BJA Advance Access originally published online on January 16, 2006
British Journal of Anaesthesia 2006 96(3):310-316; doi:10.1093/bja/ael002
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Adenosine-induced cardiac arrest and EEG changes in patients with thoracic aorta endovascular repair
1 Clinic of Anaesthesiology and 2 Department of Vascular and Endovascular Surgery, University of Heidelberg, Germany
* Corresponding author: Clinic of Anaesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. E-mail: konstanze.plaschke{at}med.uni-heidelberg.de
Accepted for publication December 13, 2005.
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Abstract |
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Background. We studied haemodynamic and metabolic variables, and cerebral function after cardiac arrest induced by high dose of adenosine in patients undergoing thoracic aorta endovascular repair.
Methods. Arterial blood pressure, blood gas values and EEG were recorded continuously in 15 patients undergoing anaesthesia (isoflurane) for endovascular thoracic aorta repair. Cardiac arrest was induced by different doses of adenosine (Adrekar®, Sanofi-Synthelabo, Berlin, Germany; 0.4–1.8 mg kg–1 body weight). Serum concentrations of neurone-specific enolase (NSE) were determined before and after stent graft implantation. Neurological function was assessed before and after surgery.
Results. After adenosine, the heart beat stopped immediately for 18–58 s in close relation to the adenosine dose. EEG power was significantly reduced to –57%, but reached normal values within 5 min after cardiac arrest. In particular, the fast alpha- and beta-EEG-frequencies sensitively reflected patients' EEG activity during the procedure. No intraoperative increases in NSE concentrations, and no neurological dysfunctions after surgery, were observed.
Conclusion. After adenosine-induced cardiac arrest, changes in haemodynamic variables and EEG power spectra reversed completely within 1 and 5 min, respectively, without persistent brain dysfunction after stent graft implantation.
Keywords: brain, electroencephalography; heart, cardiac arrest, adenosine; surgery, vascular
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Introduction |
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Endovascular reconstruction of the descending thoracic aorta offers significant advantage to conventional open surgery in a selected group of patients.1 However, despite significant improvement in anaesthesia, surgical techniques and postoperative care the morbidity remains high with both the techniques.2 Using transluminal techniques, the self-expanding stent-armed vascular endoprothesis is retrogradely passed into the aorta and the systemic pressure is then taken off the aneurysm by precise positioning of the endograft. It is useful to temporarily induce asystole, while the stent graft is being placed via the femoral artery into the thoracic aorta, to prevent distal migration of the device as a result of the propulsive flow during systole. Different methods have been used to achieve this. These include induction of hypotension [mean arterial pressure (MAP) <50 mm Hg] using nitroglycerine or nitroprusside,2 3 ventricular fibrillation4 and transient cardiac arrest using high-dose i.v. adenosine.5 Adenosine-induced cardiac arrest is a desirable method in patients with previous heart surgery, advanced age, or in an emergency setting if traditional open aortic reconstruction is not possible because of significant co-morbidities or the vascular anatomy demonstrates a short length of non-diseased aorta.
Adenosine is a known potent vasodilator of coronary and cerebral resistance vessels.6 7 Therapeutically, it is commonly used to treat supraventricular tachycardia. After a bolus injection, the heart rate is dose-dependently reduced until a complete AV-node blockade is reached. However, this effect on the AV node is transient and of short duration because of the rapid inactivation of adenosine in human plasma by uptake into erythrocytes and endothelial cells.8 In addition, experimental data in animals suggested that adenosine may be a potent endogenous, neuroprotective substance in acute and long-lasting ischaemia.9
The development of computerized EEG with conversion of EEG signals by means of Fast Fourier Transformation (FFT), which has been implemented in the CATEEM®-EEG system, provides objective and reproducible information for continuous intraoperative EEG monitoring.
In the present study, the relationship between the duration of adenosine-induced cardiac arrest and brain function was studied intraoperatively using EEG power spectral analysis during intraluminal stent placing in thoracic aorta endovascular repair.
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Methods |
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After having obtained written informed consent, 15 patients (Table 1) undergoing thoracic aorta endovascular repair were included in the present study. This study was approved by the local Ethics Committee (ethic votum 196/2004; Medical Faculty, University of Heidelberg, Germany) and Institutional Review Board and was performed in accordance with the standards of the Declaration of Helsinki.
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Three women and twelve men were continuously monitored haemodynamically and with quantitative EEG during surgery. All patients were thoroughly investigated by a neurologist before surgery. Patients with previous neurological disease, based on NIH Stroke Scale (0–22) and routine CT-scans, were excluded from the study. Because the half-life time of adenosine can be significantly prolonged in the presence of dipyridamol (Persantin®) particular care was taken to exclude all patients receiving medication interacting with adenosine.
After oral premedication with midazolam 5 mg, anaesthesia was induced with i.v. midazolam 1–3 mg, fentanyl 2–5 µg kg–1, etomidate 0.15–0.3 mg kg–1 and atracurium 0.5 mg kg–1. After tracheal intubation, anaesthesia was maintained with nitrous oxide (50%) in oxygen and isoflurane 0.2–0.6%. Atracurium and fentanyl were subsequently administered as necessary. The lungs were mechanically ventilated to maintain normocapnia (
5.0–5.5 kPa). In each patient, 5-channel-ECG data and arterial pressure changes, using a 20-gauge radial artery catheter (Abbott, Wiesbaden, Germany), were continuously recorded. For safety reasons, a pacemaker (paceportTM catheter, Baxter Germany) was placed in the right ventricle via the internal jugular vein for electrical stimulation of the heart, and its function was verified by electrical stimulation. For EEG recording, an electrode cap with an adjustable head size (Electro Cap, Co., OH, USA) was placed on the patient's head.
During surgery, arterial blood gas values (electrolytes, haemoglobin, haematocrit, arterial 
and 
) were measured 30 min before and after cardiac arrest using standard blood gas analysis (Radiometer Copenhagen). The neurone-specific enolase (NSE) in serum was determined at specific time points according to Schaarschmidt and colleagues10 using an immunoluminometric assay (Byk-Sangtec, Germany).
Heparin (3000 IE) was given 30 min before stent placement. Two minutes before inducing cardiac arrest all anaesthetized patients' lungs were ventilated with 100% oxygen. No other drugs were given to prevent drug-dependent EEG changes. After adenosine, no other medications were used. Arterial pressure changes and EEG power were monitored continuously until the end of surgery.
Adenosine was injected via the central venous catheter to reach a high dose of adenosine at its major site of action, the AV node. From previous studies we know that a bolus of adenosine ranging from 18 to 45 mg can induce cardiac asystole for 
20 s.5 11 The response of each individual patient to adenosine and to adenosine-induced AV-block was tested by an initial injection of 0.4–0.6 mg kg–1 body weight. A high dose of adenosine (0.6–1.8 mg kg–1) was then injected to induce prolonged cardiac arrest. During adenosine injections, patients were adequately ventilated using the Datex-Engström® (Freiburg, Germany) ventilator. Arterial pressure and heart rate changes were monitored continuously online, and the duration for cardiac arrest was recorded.
During surgery, heart rate and systolic and diastolic blood pressures and MAPs were monitored online using DATEX-Ohmeda system (Freiburg, Germany). All the data were saved onto a computer using the program Hypnos® (S. Esch, Bielefeld, Germany). The body temperature was monitored using an oesophageal temperature probe and maintained at 36.0–36.5°C using a warm touch system during surgery (Marquette Hellige GmbH, Freiburg, Germany).
The CATEEM® (computer-aided topographical electroencephalometry system; Medisyst, Linden, Germany) measures cerebral activity by automatic frequency analysis of all 99 (17 real and 82 virtual) electrode positions using FFT. After placing an electrode cap to facilitate accurate electrode placement, the absolute power density (µV2 Hz–1) was measured continuously with 17 electrodes positioned according to the international 10:20 standard system with the central electrode Cz as the physical reference. The high input impedance of the amplifier (AC 10 MW; DC 20 MW) ensured a sufficient signal-to-noise ratio. Electrode impedance was in the range of 5 k
. The transferred data were simultaneously displayed on a monitor for automatic user-defined identification and the elimination of artifacts (movements of the eyes, surgical electrocoagulation, muscular or sweat effects). The signal frequencies were analysed using the FFT, which is based on 4 s data acquisition sweeps with effective sample rate of 128 Hz. The resulting frequency spectra were divided into six frequency bands (delta: 1.25–4.50 Hz; theta: 4.75–6.75 Hz; alpha 1: 7.00–9.50 Hz; alpha 2: 9.75–12.50 Hz; beta 1: 12.75–18.50 Hz; beta 2: 18.75–35.00 Hz).
The patients were assessed postoperatively by routine CT-scans (Siemens, Germany) within 48 h. To ensure adequate sensory and motor functions and attention, language and orientation, a thorough neurological examination was performed by an independent neurologist when the patient had regained consciousness, 1 and 6 h later, and then daily until the patient was discharged from the intensive care unit or the hospital.
Statistical analysis
The results are expressed as mean (SD). In all patients, arterial pressure values and EEG data were set at 100% or zero at 10 min before adenosine administration, and all the data from subsequent measurements at 1 min intervals were related to these control values.
Differences within or between the normally distributed data were analysed by analysis of variance (ANOVA) using SPSS 12.0 version followed by post hoc Tukey test. Statistical significance was taken at P<0.05. Pearson's coefficients of correlation coefficients between the measured parameters were calculated.
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Results |
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The mean (range) age of the patients was 60 (32–81) yr and mean (SD) body weight was 84 (13) kg. Arterial pressure (mean, systolic and diastolic) and heart rate were in physiological ranges before the induction of cardiac arrest by adenosine. No significant blood loss was registered during vascular surgery. Adenosine-induced cardiac arrest did not significantly affect arterial blood gas parameters during surgery (Table 2). A representative example of arterial pressure changes is shown in one patient during cardiac arrest (Fig. 1). In this patient, the heart stopped for
40 s; systolic and diastolic arterial pressures decreased from 126 to 28 mm Hg and from 69 to 27 mm Hg, respectively.
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In all patients, depending upon the dose of adenosine, the induction of cardiac arrest was associated with significant reductions in arterial pressure (between –38 and –70%) more than 1 min duration. A close biphasic relationship between adenosine dose and duration of cardiac arrest is shown in Figure 2. In detail, for adenosine dose <0.6 mg a linear relationship was detected, whereas with higher dose a plateau was reached (curve-linear dependency). In all patients, arterial blood pressure values normalized in 59 (22) s after the heart spontaneously started to beat again, and these remained unchanged until the end of the surgical procedure.
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No significant differences in intraoperative serum concentrations of NSE were obtained before or after adenosine (Table 3). An example of the original intraoperative EEG data before (Fig. 3A), during (Fig. 3B) and after (Fig. 3C) adenosine are shown in Figure 3. A transient, but significant reduction in all spectral frequencies was observed after adenosine-induced heart arrest reaching an isolelectric line. One minute after administering adenosine (Fig. 4), the fast alpha 1, alpha 2 and beta 1 EEG waves exhibited a drastic reduction (>40%) and reflected more sensitively the functional deficit in the brain than the delta and theta frequencies (<40%). Five minutes after administering adenosine, all EEG frequencies had normalized completely (Fig. 5) and remained unchanged until the end of surgery. A linear relationship between absolute EEG power spectrum and the duration of cardiac arrest was observed (Fig. 6) with correlation coefficients between –0.67 for theta and –0.8 for beta 1 frequencies (P<0.001). No topographical differences were observed at the fronto-parieto-occipital and central electrode positions when comparing the right and left hemisphere. Thus, adenosine caused a global and transient reduction in total EEG power.
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: alpha; ß: beta; 
: delta; 
: theta frequencies.
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No marked signs of stroke were detected in routinely performed CT-scans within 48 h after surgery. Neurological changes were investigated after operation in the intensive care unit by an independent neurologist. NIH scale presented no marked differences in comparison with preoperative data (P<0.05). None of the patients showed neurological deficits and changes such as aphasia, hemiparesis, changes in orientation, coordination and paraesthesia. The corneal and light reflexes were normal.
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Discussion |
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Adenosine dose-dependently induced a rapid cardiac arrest during stent implantation in thoracic aorta endovascular surgery. This was paralleled by transient (<1 min) and significant (up to 70%) reductions in arterial pressure. Fast systemic regulatory mechanisms and rapid adenosine inactivation could be responsible for this short cardiac arrest.5 It is well known that adenosine is rapidly inactivated by its uptake into erythrocytes and endothelial cells. The half-life time of adenosine in human plasma was determined to be <10 s at therapeutic doses.8 Therefore, cardiac arrest can only be reached when high adenosine doses are administered by bolus injection.
A characteristic linear and curve-linear relationship was determined between changes in adenosine dose and the duration of cardiac arrest (Fig. 2). With adenosine doses below 1.0 mg kg–1, there was a linear relationship between the two parameters. In contrast, with higher adenosine doses (>1.0 mg kg–1) a plateau was reached. Based on the linear relationship, it was calculated that adenosine dose of 0.017 mg kg–1 body weight is necessary to obtain cardiac arrest for 1 s. For example, in a patient weighing 80 kg the mean dose of adenosine required to reach cardiac arrest for at least 20 s in duration would be 30 mg. In practice, however, sporadic ventricular contractions that can prevent an accurate stent graft implantation have been reported with lower adenosine doses.12 In three patients in the present study, three to five sporadic ventricular contractions were detected during asystole. However, these contractions were of no clinical relevance for haemodynamic changes in MAP because the vessels were maximally dilated after adenosine administration, as was also shown by Hashimoto and colleagues,12 and did not disturb adequate stent graft placement. From previous investigations5 we know that higher adenosine dosages (>30 mg) are necessary during thoracic aorta endografting and accurate stent graft placement to exclude some sporadic ventricular contractions. When a maximum 58 s of cardiac arrest was reached, the hearts started to beat again. As shown in these results, arterial pressure returned to control values in a rather short period of time (1 min). No significant overshoot in the course of arterial pressure was observed after cardiac activity had fully recovered even with high dosages of adenosine. Thus, the results with adenosine clearly demonstrate rapid and complete blockade of AV-node conduction, full reversibility of adenosine's action within a short period of time and a close adenosine-dose dependency to the time of cardiac arrest. These characteristic features of adenosine are the major advantages of this nucleoside in comparison with induced profound hypotension2 3 by different pharmacological substances and ventricular fibrillation.4 Kahn and colleagues4 have reported that the induction of ventricular fibrillation can facilitate endovascular stent graft repair of thoracic aortic aneurysms. However, the fibrillating myocardium is characterized by enhanced oxygen consumption, thereby generating a significant mismatch in the oxygen supply-to-demand ratio of the heart. This detrimental condition is even more pronounced when the regular sinus node activity is induced by stressful defibrillation. For similar reasons we do not recommend the application of ß-blockers or potent vasodilators for inducing hypotension during endovascular stent placement.5 Compared with adenosine the onset and offset of the action of both types of drugs are rather slow and the precise adjustment and control of heart rate and arterial systemic blood pressure is difficult. Therefore, both alternatives are not used in our institution because of the relatively higher risk of the developing myocardial ischaemia and infarction.
Significant reduction in EEG power with fast restitution in cerebral function has been described after short cardiac arrest during defibrillator implantation by several authors.13 –16 To our knowledge, the present study is the first study analysing the effect of adenosine-induced cardiac arrest in relation to EEG frequencies. The used EEG methodology can reliably measure global EEG changes. One limitation of the use of a cap may be that the leads are not rigorously and precisely attached to the proper location of the scalp in every patient. However, the results of the present study demonstrate that adenosine-induced cardiac arrest caused a global, significant reduction of up to –57% in total EEG power without topographical differences. These results are in good agreement with the studies of other investigators.13 –16 Therefore the limitation of the use of an EEG cap is probably of negligible consequences. In addition, the data of EEG monitoring demonstrate that the initial reduction in EEG power was completely reversible (Figs 3 and 5). Even repeated two short periods of circulatory arrest did not cause cumulative global EEG changes.
It is highly likely that changes in the EEG power in the present study were the result of low cerebral perfusion pressure after cardiac arrest. In addition, it is also possible that changes in EEG power can result from a specific action of adenosine on brain tissue itself. The action of increased endogenous or exogenous adenosine is described as being neuroprotective,9 17 especially during cerebral ischaemia acting via different neuronal and glial adenosine receptors.
In this study, adenosine-induced cardiac arrest was associated with differential effects on the spectral EEG frequencies. In particular, fast alpha and beta frequencies were more sensitive to global changes in systemic and cerebral perfusion than other EEG frequencies. Some authors propose that different EEG frequencies can correlate to definite neurotransmitter systems.18 –20 Because cerebral adenosine can inhibit the release of excitatory amino acids, for example, glutamate,21 or antagonize dopamine,22 it may be postulated that changes in fast alpha 2 (dopaminergic) and beta 1 (glutamatergic) EEG frequencies are more sensitive to adenosine than other EEG frequencies.23 However, more specific pharmacological studies may be helpful to characterize the specificity of this nucleoside in inducing neuroprotective effects.
Pichlmayr and Lips24 reported that short-term changes in cerebral EEG only lead to reversible functional changes without persistent structural changes. To demonstrate the structural integrity of patients' brain tissue, NSE, one marker of neuronal integrity, was measured at different time points before and after cardiac arrest in accordance with Schaarschmidt and colleagues.10 No significant changes in serum NSE concentrations were obtained after cardiac arrest. In addition, after operation neurological assessment confirmed that none of the patients included in the present study exhibited neurological signs of ischaemia or stroke, respectively.
To draw more specific conclusions, we are currently investigating the cognitive abilities of patients before and after surgery using different psychometric tests (Nuernberger Altersinventar25). Preliminary results of these investigations show no significant differences in consciousness, attention or organized thinking. In line with cognitive function, daily working activities were not disturbed up to 3 months after vascular surgery (Plaschke K and Bardenheuer HJ, unpublished observations).
In summary, we have shown that adenosine-induced cardiac arrest is an alternative technique in patients undergoing thoracic aorta endovascular repair to induce hypotensive phases without persistent cerebral disturbances because EEG changes in our study were transient, totally reversible, and short in nature, and there was adequate haemodynamic and functional stability after termination of adenosine action. Therefore, in our opinion, adenosine-induced asystole is a very useful adjunctive technique that provides unencumbered identification of important aortic branches, precise definition of the local anatomy and an ideal environment for the accurate placement of thoracic endograft systems.
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Acknowledgments |
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The present study was supported by departmental and institutional funding. We thank Prof. Fiehn and Dr Zorn for technical support with the analysis of NSE.
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References |
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1 Dake MD, Miller DG, Semba CP, et al. Transluminal placement of endovascular stent-grafts for the treatment of descending thoracic aortic aneurysms. N Eng J Med 1994; 331: 729–34
2 Diethrich EB. A safe, simple alternative for pressure reduction during aortic endograft deployment. J Endovasc Surg 1996; 3: 275[CrossRef][Medline]
3 Neuhauser B, Perkmann R, Greiner A, et al. Mid-term results after endovascular repair of the atherosclerotic descending thoracic aortic aneurysm. Eur J Vasc Endovasc Surg 2004; 28: 146–53[Web of Science][Medline]
4 Kahn RA, Marin ML, Hollier L, et al. Induction of ventricular fibrillation to facilitate endovascular stent graft repair of thoracic aortic aneurysms. Anesthesiology 1998; 88: 534–6[Web of Science][Medline]
5 Bardenheuer HJ, Schumacher H, Weigand M, et al. High-dose adenosine for induction of cardiac arrest during endovascular reconstruction of thoracic aortic aneurysms. In: Amor M, Bergeron P, Castriota F, Cremonesi A, Mathias K, Raithel D, eds. Thoracic Aortic Endografting. A Multidisciplinary Approach. Marseille: MEET. COM and Co., 2004; 125–30
6 Sweeny MI. Neuroprotective effects of adenosine in cerebral ischemia: window of opportunity. Neurosci Biobehav Rev 1997; 21: 207–17[CrossRef][Web of Science][Medline]
7 Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 1963; 204: 317–22
8 Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma of human blood. Am J Physiol 1989; 256: C799–806
9 Plaschke K, Grant M, Weigand MA, et al. Neuromodulatory effect of propentofylline on rat brain under acute and long-term hypoperfusion. Br J Pharmacol 2001; 133: 107–16[CrossRef][Web of Science][Medline]
10 Schaarschmidt H, Prange HW, Reiber H. Neuron-specific enolase concentrations in blood as a prognostic parameter in cerebrovascular diseases. Stroke 1994; 25: 558–65[Abstract]
11 Baker AB, Bookallil MJ, Lloyd G. Intentional asystole during endoluminal thoracic aortic surgery without cardiopulmonary bypass. Br J Anaesth 1997; 78: 444–8
12 Hashimoto T, Young WL, Aagaard BD, et al. Adenosine-induced ventricular asystole to induce transient profound systemic hypotension in patients undergoing endovascular therapy. Dose–response characteristics. Anesthesiology 2000; 93: 998–1001[CrossRef][Web of Science][Medline]
13 Behrens S, Spies C, Neumann U, et al. Cerebral ischemia during implantation of automatic defibrillators. Z Kardiol 1995; 84: 798–807[Medline]
14 Clute HL, Levy WJ. Electroencephalographic changes during brief cardiac arrest in humans. Anesthesiology 1990; 73: 821–5[Medline]
15 Vriens EM, Bakker PFA, De Vries JW, et al. The impact of repeated short episodes of circulatory arrest on cerebral function. Reassuring electroencephalographic (EEG) findings during defibrillation threshold testing at defibrillator implantation. Electroencephalogr Clin Neurophysiol 1996; 98: 236–42[CrossRef][Web of Science][Medline]
16 Visser GH, Wieneke GH, Van Huffelen AC, et al. The development of spectral EEG changes during short periods of circulatory arrest. J Clin Neurophysiol 2001; 18: 169–77[CrossRef][Medline]
17 Plaschke K, Kreutzer S, Sommer C, et al. Does permanent carotid artery occlusion produce a ‘preconditioning-like’ effect towards more severe hypotension in energy metabolites? Role of cerebral adenosine. Clin Exp Pharmacol Physiol 2005; 32: 54–9[Medline]
18 Luthringer R, Boeijinga PH. Pharmaco-electroencephalography in Phase I. Methods Find Exp Clin Pharmacol 2002; 24 Suppl D: 95
19 Luthringer R. The place of electrophysiology in the proof of concept approach of psychotropic drug development. Methods Find Exp Clin Pharmacol 2002; 24 Suppl C: 65
20 Dimpfel W. Preclinical data base of pharmaco-specific rat EEG fingerprints (tele-stereo-EEG). Eur J Med Res 2003; 30: 199–207
21 Phillis JW, Smith-Barbour M, Perkins LM, et al. Characterization of glutamate, aspartate, and GABA release from ischemic rat cerebral cortex. Brain Res Bull 1994; 34: 457–66[CrossRef][Web of Science][Medline]
22 Nagel J, Hauber W. Reverse microdialysis of a dopamine D2 receptor antagonist alters extracellular adenosine levels in the rat nucleus accumbens. Neurochem Int 2004; 44: 609–15[CrossRef][Web of Science][Medline]
23 Cauli O, Morelli M. Caffeine and the dopaminergic system. Behav Pharmacol 2005; 16: 63–77[CrossRef][Web of Science][Medline]
24 Pichlmayr I, Lips U. EEG monitoring in anesthesiology and intensive care. Neuropsychobiology 1983; 10: 239–48[Medline]
25 Oswald WD, Fleischmann UM. Nuerberger Altersinventar (NAI), 4th edn. Goettingen: Hofgrefe Verlag, 1999; 1–351
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