Eur J Cardiothorac Surg 2007;32:507-513. doi:10.1016/j.ejcts.2007.06.006
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Cognitive brain function after hypothermic circulatory arrest assessed by cognitive P300 evoked potentials
Takashi Kuniharaa,
Dietmar Tscholla,
Frank Langera,
Günter Heinzb,
Fumihiro Satac,
Hans-Joachim Schäfersa,*
a Department of Thoracic and Cardiovascular Surgery, University Hospital of Saarland, Homburg, Germany
b Department of Psychiatry and Psychotherapy, University Hospital of Saarland, Homburg, Germany
c Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Received 20 November 2006;
received in revised form 14 May 2007;
accepted 4 June 2007.
* Corresponding author. Address: Department of Thoracic and Cardiovascular Surgery, University Hospital of Saarland, 66421 Homburg, Germany. Tel.: +49 6841 1632000; fax: +49 6841 1632005. (Email: h-j.schaefers{at}uniklinikum-saarland.de).
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Abstract
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Background: The role of hypothermic circulatory arrest (HCA) in cardiovascular surgery is controversial and assumed to result in neurocognitive dysfunction that is not always detected by standard clinical observation. We assessed cognitive P300 visual evoked potentials (P300) in patients undergoing either HCA or coronary artery bypass grafting (CABG) to elucidate whether HCA was associated with postoperative cognitive decline. Methods: Thirteen patients undergoing either aortic arch replacement (n
= 4) or pulmonary thromboendarterectomy (n
= 9) using HCA (mean: 28 ± 11 min, 22 ± 2 °C) were studied. They were compared to 13 patients undergoing on-pump CABG. P300s were measured 1 day before and 1 week after the operation. We assessed an area under the curve (AUC) between 280 and 600 ms and center of this area [Ct (time), Cv (voltage)]. The ratio of these parameters acquired by target (TG) and non-target (NTG) stimulus (TG/NTG) was calculated to assess concentration on TG stimulus and defined as concentration index (CI: CI(AUC), CI(Ct), and CI(Cv)). Results: There was no significant difference in preoperative characteristics between groups. There were neither strokes nor hospital deaths. Preoperatively, the HCA group could not concentrate on target stimulus as well as the control group in frontal leads (CI(AUC) and CI(Cv) were lower in HCA group than in control group). However, the HCA group could concentrate on target stimulus better than the control group postoperatively because postoperative CI(AUC) (pre-operation: 1.1 ± 0.5 to post-operation: 1.7 ± 0.4, P
= .02) and CI(Cv) (1.1 ± 0.4 to 1.6 ± 0.4, P
= .01) were significantly improved in the HCA group, whereas these were significantly impaired in the control group (CI(AUC): 1.6 ± 0.6 to 1.3 ± 0.4, P
= .03, CI(Cv): 1.5 ± 0.5 to 1.2 ± 0.3, P
< .01). Postoperative CI(Ct) in the HCA group were significantly impaired in all leads. The duration of HCA did not correlate with any values of postoperative P300. No specific trends were observed in either preoperative or postoperative P300 values between patients with or without postoperative temporary neurological dysfunction (one in each group). Postoperative improvement of CI(AUC) and CI(Cv) in Fz lead were found in 85 and 69% in the HCA group and 23 and 23% in the control group, respectively (CI(AUC): P
< .01, CI(Cv): P
< .05). Conclusions: P300 detected no significant neurocognitive impairment due to the relatively brief period of HCA (approximately 28 min).
Key Words: Hypothermic circulatory arrest • Neurocognitive dysfunction • P300 visual evoked potentials • Aortic arch replacement • Pulmonary thromboendarterectomy
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1. Introduction
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In recent years, neurocognitive dysfunction has received increasing attention as a complication of cardiac surgery with cardiopulmonary bypass (CPB) [1]. The use of hypothermic circulatory arrest (HCA) for special cardiovascular operations, such as arch replacement or pulmonary thromboendarterectomy (PTE), is likely to be associated with an even higher degree of neurologic dysfunction [2–4].
In pediatric cardiac surgery, prolonged periods of HCA have been found to be associated with seizures, choreoathetosis, and impaired intellectual development [2]. In aortic arch surgery using HCA, stroke, temporary neurologic deficits, and cognitive impairment have been observed [3–6]. In aortic surgery, however, neurologic complications may be due to cerebral hypoxia (as part of HCA) or embolic complications. The relative importance of these two factors has not been clearly defined yet. Apart from irreversible neurologic complications, temporary neurological dysfunction (TND) is observed in a considerable proportion of patients, which has been related to non-embolic brain injury [3].
To date, only a few studies have been carried out to evaluate cognitive outcome after aortic surgery and relating it to the use of HCA and its duration [4–6]. In one investigation, no control group was studied in order to define the effect of cardiac surgery alone [4]. All investigations were performed using psychometric test batteries, and a variable degree of cognitive dysfunction was observed if HCA exceeded 25 min [5]. The psychometric tests used in these studies, however, show different sensitivities in relation to different cognitive brain functions [4–6]. In addition, these tests are affected by various influences such as age, education [7], language, socio-cultural background, and repetitive testing [8].
In contrast to psychometric tests, so-called cognitive evoked potentials, such as the P300 wave, are highly sensitive in the evaluation of cognitive function in various neurologic, metabolic, or hemodynamic disorders [9–11]. The P300 wave, a long-latency event-related potential, is known to be associated with psychological processing of stimulus information and thus can provide a quantification of impaired cognitive brain function [11–13]. P300 latency increases with age and is a neuropsychological correlate of information processing, such as stimulus evaluation, alertness, and memory updating [14]. The use of the P300 technique has proved to be even more sensitive than electroencephalogram and standard psychometric tests for detecting sub-clinical impairment of cognitive brain function [10,13,15].
The purpose of this study is to objectively assess neurocognitive function before and after cardiac operations with HCA in patients undergoing arch replacement or PTE. The patients were to be compared to patients undergoing on-pump coronary artery bypass grafting (CABG) without HCA. Then we sought to elucidate whether HCA was associated with postoperative cognitive decline or not. Since all patients were studied sequentially, each served as his own control.
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2. Material and methods
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2.1 Patient profile
Twenty patients who underwent either replacement of the aortic arch (n
= 7: five total arch and two proximal arch) or bilateral PTE for chronic thromboembolic pulmonary hypertension (n
= 13) using HCA were measured P300 preoperatively and postoperatively. In the same period, 17 patients who underwent isolated on-pump CABG were also measured P300. Next, 13 gender- and age-matched patients were randomly selected from each group and involved in this study (HCA group and control group). In the HCA group, four patients underwent replacement of the aortic arch (three total arch and one proximal arch) and nine patients underwent bilateral PTE using HCA. The underlying etiology of aortic arch pathology was non-dissection degenerative disease in all four patients. Thirteen patients who underwent isolated on-pump CABG were used as a control group. The patients in the control group were almost comparable with those in the HCA group (Table 1
). Concomitant cardiac operations were necessary in four patients (31%) in the HCA group: aortic valve or root repair/replacement in one (8%) and CABG in three (23%). All operations were performed as elective procedures.
2.2 Anesthesia and cardiopulmonary bypass
All patients received general anesthesia using the same standard technique including continuous intravenous administration of Propofol and Sufentanyl. No particular cerebral protective strategies, including barbiturates or steroids, were employed other than topical cooling of the head with ice during HCA. To avoid cerebral embolism, patients who underwent aortic arch replacement were placed in head-down position during HCA. The anesthetic depth was held constant to prevent changes in cerebral metabolism. The rectal temperature (RT) was continuously monitored during the operation. A non-heparin-coated circuit (RaumedicTM, Rehau AG + Co., Rehau, Germany), a roller pump (Stöckert Instrumente GmbH, München, Germany), a membrane oxygenator (QuadroxTM, Jostra Medizintechnik GmbH & Co. KG, Hirrlingen, Germany), and an arterial filter (QuartTM, 40 µm pore size, Jostra Medizintechnik GmbH & Co. KG, Hirrlingen, Germany) were used for CPB. The CPB system was primed mainly with lactated Ringer's solution. Alpha-stat strategy was applied during CPB. A cell saving device (C.A.T.S, Fresenius AG, Bad Homburg, Germany) was used in all patients for reprocessing of shed blood.
2.3 Operative technique
All operations were performed through a median sternotomy. CPB was established between an ascending aortic cannula and a single venous cannula except for patients undergoing PTE who required bicaval cannulation. Our standard operative technique for each operation has been described in detail previously [16,17]. For aortic arch replacement and PTE, a nasopharyngeal temperature of 18–20 °C was used for HCA.
For CABG, conventional CPB with a rectal temperature of 32 °C, aortic cross-clamping, and cold blood cardioplegic cardiac arrest was used. T-grafting with the left internal thoracic artery and the left radial artery was performed in nine patients. The other four patients underwent conventional CABG with left internal thoracic artery and saphenous vein grafts using a side-biting clamp.
2.4 P300 measurement
All patients were measured P300 at the department of psychiatry in the University Hospital Homburg 1 day before and 1 week after the operation. P300 measurement was approved by the medical ethics committee of University Hospital Homburg, and a written informed consent was given by all patients. Cognitive P300 visual evoked potentials were recorded with Ag/AgCl electrodes on a Nicolet HGA300TM (Nicolet, Madison, WI). P300 evoked potentials were recorded in response to visual stimuli made by a checkerboard pattern that changed about 100 times. Checkerboard stimuli were presented on a split screen: target stimuli (TG) were given in the lower half of a standard 20 in. monitor with a random interstimulus interval (ISI) of 4–10 s; non-target stimuli (NTG) were given in the upper half with a constant ISI of 7 s. Patients kept a running mental count of TG but not of NTG stimuli. The bandpass filter was 0.01–30 Hz, the analysis time was 500 ms pre-trigger and 1500 ms post-trigger. Active electrodes were placed at Cz (vertex), Fz (frontal), and Pz (parietal), respectively, and referenced to linked earlobes. P300 evoked potential recording resulted in a sequence of positive and negative peaks. To standardize variable data, we assessed an area under the curve (AUC) that was surrounded by the P300 curve and the adjusted baseline (X-line) between 280 and 600 ms (Fig. 1
). The center of this area (Ct, Cv) was also measured. Ct represented time after stimuli and Cv represented voltage of P300. To investigate the degree of concentration of patients on target, the ratio of these parameters acquired by target and non-target stimulus (TG/NTG) was calculated and named as concentration index (CI: CI(AUC), CI(Ct), and CI(Cv)). CI(AUC) > 1 or CI(Cv) > 1 or CI(Ct) < 1 means that patients can concentrate on target stimulus. To confirm reproducibility, two sets of P300 measurements were recorded in all patients.
2.5 Statistical analysis
All values are expressed as mean ± standard deviation. Statistical analysis was performed using StatViewTM 5.0 program (SAS Institute Inc., North Carolina, USA) except for repeated measures analysis of variance (ANOVA) performed using SPSS version 14. Student t-test was used for comparison of the continuous variables. Paired t-tests were performed for comparison between two groups. Unpaired t-tests were performed for comparison between preoperative and postoperative variables among each group. Mann–Whitney test was used only for comparison of postoperative blood loss and hospital stay instead of unpaired t-test. Chi-square test with Yates correction was used for comparison of frequencies between the groups. A linear correlation analysis was used to test the relationship between the duration of HCA and postoperative P300. Repeated measures ANOVA were used for comparison of postoperative changes between the groups. A significant interaction in the repeated measures ANOVA would be an indicator for differences between groups. A P-value less than .05 was considered statistically significant. No correction for multiple testing but a Bonferroni correction was performed in all analyses.
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3. Results
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3.1 Operative results
No hospital death or postoperative stroke occurred. No re-exploration for bleeding was necessary. TND developed in two patients (one in each group) and was resolved completely before discharge. Mean duration of CPB was significantly longer in the HCA group than in the control group (132 ± 20 min vs 82 ± 15 min, P
< .01). Mean duration of aortic cross-clamping was also significantly longer in the HCA group than in the control group (72 ± 20 min vs 57 ± 12 min, P
= .03). The duration of HCA was 28 ± 11 min: 24 ± 3 min in total arch replacement and 30 ± 13 min in PTE. The minimum rectal temperature was 22 ± 2 °C in the HCA group and 33 ± 1 °C in the control group (P
< .01). There was no re-exploration for bleeding. Postoperative hospital stay of the HCA group was also longer than that of the control group (15.3 ± 10.1 days vs 9.5 ± 4.6 days, P
= .22), although this difference was not significant (Table 2
).
3.2 P300 results
All patients could concentrate on target stimulus preoperatively (CI > 1). In preoperative Fz lead, patients in the control group could concentrate on target stimulus better than those in the HCA group (CI(AUC): 1.6 ± 0.6 vs 1.1 ± 0.5, P
= .04, CI(Cv): 1.5 ± 0.5 vs 1.1 ± 0.4, P
= .03).
In the control group, AUC (Cz: 56 ± 29 to 47 ± 24 µV ms, P
= .03, Fz: 52 ± 28 to 42 ± 22 µV ms, P
< .05) and Cv (Cz: 34 ± 14 to 28 ± 13 µV, P
= .02, Fz: 32 ± 13 to 25 ± 11 µV, P
= .01) acquired by TG stimulus in both Cz and Fz leads were significantly altered postoperatively. CI(AUC) (1.6 ± 0.6 to 1.3 ± 0.4, P
= .03) and CI(Cv) (1.5 ± 0.5 to 1.2 ± 0.3, P
< .01) in Fz leads were also impaired after the operation. CI(Ct) in Fz leads slightly prolonged after surgery (0.97 ± 0.04 to 1.00 ± 0.05, P
< .05) (Figs. 2–4
).
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Fig. 2. P300 measurement on vertex lead (Cz) acquired by target (TG) stimulus (left) and concentration index (CI) of them (right). AUC: area under the curve; Ct: center of area under the curve/time scale; Cv: center of area under the curve/voltage scale.
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Fig. 3. P300 measurement on frontal lead (Fz). acquired by target (TG) stimulus (left) and concentration index (CI) of them (right). AUC: area under the curve; Ct: center of area under the curve/time scale; Cv: center of area under the curve/voltage scale.
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Fig. 4. P300 measurement on posterior lead (Pz) acquired by target (TG) stimulus, (left) and concentration index (CI) of them (right). AUC: area under the curve; Ct: center of area under the curve/time scale; Cv: center of area under the curve/voltage scale.
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In the HCA group, no significant postoperative change was observed in all leads on TG stimulus. Postoperative CI(AUC) (1.1 ± 0.5 to 1.7 ± 0.4, P
= .02) and CI(Cv) (1.1 ± 0.4 to 1.6 ± 0.4, P
= .01) were significantly improved in the Fz lead. However, CI(Ct) was significantly impaired in all the leads (Cz: 0.98 ± 0.03 to 1.06 ± 0.07, P
< .01; Fz: 0.98 ± 0.06 to 1.05 ± 0.08, P
= .04; Pz: 0.97 ± 0.05 to 1.04 ± 0.05, P
< .01) (Figs. 2–4). Those in Cz and Pz were also statistically significant after a Bonferroni correction. We found no statistical significant difference in all P300 variables measured between patients who underwent replacement of the aortic arch and PTE.
In comparing postoperative measurements between the two groups, reactive P300 parameters on TG stimulus were comparable in all values in all leads. However, in contrast to preoperative value, CI(AUC) (HCA group 1.7 ± 0.4 vs control group 1.3 ± 0.4, P
= .02) and CI(Cv) (1.6 ± 0.4 vs 1.2 ± 0.3, P
< .01) in the Fz leads were rather significantly better in the HCA group (Figs. 2–4). These differences were both statistically significant between the groups using repeated measures ANOVA (P
< .01). In addition, there was also significant difference in CI(Ct) in the Pz leads between groups using repeated measures ANOVA (P
< .05). The duration of HCA did not significantly correlate with any values of postoperative P300 (Table 3
). No particular tendency was found in either preoperative or postoperative P300 values between patients with or without postoperative TND. Postoperative P300 values of patients with or without postoperative TND are shown in Table 4
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Table 4 Comparison of P300 between patients with (n
= 2, one in each group) or without postoperative temporary neurological dysfunction (TND)
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Postoperative improvement of CI(AUC) in the Fz lead were found in 11 patients (85%) in the HCA group, whereas it was achieved in only three patients (23%) in the control group (P
< .01). Postoperative improvement of CI(Cv) in the Fz lead was found in nine patients (69%) in the HCA group, whereas it was achieved in only three patients (23%) in the control group (P
< .05).
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4. Comment
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It is well known that even cardiac surgery may be associated with a considerable incidence of neurocognitive dysfunction [1]. A recent review estimated that 22.5% of patients developed cognitive decline 2 months after CABG [1]. In addition, long-term follow-up indicated that this impairment was observed up to 5 years after CABG [18]. However, the reported incidence of this sub-clinical neurological impairment varies widely because of the variability of definition, the psychometric test batteries administered, and test–retest intervals. Furthermore, psychometric tests are an expensive and cumbersome tool and affected by various biases such as practice effects or visual impairment [1,19].
Cognitive P300 evoked potentials, a long-latency endogenous evoked potential associated with psychological processing of stimulus information, can provide a quantification of impaired cognitive brain function [9–13,15]. It has been also reported that P300 technique is more sensitive in detecting sub-clinical impairment of cognitive brain function than standard psychometric tests [10,13,15]. In addition, its high intra-individual reproducibility is further emphasized [13,15]. Therefore, P300 has been used to evaluate impaired cognitive brain dysfunction for various disorders from its beginnings in the 1980s [11]. Only from the early 1990s has P300 also been applied to detect sub-clinical impairment of cognitive brain function in the field of cardiac surgery using CPB [12]. P300 thus appears as an ideal tool in patients undergoing HCA.
For these reasons, we decided to investigate cognitive brain function using P300 in patients undergoing HCA. We found that both the voltage and the area of the P300 peak after CABG decreased compared with preoperative values. Furthermore, the ability to concentrate on target stimulus was worse after the operation. By contrast, patients undergoing HCA could concentrate on target stimulus better than before operation, although the latency was somewhat prolonged postoperatively. In a postoperative comparison of two groups, the ability to concentrate on target stimulus was better in the HCA group and there was no significant difference in the latency. These trends were distinct in the frontal lobe that is considered to play an important role in cognitive function [20]. Our results thus suggest that our protocol of HCA seems clinically safe. We speculate that patients who underwent PTE might regain their ability of oxygenation postoperatively. Unfortunately, we have no obvious data to prove it, but it might be one of the reasons of cognitive improvement in the HCA group.
Although the use of HCA imposes a more clinical and pathophysiological complex on patients, its influence on sub-clinical neurological function has not been well understood. Because of its severity, surgeons have mainly focused on clinically detectable brain injury: stroke and TND [3,21]. Only recently, however, sub-clinical neurological impairment, i.e. ‘cognitive brain dysfunction’ has gained increasing attention. Neurocognitive deficit is associated with prolonged hospital stay or rehabilitation, which leads to an increased use of resources. Furthermore, it is reported that neurocognitive impairment at discharge is an independent predictor for that at 5 years after CABG [18]. Therefore, neurocognitive deficit has enormous clinical, social, and economic implications. However, standard psychometric test fails to reveal trivial neurocognitive decline [13]. Even contemporary radiological diagnosis modality such as diffusion-weighted magnetic resonance imaging could not find significant correlation between new ischemic lesions and cognitive dysfunction [22]. For detection of sub-clinical cognitive decline, a highly sensitive tool, such as P300, is necessary.
The underlying mechanism of neurocognitive deficit is supposed to be injury to the hippocampus; that is the most vulnerable lesion to hypoxia. The hippocampus plays a key role in episodic memory and the acquisition of semantic or factual knowledge [23]. It has been found that prolonged HCA is associated with hippocampal neuronal death [24]. However, it is still controversial whether any duration of HCA correlates with the incidence of neurocognitive dysfunction or not. The Mount Sinai group has repeatedly reported that the duration of HCA correlates with the incidence of TND or neuropsychologic dysfunction [5,21]. Reich and colleagues reported that HCA of 25 min or more was associated with memory and fine motor deficits [5]. In the current study, however, the duration of HCA did not have a significant influence on any parameters of postoperative P300. This difference may be primarily related to the duration of HCA. In the publications of the Mount Sinai group, many patients with HCA of 30 min or longer were included, while this was rare in our patients. The current findings thus correspond to the low incidence of stroke and confusion in a standard clinical setting of HCA of mostly less than 30 min [16]. The total duration of HCA (mean 24 ± 3 min) was longer in the PTE patients (mean 30 ± 13 min), but a period of reperfusion was utilized between endarterectomy of each side.
The results of the current study must be carefully interpreted. First, this is not a randomized trial but a cohort study with consecutive patients after gender and age matching. To arrange a randomized trial, patients who will undergo total/partial arch replacement or PTE should be assigned to HCA alone or continuous antegrade cerebral perfusion under the same temperature. HCA provides a completely bloodless field, eliminates clamp-compromised tissue, avoids manipulation of aortic arch vessels, and is unquestionably simple and economical [16]. Therefore, it seems unethical for us to perform such a randomized trial. Svensson and associates had already performed this type of randomized study in aortic arch surgery and found no beneficial effect of continuous antegrade cerebral perfusion with relatively brief period of HCA like ours [6].
Second, two procedures: aortic arch surgery and PTE were included in this study and they were compared with CABG. Therefore, the study group seems heterogeneous. However, we would like to investigate the pure effect of HCA on cognitive function. Microembolism caused by air or debris is always inherent in aortic arch surgery. PTE requires no aortic manipulation, thus seeming the ideal procedure to assess the pure effect of HCA. However, patients who undergo PTE are relatively young. Therefore, we measured P300 also in patients who underwent aortic arch surgery and performed gender and age matching with CABG patients. Indeed, there was no significant difference in P300 variables between aortic arch surgery and PTE, which might suggest that the effect of this heterogeneity seemed minimal.
Third, our study lacks long-term follow-up data that were recommended in a consensus meeting on neuropsychologic assessment after CPB in 1994 [25]. Because some of our patients were referred from distant areas, it was difficult to call them to us only for study. In addition, we set the timing for postoperative assessment at 1 week after the surgery. This may be a bit earlier than the period when the patients become neuropsychologically stable. However, most of patients are discharged from our hospital between 7 and 10 days postoperatively. This is one of the reasons why we did not perform neuropsychological tests together. Therefore, we think that our study design seems reasonable as a clinical investigation without any special management.
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5. Conclusion
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HCA slightly prolonged P300 latency on target stimulus compared with that on non-target stimulus, which seemed the same after conventional CABG. HCA improved P300 voltage on target stimulus in frontal lead compared with that on non-target stimulus and also compared with that after mild hypothermic CPB. In this clinical setting, the relatively brief period of HCA did not result in significant neurocognitive impairment.
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Acknowledgments
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We thank Mathias Rubly, Ulrike Firmont, and Jutta Müller for their help in measuring P300.
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Abstract
1. Introduction
