aortic valves. Conclusion: Postoperative neurocognitive damage is not reversible in (-elderly) patients with biological aortic valve replacement, while in contrast postoperative neurocognitive damage is reversible in (-younger) patients with mechanical valve replacement. For this contrary development, age seems to be most important, whereas damage related to type of valve prosthesis may be overestimated.

Key Words: Valve replacement • Neurocognitive function • Cardiopulmonary bypass

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

 
Neurocognitive deficit has increasingly been recognized as a complication of cardiac surgery as it has profound clinical and financial implications [1,2]. Whereas incidence, magnitude and time course of neurocognitive deficit after coronary artery bypass grafting are well documented, knowledge with regard to aortic valve surgery is rare. Data obtained in patients undergoing coronary artery bypass grafting cannot be extrapolated on patients undergoing aortic valve surgery as operative procedures are different, and the possible pathologic impact of different valve types is subject of discussion.

Using Transcranial Doppler Systems, mechanical aortic valve prostheses have been reported to produce significant higher numbers of cerebral emboli as compared to biological aortic valve prosthesis [3]. However, it is uncertain if emboli detected by Transcranial Doppler Systems have any impact on neurocognitive function and if there is a difference between mechanical and biological aortic valve prostheses [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 the evaluation of neurocognitive function. 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 function [5–10].

The aim of this prospective study was to objectively measure neurocognitive deficit after biological and mechanical aortic valve replacement and to elucidate if the type of prosthesis has any impact on neurocognitive function 4 months after surgery.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

 
2.1. Patients
After approval was obtained by the Ethics Committee of the University of Vienna 53 consecutive patients undergoing aortic valve replacement with a biological prosthesis (mean age=73±5 years) and 29 patients undergoing aortic valve replacement with a mechanical prosthesis (mean age=58±9 years) were enrolled in this prospective study. Exclusion criteria were: (1) a haemodynamically relevant carotid artery stenosis (of more than 75%) and a history of one of the following medical conditions; (2) prior stroke with residual deficit; (3) uncontrolled hypertension; (4) psychiatric illness requiring treatment; (5) alcoholism; (6) renal disease (defined as a creatinine more than 2.0 mg/dL); and (7) active liver disease. 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).

2.2. Preoperative risk stratification
Preoperative risk stratification was performed using the EuroSCORE. EuroSCORE stands for 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].

2.3. Neurocognitive testing
Neurocognitive testing and physical examinations were completed preoperatively, 7 days and 4 months after surgery, respectively. All examinations were performed by the same investigator who was blinded to the group classification of each patient. Neurocognitive testing consisted of P300 auditory evoked potentials, Mini Mental State Examination, and Trailmaking Test A. To avoid any influences due to biorhythm, all investigations were performed in the afternoon under comparable conditions.

2.4. P300 auditory evoked potentials
Objective P300 auditory evoked potential are the result of an activation of a widespread network of cortical structures, including association areas in the parietal, temporal and prefrontal cortex, as well as the hippocampus [12]. As a result of the involvement of many brain regions in the P300 generation the P300 can be used as a general indicator for neurocognitive function [5–10]. Objective P300 auditory evoked potentials were recorded with Ag/AgCl electrodes on a ‘Nicolet 2000’ (Nicolet, Madison, WI). P300 evoked potentials were generated following 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 0.01–30 Hz. Active electrodes were placed at Cz (vertex) and Fz (frontal), respectively, and referenced to linked earlobe A1/2 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 >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. Special care was taken that studied patients were free from narcotics or sedatives for at least 48 h.

2.5. Psychometric tests
Immediately after P300 recording, the standard psychometric tests Trailmaking Test A (TTA) and Mini Mental State Examination (MMSE) were performed to test neurocognitive impairment and psychometric performance. To minimize learning effects, five different Trailmaking Tables were randomly used. The Trail Making Test (part A) requires subjects to connect, by drawing a line, a series of numbers and letters in sequence (i.e. 1-2-3) as quickly as possible [13]. The MMSE is a widely used method for assessing neurocognitive 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 individual on a scale of cognitive function [14].

2.6. Follow-up
In addition to neurocognitive testing, patients were studied by means of echocardiography, ECG, blood tests and clinical investigation at all points of follow-up. Echocardiography was used to assess functional state of heart valves and to assure that all patients were free from LV-thrombus during the period of follow-up.

2.7. Anaesthesia and surgical procedure
Patients were premedicated with midazolam. Additionally midazolam in 1 mg increments was administered intravenously as needed for general anaesthesia 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, positive endexpiratory pressure (PEEP) 5. Transesophageal echocardiography (TEE) probe was placed after anaesthetic 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 via a median sternotomy. All patients underwent mildly hypothermic cardiopulmonary bypass (CPB; 35°C) 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 Inc, Havorhill, MA) and a lining system primed with ringer lactate, mannitol, heparin and apoprotein. Flow during CPB was maintained at 2.5 l/min per m². Blood cardioplegia was maintained at 4:1 ratio. Haematocrit was kept above 20% with packed red blood cells if necessary. Perfusion pressure during CPB was kept above 50 mmHg with phenylephrine if necessary. Before opening of cross-clamp as well as weaning from cardiopulmonary bypass careful deairing was performed via 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 protamin sulfate until preoperative activated clotting time was achieved. Mean arterial pressure after CPB was kept above 60 mmHg with volume and vasoactive drugs as appropriate. ICU treatment was performed according to institutional standards.

2.8. Anticoagulation
2.8.1. Mechanical valve replacement
Perioperative 2x7500 IE/d low molecular weight heparin Dalteparin-Natrium (Fragmin^®, Pharmacia & Upjohn GmbH; Vienna, Austria), on day 5 start with Phenoprocoumon (Marcumar^®; Roche Austria GmbH; Vienna, Austria) life long (targeted INR range: 2.5–3.5; targeted INR: 3.0). No change in anticoagulation regime in patients with atrial fibrillation.

2.8.2. Biological valve replacement
Perioperative 2x5000 IE/d low-molecular weight heparin Dalteparin-Natrium (Fragmin^®, Pharmacia & Upjohn GmbH; Vienna Austria); in case of atrial fibrillation 2x7500 IE Dalteparin-Natrium. On day 5 start with Phenoprocoumon (Marcumar^®; Roche Austria GmbH; Vienna, Austria) for 4 months (targeted INR range 1.4–2.5; targeted INR 2.0). After that Aspirin (Thrombo Ass^®; Lannacher Heilmittel GmbH; Lannach, Austria) life long; in case of persistent atrial fibrillation Phenoprocoumon (Marcumar^®; Roche Austria GmbH; Vienna, Austria) life long (targeted INR range 1.4–2.8, targeted INR 2.0).

2.9. Statistical analysis
Data are reported as mean±SD. Comparison of P300 auditory evoked potentials and standard psychometric test were performed using analysis of variance after testing for normality of distribution. The time course of neurocognitive brain function was analyzed by means of paired t test for the different groups. Furthermore, to identify patients with neurocognitive deficit at 7-day as well as 4-month follow-up, neurocognitive deficit was defined as a decline of more than 1 standard deviation as compared to preoperative measures. Categorical variables were compared using the Chi-Square test or Fisher's exact test as appropriate. P-values <0.05 were considered as significant, two sided. The study was analyzed using SAS, version 8.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

 
Eighty two consecutive patients undergoing aortic valve surgery (biological valve replacement n=53, mechanical valve replacement n=29) at our institution were prospectively followed. Age and preoperative risk measured using the EuroSCORE were higher in patients undergoing biological aortic valve replacement. Patient characteristics are given in Table 1. A detailed information on the used mechanical and biological aortic valves is given in Table 2.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Linear regression analysis showing age dependence of preoperative peak latencies. Individual measurements are indicated by dots.

View larger version (11K): [in this window] [in a new window]   Fig. 2. Graph showing serial assessments of cognitive brain function by P300 auditory evoked potentials. The solid line represents patients with biological aortic valves, the dotted line patients with mechanical aortic valves. *P<0.05 compared with preoperative values. P<0.05 within the two groups.

View larger version (22K): [in this window] [in a new window]   Fig. 3. (a) Graph showing serial assessments of cognitive brain function by P300 auditory evoked potentials in patients with mechanical aortic valves. ---- Medtronic Hall mechanical aortic valveTM; - - - - Carbomedics mechanical aortic valveTM; -·-·-·-· Edwards Mira mechanical aortic valveTM; and --··--··--Medtronic Mosaic mechanical aortic valveTM. On-XTM mechanical aortic valve. (b) Graph showing serial assessments of cognitive brain function by P300 auditory evoked potentials in patients with biological aortic valves. ---- Carpentier Edwards biological aortic valveTM; and - - - - Medtronic Mosaic biological aortic valveTM.

3.3. Standard psychometric tests
To detect clinically overt changes of neurocognitive function we used ‘MMSE’ and ‘TTA’. Both tests showed no statistically significant changes throughout the study period. This only suggests that all patients were without clinical neurological problems. Results of TTA and MMSE are given in Table 4.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

Deficits in memory, learning, concentration and visual motor response – known as neurocognitive deficit – affect up to 80% of patients undergoing open heart surgery with CPB [2,15,16]. The clinical and financial implications of neurocognitive deficit are profound, since major and even minor neurocognitive disturbances are associated with prolonged hospitalization and a prolonged process of rehabilitation, causing an increased use of resources [1,2]. In addition to this – and at least of equal importance, neurocognitive deficit is demoralizing and disconcerting for the patient and his family. The importance of postoperative neurocognitive deficit may be underlined by the finding that neurocognitive decline at hospital discharge is an independent predictor for neurocognitive impairment 5 years after surgery [16].

At 7-day follow-up, impairment of neurocognitive processing was similar within patients after mechanical/biological aortic valve replacement. Although change of neurocognitive function took place on a different level – as a result of age dependency of P300 peak latencies (Fig. 1) – incidence and amount were comparable. This strongly indicates that 7-day postoperative neurocognitive deficit relates to the operative procedure and operative trauma and not to the type of valve used (biological/mechanical). Possible mechanism of postoperative neurocognitive decline are inadequate cerebral perfusion during CPB, intraoperative micro (particles of less than 200 µm in diameter) and macroembolism as well as postoperative systemic inflammatory response [2,15]. As a result of the operative procedure (e.g. crossclamping of calcified aorta, opening of the ascending aorta, cutting out of severely calcified valves, decalcification of the valvular ring), patients undergoing aortic valve surgery are at special risk to exhibit intraoperative cerebral microembolism.

Thereafter, 4 months after surgery, neurocognitive deficit resolved in patients with mechanical aortic valve replacement, while in contrast there was lack of neurocognitive recovery in patients with biological aortic valve replacement. This finding suggests a different pathophysiology of postoperative neurocognitive decline. Patients with biological valves are older in this series and are therefore prone to have increased atherosclerosis of the ascending aorta and occult cerebrovascular disease [17]. Advanced atherosclerosis of the ascending aorta is a possible source for emboli (consisting of particular matter) entering the cerebral blood circuit and therefore a major risk factor for cerebral embolism resulting in major neurological and neurocognitive deficit [18]. The potential contribution of occult cerebral arterial disease to neurocognitive deficit remains uncertain. Taking this into account, more severe – and probably irreversible operative damage – seems to occur in (-elderly) patients with biological aortic valve replacement. In addition to this, younger patients (receiving mechanical aortic valves) have a higher physiologic reserve enabling them to compensate for operative damage.

Not a single patient (independent whether mechanical and biological group) who presented free from neurocognitive damage at 7-day measurement, developed neurocognitive impairment at 4-month follow-up. Using Transcranial Doppler Systems, both mechanical as well as biological valves have been shown to cause cerebral embolism (detected as high intensity transient signals, HITS) [3,4]. Nevertheless, a correlation between number of HITS and neurocognitive deficit is uncertain [4]. Since we found no new onset of neurocognitive deficit in the follow-up period (7-day through 4-months), we may estimate that the role of different valve prosthesis seems to be of minor importance. Nevertheless, the impact of cerebral emboli produced by prosthetic cardiac valves might summate and therefore might become evident to a later time point, which is not covered by the present measurements.

Neurocognitive function was objectively measured using a previously described diagnostic tool consisting of objective P300 auditory evoked potentials and two standard psychometric tests [8,19–22]. Objective P300 evoked potentials, elicited by a tone discrimination paradigm, represent an objective and valid measure of neurocognitive function [6,8–10]. P300 peak latencies, increasing with age in healthy subjects were shown to be related to neurocognitive impairment rating, rapid evaluation of cognitive function test, orientation, stimulus evaluation, selective attention, visual pattern recognition, and digit span and were shown P300 auditory evoked potentials were shown to be much more sensitive in detecting neurocognitive function than psychometric tests or electroencephalograms [6–10]. Moreover, the P300 technique has a very low intra-individual test-retest variability, with a coefficient of variation of below 2%, which further stresses its usefulness for neurocognitive follow-up studies [5,6,8–10,19,20,22]. In our series psychometric tests failed to reveal any subtle cognitive decline suggesting that all patients were without any overt neurological disorders throughout the study period. It is generally accepted that psychometric tests are not without bias, e.g. in part because of long performance times (stressing attention), visual impairment (of special interest in elderly patients, influence of psychomotor function, level of education, or learning effects [23,24]. The latter are of particular interest for follow-up studies.

4.1. Limitations
The primary limitation is that patients did not receive valve types in a randomized fashion. A randomized fashion would be necessary to differentiate influence of age and valve type in an independent manner, which was not possible in this study as age and valve type are dependent variables. However, it would be ethically questionable to randomize patients to biological and mechanical valve prostheses. A paired comparison of patients receiving biological and mechanical aortic valves did not enter this study, as the majority of patients receiving mechanical valves suitable for paired comparison suffered form chronically atrail fibrillation. We neither performed transcranial doppler measurements intraoperatively nor during the period of follow-up. The reason for this is the inability of currently available transcranial doppler systems to differentiate between size and nature (particular/gaseous) of emboli. It seems plausible that more severe damage is caused by particular emboli. Therefore data obtained by the currently available transcranial doppler systems might be misleading. From the present data we unable to exclude an extremely delayed return of neurocognitive function in patients with biological aortic valves.

Taking these limitations into account we conclude that postoperative neurocognitive damage is not reversible in (-elderly) patients with biological aortic valve replacement, while in contrast postoperative neurocognitive damage is reversible in (-younger) patients with mechanical valve prosthesis. For this contrary development, age seems to be much more important, while damage related to type of valve prosthesis may be overestimated.

	Acknowledgments

 
We thank Daniela Dunkler, MSc (Stat), for the statistical analysis of the work.

	Footnotes

 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.

	Appendix A. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

 
Dr J. Revuelta (Santander, Spain): You were not able to randomize this study. If you were able to randomize it, let's say, with patients 65 years old, are you expecting the same results with mechanical versus biological valves, or in your opinion there will be a significant difference.

Dr Zimpfer: I guess that, at least, our results show that the type of valve prosthesis used has no further influence on neurocognitive function. And what we primarily found is that elderly patients are more vulnerable to the operative procedure.

Dr L. Cohn (Boston, MA): I'd like to ask one question. If you took just people over 65 or 70 with either valve type, was there any difference in these neurocognitive functions?

Dr Zimpfer: We only have a few elderly patients in this study, who were treated with mechanical aortic valves. All those patients had chronic arterial fibrillations. Therefore it is hard to draw any conclusions from the findings in these patients.

Dr Cohn: So you had nobody older in sinus rhythm with a mechanical heart?

Dr Zimpfer: No, we didn't have.

Dr Cohn: I see. Well, I think, just as a comment, I think that would be very important, because the implication is that age rather than the type of valve device is perhaps more important. Is that what you conclude?

Dr Zimpfer: That's our conclusion.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Discussion References

 

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