Ventricular assist devices (VADs) are an accepted treatment for patients with life-threatening, terminal heart failure as bridge to cardiac transplantation. Both continuous and pulsatile blood flow devices are widely used.1 However, the impact of devices with chronic continuous blood flow on end-organ function is subject of discussion, because data regarding the effects of nonpulsatile organ perfusion are limited.
The aim of this prospective study was to objectively measure the impact of VADs producing pulsatile and continuous blood flow on neurocognitive function by means of cognitive P300 evoked potentials.
Materials and Methods
After approval was obtained from the Ethics Committee of the University of Vienna, 29 consecutive survivors of VAD implantation gave their written and informed consent and were enrolled in this prospective study. During the recruiting period, two patients fulfilling the inclusion criteria were not included because they were in severe cardiogenic shock and written and informed consent could not be obtained. Exclusion criteria were a history of one of the following medical conditions: (1) prior stroke with residual deficit, (2) death, (3) renal disease (defined as a creatinine more than 2.0 mg/dl [177 μmol/l]), (4) active liver disease, and (5) stroke/cerebral hemorrhage during the follow-up period.
For nonsurgical controls, we screened patients admitted to the Department of Internal Medicine. Patients were contacted by the study coordinator and informed about the planned tests as well as the frequency of reexamination. All patients serving as controls had to give their written and informed consent. Tests were not performed as part of another study. All patients serving as controls were free from a history of heart failure and prior CVA, TIA, or other neurological problems.
P300 evoked potentials and physical examinations were completed preoperatively, at intensive care unit (ICU) discharge, and at the 8-week and 12-week follow-up. All examinations were performed individually by the same experienced investigator. Neurocognitive testing was performed by means of cognitive P300 evoked potentials. To avoid any influences due to biorhythm, all investigations were performed under comparable conditions. Special care was taken to ensure that patients were free from narcotics and sedatives for at least 2 days before testing. A right heart catheter was performed at baseline and the 12-week follow-up.
Cognitive P300 Evoked Potentials.
Cognitive P300 evoked potentials have previously been used to measure neurocognitive function in various metabolic disorders, patients undergoing heart transplantation, and patients undergoing open heart surgery.2–6 In addition to this and of special interest in the present setting, cognitive P300 auditory evoked potentials have been shown to be negatively correlated with regional cerebral blood flow.7,8 Cognitive P300 evoked potentials 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.9 As a result of the involvement of major brain regions in P300 generation, P300 can be used as a general indicator for neurocognitive function.10–14 Cognitive P300 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 1,000 Hz and rare (20%) target-tones of 2,000 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).15 During the paradigm, the subjects were instructed to keep a running mental count of the rare 2,000 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 (in milliseconds) of the cognitive P300 peak were assessed. To confirm reproducibility, two sets of P300 measurements were recorded in all patients.
Anticoagulation protocol was identical in all patients. During extracorporeal circulation and implantation of the pump, patients received heparin 300 U/kg body weight intravenously; the heart-lung machine was primed with 1,000,000 IU aprotinin. After discontinuation of extracorporeal circulation, heparin was reversed with an appropriate dose of protamine. Intravenous heparin was instituted 6 hours after surgery to achieve activated partial thromboplastin target times of 50 to 60 seconds. Platelet antiaggregation therapy with 150 mg/d aspirin and 225 mg/d dipyridamole was started after removal of all chest drains. Administration of heparin was stopped when anticoagulation with coumarin reached target levels of INR 2.5 to 3.5.
Devices and Implantation.
Three different devices were implanted in the present study. In the continuous flow group, we used the Micromed DeBakey left VAD; in the pulsatile group, the Thoratec and Novacor left VADs. Technical details as well as implantation procedures of all devices used have previously been described.16–18
The statistical analysis was performed with SPSS 10.0.0 for Windows (SPSS Inc., Chicago, IL). Data are reported as mean ± SD. Comparison of P300 evoked potentials was performed using Student’s t test after testing for normality of distribution. The time course of neurocognitive function was analyzed by means of paired t test. Because multiple testing was performed, a Bonferroni-Holm correction was performed. To test if there was any correlation between development of cognitive P300 peak latencies and development of cardiac index, a correlation analysis was performed. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. Two-sided p values < 0.05 were considered as significant.
Twenty-nine operative survivors undergoing VAD implantation were prospectively followed up (pulsatile flow n = 18, continuos flow n = 11 [Thoratec n = 16, Novacor n = 2]). Patient characteristics are given in Table 1. No death was observed during the 12-week follow-up period. Operative data and clinical outcome are given in Table 2.
Cognitive P300 Evoked Potentials.
A total of 29 patients completed baseline and follow-up measurements. Before the operation peak latencies of cognitive P300 auditory evoked potentials were prolonged (impaired) in patients scheduled for VAD implantation (437 ± 39 milliseconds) compared with age- and sex-matched controls (355 ± 16 milliseconds; p < 0.001). Peak latencies of patients with pulsatile (434 ± 45 milliseconds) and continuos flow (443 ± 45 milliseconds) ventricular assist devices were comparable before the operation (p = 0.767). After successful VAD implantation, P300 peak latencies continuously improved (was shortened) compared with before the operation (ICU discharge 399 ± 37, p = 0.007; 8-week follow-up 403 ± 41, p = 0.022, 12-week follow-up 394 ± 38 p < 0.0001). The course of P300 auditory evoked potentials was comparable within patients treated with VADs with continuous and pulsatile blood flow devices at ICU discharge (p = 0.736) as well as at the 8-week (p = 0.911) and 12-week (p = 0.397) follow-up (Figure 1). Nevertheless, P300 peak latencies did not fully normalize at the 12-week follow-up compared with controls (p = 0.012).
Correlation of Cognitive P300 Evoked Potentials and Cardiac Index.
To test the influence of improvement of cognitive P300 evoked potentials and improvement of cardiac index from baseline to the 12-week follow-up, a correlation analysis was performed. A good correlation of improvement of P300 evoked potentials and improvement of cardiac index was found (R = 0.516, p = 0.008) (Figure 2).
As shown by cognitive P300 evoked potential measurement, VAD implantation improves neurocognitive function in patients with end-stage heart failure. However, it does not fully normalize neurocognitive function. Interestingly, the type of device, either continuous or pulsatile, has no influence on neurocognitive improvement.
Patients undergoing VAD implantation are terminally ill. In this context, neurocognitive function seems to be of only little importance. However, because patients undergoing VAD implantation are actively involved in their medical treatment (anticoagulation, taking care of their VAD and themselves) in the postoperative course, especially as soon as they are treated on an outpatient basis (a treatment standard at our department), the importance of neurocognitive function should not be underestimated.19,20 Neurocognitive function is important for patients’ adherence to treatment and for doctor–patient interactions. Additionally, it is an important factor contributing to quality of life.
We found neurocognitive deficit in patients before VAD implantation when compared with age- and sex-matched healthy subjects. Terminal heart failure has previously been associated with neurocognitive deficit.3,21–23 It has been suggested to depend on heart failure–associated systolic hypotension and decreased cerebral blood flow. Systolic hypotension causes white matter and subcortical lesions (both are associated with increased incidence of dementia), decreased cerebral arterial blood flow, and impairment of neuronal oxygen supply and glucose utilization.24–27 Our findings of prolonged P300 peak latencies in patients with terminal heart failure support the hypothesis of chronic cerebral hypoperfusion because cognitive P300 peak latencies have been shown to be negatively correlated with regional cerebral blood flow.7,8
After successful VAD implantation, neurocognitive function improved in the present study. The distinct mechanism for neurocognitive improvement after VAD implantation is uncertain. Like VAS implantation in our study, heart transplantation and correction of bradycardia by pacemaker implantation also improve neurocognitive function.3,22,23,28 VAD implantation, heart transplantation, and pacemaker implantation result in increased cardiac output, which seems to be associated with improvement of cerebral oxygen and nutrient supply and, consequently, improvement of neurocognitive function.29 This is supported by our finding of a correlation between improved cognitive P300 evoked potentials and cardiac index. However, it has to be stressed that improvement of neurocognitive function can only be achieved in cases of neurologically uneventful ventricular assist implantation.
In contrast to heart transplantation, VAD implantation did not fully normalize neurocognitive function.3,22,23 A variety of possible reasons must be stressed. VADs serve as a possible source for cerebral microembolization as a result of blood–device surface interactions.30 Furthermore, longstanding cerebral hypoperfusion leads to irreversible neurocognitive impairment through the induction of degenerative brain abnormalities, including subcortical lesions.24–26 Finally, we cannot rule out that neurocognitive function fully normalizes at a later time point not covered by the12-week follow-up period.
We have shown that improvement of neurocognitive function is independent of the type of VAD used, whether continuous or pulsatile. There is ongoing discussion on the importance of pulsatile flow for end-organ function. However, little is known about the effect of pulsatile flow on the brain and cerebral perfusion. Recent publications found no difference between cortical and medullar blood flow during pulsatile and continuous flow ventricular support.31,32 This is also true for release of molecular markers for cerebral damage.33 Our findings of similar development of cognitive P300 evoked potentials in patients with pulsatile and continuous flow VADs strongly suggest comparable regional cerebral blood flow in patients with pulsatile and continuous flow VADs, because P300 peak latencies have been shown to strongly correlate with regional cerebral blood flow.
Neurocognitive function was measured by means of P300 auditory evoked potentials. P300 peak latencies increase with age in healthy subjects. The clinical relevance of cognitive P300 evoked potentials is based on the fact that they were shown to be related to cognitive impairment rating, rapid evaluation of cognitive function tests, orientation, stimulus evaluation, selective attention, visual pattern recognition, and digit span, and were shown to be much more sensitive in detecting neurocognitive deficit than psychometric tests or electroencephalograms.2–4 Moreover, the P300 technique has a very low intraindividual test-retest variability with a coefficient of variation of below 2%, which further stresses its usefulness for cognitive follow-up studies.3
We used cognitive P300 evoked potentials to assess neurocognitive function; however, no standard psychometric tests were performed. The main reason for this is that before VAD implantation, patients are terminally ill. Therefore, assessment of neurocognitive function has to be kept short and simple to avoid long performance times with significant influence on test scores. The main benefit of cognitive P300 evoked potentials in this setting is their high sensitivity and short examination times. The study was limited by a small sample size and may need to be reevaluated as the field grows and the number of implants expands.
As shown by means of objective measures, VAD implantation improves neurocognitive function in patients with end-stage heart failure; however, it does not fully normalize it as compared with age- and sex-matched controls. Furthermore, improvement of neurocognitive function is independent of the type of device used, whether continuous or pulsatile flow.
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