Neuroscience Letters 417 (2007) 16–20
Significant correlation between plasma and CSF anticholinergic activity in presurgical patients Konstanze Plaschke a,∗ , Christine Thomas b,1 , Ria Engelhardt a , Peter Teschendorf a , Ute Hestermann c , Markus A. Weigand a , Eike Martin a , Juergen Kopitz d a
Department of Anesthesia, Medical Faculty of the University of Heidelberg, Germany Department of Psychiatry, Medical Faculty of the University of Heidelberg, Germany c Geriatric Center at the University Hospital Heidelberg, Medical Faculty of the University of Heidelberg, Germany d Institute of Molecular Pathology, Medical Faculty of the University of Heidelberg, Germany b
Received 22 September 2006; received in revised form 11 January 2007; accepted 7 February 2007
Abstract Previous studies have suggested a possible link between cognitive impairment and anticholinergic burden as reflected by high serum anticholinergic activity (SAA). Thus, we hypothesized a close relationship between anticholinergic activity in cerebral spinal fluid (CSF) and blood. However, it has never been convincingly demonstrated that peripheral anticholinergic activity correlates with central anticholinergic levels in presurgical patients. Therefore, anticholinergic activity was measured in blood and CSF from 15 patients with admission scheduled for urological surgery to compare peripheral and central anticholinergic level. Blood and CSF probes were taken after routine premedication and before spinal anesthesia. Anticholinergic activity was determined by competitive radioreceptor binding assay for muscarinergic receptors. Correlation analysis was conducted for peripheral and central anticholinergic levels. The mean anticholinergic levels were 2.4 ± 1.7 in the patients’ blood and 5.9 ± 2.1 pmol/mL of atropine equivalents in CSF. Interestingly, the anticholinergic activity in CSF was about 2.5-fold higher than in patients’ blood. A significant linear correlation was detected between blood and CSF levels. Therefore we conclude that SAA levels adequately reflect central anticholinergic activity. When patients receiving or not receiving anticholinergic medication were compared, anticholinergic activity tended to increase in blood and CSF after receiving anticholinergic medication ≥4 weeks (p > 0.05). © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Anticholinergic activity; Plasma; CSF; Correlation; Diagnostic marker
One hypothesis on the pathogenesis of delirium suggests that cerebral cholinergic transmission is impaired [35,36]. The clinical observation that delirium is one manifestation of anticholinergic toxicity [15] supports this hypothesis. Interest in the anticholinergic burden has recently increased, particularly in surgical patients due to the high risk of postoperative delirium [4,14,19]. The concept of an anticholinergic burden addresses the situation with regard to a variety of medications taken by elderly patients in particular. Older patients are at risk of an increased anticholinergic burden due to age-related physiolog∗ Corresponding author at: Department of Anesthesiology, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Tel.: +49 6221 566451; fax: +49 6221 564399. E-mail address:
[email protected] (K. Plaschke). 1 Present address: Department of Geriatric Psychiatry, Clinic of Psychiatry and Psychotherapy Bethel, Ev. Hospital, Bielefeld, Germany.
0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2007.02.015
ical changes, comorbidity, and the use of multiple medications (polypharmacy) [6,16,32,35]. Delirium, defined as an acute change in mental status or a fluctuating course, impaired attention, and disorganized thinking, is associated with underlying illnesses such as medical problems, drug abuse, or withdrawal [1,4,13,17]. For anesthetists, postoperative delirium is of particular significance due to its association with worsened outcome in hospitalized patients, including prolonged hospital stay [7] and increased mortality in intensive care units (ICU) [3,8,23]. Previous work had suggested a possible link between delirium and serum anticholinergic activity (SAA) [9]. SAA reflects the cumulative binding capacity of endogenous substances, exogenous drugs, and their metabolites to muscarinic receptors [37]. Several studies reported a correlation of SAA with delirium in surgical ICU patients [12,39]; increased SAA levels were also associated with cognitive impairment during depression [29] or dementia [2,33]. However, whether SAA levels correlate
K. Plaschke et al. / Neuroscience Letters 417 (2007) 16–20
with anticholinergic drugs is a subject of controversy [10,24]. It is unclear whether SAA reflects a central cholinergic burden or inhibition. CSF levels have previously only been measured in 9 patients. Of these subjects 5 had received a scopolamine challenge [24]. Therefore, the aim of the present study was to investigate whether SAA measurements reliably reflect the cerebral anticholinergic activity in CSF in a typical presurgical population (urological patients) who did not receive scopolamine preoperatively. If such a close correlation between peripheral and central anticholinergic activity did exist, preoperative SAA level might become a prognostic/diagnostic marker to identify patients with a high risk for postoperative delirium due to high anticholinergic medication. Fifteen patients receiving spinal anesthesia (SA) for a planned urological procedure were recruited for the present study at the Department of Anesthesiology of the University of Heidelberg. They had given their written informed consent and the study was conducted in accordance with the Declaration of Helsinki and was approved by the University’s Ethics Review Board (University of Heidelberg, Germany, no. 196/2004). Patients’characterization included age, ASA (American Society of Anesthesiology) classification, reason for surgery, anticholinergic medication, and kind of medication in patients’ history according to Lu and Tune [20] and Tune and Egeli [40] for at least 4 weeks before surgery. The SA was performed by the same investigator (PT) in a standardized manner. The patients were orally premedicated with 7.5 mg midazolam at 24 h and 1 h before surgery. During induction the patients were connected to a standard monitor (EKG-, SpO2 -, noninvasive blood pressure measurements). Following the placement of an i.v. cannula, 5 ml of blood was drawn into an EDTA vial and immediately stored at 4 ◦ C for 1 h. Then the SA was performed under local anesthesia (s.c. scandicaine® 1%) in the right lateral position at the lumbar interspace L2/3 or L3/4 after sterile preparation of the skin and after applying a sterile dressing. The subarachnoid space was identified with a 25-gauge Sprotte spinal needle. Thereafter, 2 ml of CSF were withdrawn using a syringe followed by the injection of 2 ml of hyperbaric mepivacaine (4%) and 5 g of sufentanil. CSF was immediately stored at 4 ◦ C. For determination of SAA, the blood was centrifuged for 10 min at 7000 rpm; the supernatant was then taken and stored at −80 ◦ C together with the CSF probes until further analysis. An investigator blinded to all clinical data conducted the anticholinergic activity measurements by competitive radioreceptor binding assay as described by Tune and Coyle [37]. Briefly, homogenized cerebral cortex from untreated adult Wistar rats was used as the source of muscarinergic receptors (mACH). Anticholinergic agents in patients’ serum or cerebral spinal fluid (CSF) competitively inhibit binding of tritiated lquinuclidinyl(phenyl-4-3 H) (3 H-QNB, Amerham Biosciences), which binds with high and specific affinity to all five mACH receptor subtypes obtained from a rat homogenate cortex. The displacement of 3 H-QNB can be used to quantify the anticholinergic activity of serum or CSF in comparison to an atropine standard curve. The results are reported in picomole per milliliter
17
(pmol/mL) of atropine equivalents. Interassay accuracy was determined with spiked serum and CSF over 5 days at different concentrations, ranging from 5–25 pmol/mL atropine, and ranged between 95 and 106%. A correlation analysis for anticholinergic activity in serum and CSF was performed according to Pearson with SPSS version 14.0. Significant differences (p < 0.05) between two patient groups, (i) patients receiving anticholinergic medication and (ii) not receiving anticholinergic medication ≥4 weeks before surgery, were calculated using the Student t-test. During spinal anesthesia (SA), the mean heart rates (65 ± 14 min−1 ), the SpO2 values (98% ± 2%), and the mean blood pressure (115/65 ± 11/5 mm Hg) were in physiological ranges. Patients’ data are given in Table 1. The mean age of patients was 70.4 + 6.0 years, ranging from 58–78 years: 14 out of 15 patients were male. Twelve of 15 patients had received anticholinergic medication ≥4 weeks before surgery and were compared with patients who had not received anticholinergic medication (n = 3). All additional medications given before SA and surgery (≤24 h) are listed in Table 1. The mean SAA level (in atropine equivalents) for all patients amounted to 2.4 ± 1.7 pmol/mL (range 0–5), while the mean anticholinergic activity in CSF was 5.9 ± 2.1 pmol/mL (range 2–12). Patient number 6, who demonstrated a CSF anticholinergic level of 12, was pretreated with chlorazepate in addition to midazolam (≤24 h). In all, CSF anticholinergic activity was about 2.5-fold higher than blood levels. In subjects who received anticholinergic medication, the mean SAA was 2.7 ± 1.7 and to 6.4 ± 2.0 in CSF as compared to patients who did not receive anticholinergic medication with 1.0 ± 1.0 and 4.0 ± 1.7 pmol/mL in blood and CSF, respectively. These levels did not significantly differ between the two groups. Gathering the data from all 15 patients, a significant correlation of anticholinergic levels (r = 0.86; p < 0.001) indicated a close linear relation between anticholinergic activity in CSF and blood (Fig. 1). Thus, we conclude that SAA adequately
Fig. 1. Anticholinergic activity. Correlation analysis according to Pearson (r = 0,861; p < 0,001). The results are reported in pmol/mL of atropine equivalents.
18
K. Plaschke et al. / Neuroscience Letters 417 (2007) 16–20
Table 1 Patient’s data No.
Sex
Age
ASA
Admission diagnosis
SAA (pmol/mL atrop. equ.)
CSF-AA (pmol/mL atrop. equ.)
1 2
M F
67 79
2 4
PGH Renal failure
1 1
5 5
3
M
75
3
PGH
0
4
4
M
77
4
PGH
2
6
5 6 7
M M M
66 64 70
2 1 3
Oedema testis left PGH PGH
3 5 1
7 12 5
8
M
67
3
Vacuseal change
4
7
9
M
70
3
Urethra constriction
2
6
10 11 12 13 14 15
M M M M M M
58 66 69 74 78 76
2 2 2 2 2 3
PGH PGH PGH Prostate carcinoma PGH Prostate carcinoma
5 2 5 0 3 2
7 5 7 2 6 5
Medication (≥4 weeks)
Medication (≤24 h)
Tam, ibu Metop, sim, eso, felo, val, digi, zop, pyr Levof, car, allo, sim, digi, enal, nif, mol, pan, diclo Nal, gli, hyd, spi, eso, ator, allo, eno, tio Ator, hyd Digi, enal, nif Thyr, bisi, furo, pan, hyd, sim, tam, diclo Pan, metop, gaba, hyd, trama, metoc, meta Bisi, pan, amp, capto, hyd, xip, met, diclo l-dopa, c-dopa metop, allo, enal Bisi, hyd, flec ator Hyd, lisi, bisi, amp Ran, thyr
Mida, levof Mida Mida Mida Mida Mida, chlorazepate Mida Mida Mida Mida Mida Mida Mida, ran Mida Mida, ran
M: male; F: female; SA: spinal anesthesia; ASA: American Society of Anesthesiologists classification; SAA: serum anticholinergic activity; CSF-AA: cerebral spinal fluid anticholinergic activity; atrop. equiv.: atropine equivalents; PGH: prostate gland hyperplasia; adm.: admission. Medication: allopurinol: allo; amplodipine: amp; atorvastatin: ator; bisiprolol: bisi; captopril: capto; carvedilol: car; carbodopa: c-dopa; diclofenac: diclo; digitoxin: digi; enalapril: enal; enoxaparin: eno; esomeprazole: eso; felodipine: felo; flecainid: flec; furosemide: furo; gabapentin: gaba; glimepiride: gli; hydrochlorathiazide: hyd; ibuprofen: ibu; levodopa: l-dopa; levofloxacin: levof; lisinopril: lisi; midazolam: mida; metamizole: meta; metformin: met; metoclopramide: metoc; metoprolol: metop; molsidomin: mol; naloxone: nal; nifidipin: nif; pantoprazole: pan; pyrazolone: pyr; ranitidine: ran; simvastatin: sim; spironolactone: spi; tamsulosine: tam; thyroxine: thyr; tiotropiumbromide: tio; tramadol: tram; valsartane: val; xipamide: xip; zopiclon: zop.
reflects the central anticholinergic capacity measured by CSF levels. The close linear correlation between anticholinergic activity in blood and CSF as shown by our study for a typical, nonselected, routinely premedicated patient group undergoing a planned urological surgical procedure confirms the hypothesis that SAA reflects central cholinergic changes. This supports and extends the findings of Miller et al. [24] also demonstrating a significant association between anticholinergic activity in serum and CSF, however, particularly only after administration of scopolamine. To our knowledge, no comparable studies measuring anticholinergic activity in CSF have been carried out so far. We demonstrate measurable anticholinergic activity without scopolamine medication in a representative cohort of elderly patients undergoing planned urological surgery. Interestingly, the anticholinergic activity in CSF measured in the present study was higher than in blood and higher than the CSF levels presented in Miller’s study [24]. Although the reasons for this are difficult to elucidate, the following possible explanations might be considered. An effect of the local anesthetic mepivacaine on CSF can be excluded because it was applied after the CSF samples were taken. It appears more likely that the 2.5-fold increased levels of anticholinergic activity in CSF as compared to SAA are due to the effect of midazolam used as premedication in all patients. A central anticholinergic mechanism may be involved in the sedative action of midazolam, as shown by Ebert et al.
[5]. In addition, the patients in this study show a high number of medications in their history (polypharmacy), including potentially and definitely anticholinergic medication [20,33,40], as listed in Table 1. The higher level of anticholinergic activity in patient no. 6 (12 pmol/mL in CSF) might be associated with the benzodiazepine chlorazepate premedication. Centrally acting anticholinergic drugs such as neuroleptics, benzodiazepines, and barbiturates were significantly more common with higher SAA [21,28]. Anticholinergic activity tends to be higher in patients who receive diverse anticholinergic medication ≥4 weeks before surgery than in patients without defined anticholinergic medication in their history, as shown by the present analysis. Diverging answers to the question of whether SAA correlates with anticholinergic drug use or cognitive dysfunction have been reported [30,31,33]. Due to the relatively small number of patients included in this study, a more detailed correlation analysis including specific medication and anticholinergic activity was not feasible, and therefore should be the subject of a larger study. Although most previous studies suggested a clear association between SAA levels and cognitive impairment [27,34,39], SAA concentrations are only a transient and global measure that might not represent cerebral levels in every case. Notably, the differential permeability of the blood-brain barrier (BBB), in particular in the elderly [18], must be taken into account. Cognitive impairment and even delirium have been reported with
K. Plaschke et al. / Neuroscience Letters 417 (2007) 16–20
several drugs, despite SAA levels being well within the normal limits [26]. Endogenous sources of SAA, related to fever, acute infection or stress, have been postulated independently of anticholinergic medication [9,10,24]. Delirium itself does not seem to correlate with an overall anticholinergic burden [9,22], whereas a correlation with specific centrally active drugs was reported [11,16]. Sources of the anticholinergic burden can be highly individual, and the SAA therefore may be considered a conglomerate of anticholinergic properties of endogenous and exogenous origin. Moreover, medications that do not cross the BBB will contribute to SAA without necessarily having a corresponding cerebral effect, thereby possibly weakening any relation between SAA and performance. However, determination of anticholinergic activity seems to be a useful means of assessing drug intoxication. The SAA levels from the present study of presurgical patients with a mean age of about 70 years were shown to be 2.4 ± 1.7 pmol/mL of atropine equivalents. SAA levels reported in the literature were measured with comparable methods but revealed very divergent results [2,38], which may be due to the different populations studied. While in younger patients and healthy people SAA levels were undetectable or small [27,29], surgical patients with scopolamine or atropine derived SAA levels revealed the highest values [12,24,25]. In some studies relatively high values were detected in the oldest individuals [28,33], whereas other groups found much smaller SAA in quite similar patients [2,9,21], especially in patients who did not develop delirium. The present study is limited by the relatively small number of patients and the fact that no cognitive tests were conducted. The present study was carried out mainly for methodological reasons. Therefore, it could be conducted with a relatively small number of patients and only one time point was chosen. In the meantime, a new study with about 300 patients was started in our clinic to determine cognitive changes in postoperative patients in parallel to SAA and EEG changes. The aim is to obtain more detailed information about the correlation of SAA to anticholinergic medication and delirium risk in patients with postoperative delirium. Acknowledgements This work was supported in part by the Else KroenerFresenius-Stiftung, Bad Homburg v.d.H., Germany. We want to thank Mrs. S. Himmelsbach for excellent technical assistance. References [1] M. Aldemir, S. Ozen, I.H. Kara, A. Sir, B. Bac, Predisposing factors for delirium in the surgical intensive care unit, Crit. Care 5 (2001) 265–270. [2] M.L. Chew, B.H. Mulsant, B.G. Pollock, Serum anticholinergic activity and cognition in patients with moderate-to-severe dementia, Am. J. Geriatr. Psychiatry 13 (2005) 535–538. [3] D. Crippen, Life-threatening brain failure and agitation in the intensive care unit, Crit. Care 4 (2000) 81–90. [4] M.J. Dubois, N. Bergeron, M. Dumont, S. Dial, Y. Skrobik, Delirium in an intensive care unit: A study of risk factors, Intensive Care Med. 27 (2001) 1297–1304.
19
[5] U. Ebert, R. Oertel, W. Kirch, Physostigmine reversal of midazolaminduced electroencephalographic changes in healthy subjects, Clin. Pharmacol. Ther. 67 (2000) 538–548. [6] A. Edlund, M. Lundstrom, S. Karlsson, B. Brannstrom, G. Bucht, Y. Gustafson, Delirium in older patients admitted to general internal medicine, J. Geriatr. Psychiatry Neurol. 19 (2006) 83–90. [7] E.W. Ely, S. Gautam, R. Margolin, J. Francis, L. May, T. Speroff, B. Truman, R. Dittus, R. Bernard, S.K. Inouye, The impact of delirium in the intensive care unit on hospital length of stay, Intensive Care Med. 27 (2001) 1892–1900. [8] E.W. Ely, A. Shintani, B. Truman, T. Speroff, S.M. Gordon, F.E. Harrell Jr., S.K. Inouye, G.R. Bernard, R.S. Dittus, Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit, JAMA 291 (2004) 1753–1762. [9] J.M. Flacker, V. Cummings, J.R. Mach Jr., K. Bettin, D.K. Kiely, J. Wei, The association of serum anticholinergic activity with delirium in elderly medical patients, Am. J. Geriatr. Psychiatry 6 (1998) 31–41. [10] J.M. Flacker, J.Y. Wei, Endogenous anticholinergic substances may exist during acute illness in elderly medical patients, J. Gerontol. A. Biol. Sci. Med. Sci. 56 (2001) M353–M355. [11] J.D. Gaudreau, P. Gagnon, F. Harel, M.A. Roy, A. Tremblay, Psychoactive medications and risk of delirium in hospitalized cancer patients, J. Clin. Oncol. 23 (2005) 6712–6718. [12] R.C. Golinger, T. Peet, L.E. Tune, Association of elevated plasma anticholinergic activity with delirium in surgical patients, Am. J. Psychiatry 144 (1987) 1218–1220. [13] A.I. Granberg, C.W. Malmros, I.L. Bergbom, D.B. Lundberg, Intensive care unit syndrome/delirium is associated with anemia, drug therapy and duration of ventilation treatment, Acta Anaesthesiol. Scand. 46 (2002) 726–731. [14] L. Han, J. McCusker, M. Cole, M. Abrahamowicz, F. Primeau, M. Elie, Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients, Arch. Intern. Med. 161 (2001) 1099–1105. [15] R. Hall, M. Popkin, L. Henry, Angel’s trumpet psychosis: a central nervous system anticholinergic syndrome, Am. J. Psychiatry 134 (1977) 312– 314. [16] S.K. Inouye, Delirium in older persons, N. Engl. J. Med. 354 (2006) 1157–1165. [17] S.K. Inouye, S.T. Bogardus Jr., P.A. Charpentier, L. Leo-Summers, D. Acampora, T.R.L.M. Holford, A. Cooney Jr., Multicomponent intervention to prevent delirium in hospitalized older patients, N. Engl. J. Med. 340 (1999) 669–676. [18] G.G. Kay, M.B. Abou-Donia, W.S. Messer Jr., D.G. Murphy, J.W. Tsao, J.G. Ouslander, Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients, J. Am. Geriatr. Soc. 53 (2005) 2195–2201. [19] N. Lechevallier-Michel, M. Molimard, J.F. Dartigues, C. Fabrigoule, A. Fourrier-Reglat, Drugs with anticholinergic properties and cognitive performance in the elderly: results from the PAQUID Study, Br. J. Clin. Pharmacol. 59 (2005) 143–151. [20] C.J. Lu, L.E. Tune, Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease, Am. J. Geriatr. Psychiatry 11 (2003) 458–461. [21] J.R. Mach Jr., M.W. Dysken, M. Kuskowski, E. Richelson, L. Holden, K.M. Jilk, Serum anticholinergic activity in hospitalized older persons with delirium: a preliminary study, J. Am. Geriatr. Soc. 43 (1995) 491–495. [22] E.B. Milbrandt, D.C. Angus, Potential mechanisms and markers of critical illness-associated cognitive dysfunction, Curr. Opin. Crit. Care 11 (2005) 355–359. [23] E.B. Milbrandt, S. Deppen, P.L. Harrison, A.K. Shintani, T. Speroff, R.A. Stiles, B. Truman, G.R. Bernard, R.S. Dittus, E.W. Ely, Costs associated with delirium in mechanically ventilated patients, Crit. Care Med. 32 (2004) 955–962. [24] P.S. Miller, J.S. Richardson, C.A. Jyu, J.S. Lemay, M. Hiscock, D.L. Keegan, Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients, Am. J. Psychiatry 145 (1988) 342–345.
20
K. Plaschke et al. / Neuroscience Letters 417 (2007) 16–20
[25] F.M. Mondimore, N. Damlouji, M.F. Folstein, L. Tune, Post-ECT confusional states associated with elevated serum anticholinergic levels, Am. J. Psychiatry 140 (1983) 930–931. [26] A.R. Moore, S.T. O’Keeffe, Drug-induced cognitive impairments in the elderly, Drugs Aging 15 (1999) 15–28. [27] B.H. Mulsant, B.G. Pollock, M. Kirshner, C. Shen, H. Dodge, M. Ganguli, Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance, Arch. Gen. Psychiatry 60 (2003) 198–203. [28] C. Mussi, R. Ferrari, S. Ascari, G. Salvioli, Importance of serum anticholinergic activity in the assessment of elderly patients with delirium, J. Geriatr. Psychiatry Neurol. 12 (1999) 82–86. [29] R.D. Nebes, B.G. Pollock, B.H. Mulsant, M.A. Kirshner, E. Halligan, M. Zmuda, C.F. Reynolds III, Low-level serum anticholinergicity as a source of baseline cognitive heterogeneity in geriatric depressed patients, Psychopharmacol. Bull. 33 (1997) 715–720. [30] A.J. Remillard, A pilot project to assess the association of anticholinergic symptoms with anticholinergic serum levels in the elderly, Pharmacotherapy 14 (1994) 482–487. [31] B.W. Rovner, A. David, M.J. Lucas-Blaustein, B. Conklin, L. Filipp, L. Tune, Self-care capacity and anticholinergic drug levels in nursing home patients, Am. J. Psychiatry 145 (1988) 107–109. [32] J.D. Schor, S.E. Levkoff, L.A. Lipsitz, C.H. Reilly, P.D. Cleary, J.W. Rowe, D.A. Evans, Risk factors for delirium in hospitalized elderly, JAMA 267 (1992) 827–831.
[33] O.J. Thienhaus, A. Allen, J.A. Bennett, Y.M. Chopra, F.P. Zemlan, Anticholinergic serum levels and cognitive performance, Eur. Arch. Psychiatry Clin. Neurosci. 240 (1990) 28–33. [34] G.D. Tollefson, J. Montague-Clouse, S.P. Lancaster, The relationship of serum anticholinergic activity to mental status performance in an elderly nursing home population, J. Neuropsychiatry Clin. Neurosci. 3 (1991) 314–319. [35] P. Trzepacz, The neuropathogenesis of delirium. The clinical observation that delirium is one manifestation of anticholinergic toxicity, Psychosomatics 4 (1994) 374–391. [36] P.T. Trzepacz, Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine, Semin. Clin. Neuropsychiatry 5 (2000) 132–148. [37] L. Tune, J.T. Coyle, Serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects, Arch. Gen. Psychiatry 37 (1980) 293–297. [38] L.E. Tune, Serum anticholinergic activity levels and delirium in the elderly, Semin. Clin. Neuropsychiatry 5 (2000) 149–153. [39] L.E. Tune, N.F. Damlouji, A. Holland, T.J. Gardner, M.F. Folstein, J.T. Coyle, Association of postoperative delirium with raised serum levels of anticholinergic drugs, Lancet 2 (1981) 651–653. [40] L.E. Tune, S. Egeli, Acetylcholine and delirium, Dement. Geriatr. Cogn. Disord. 10 (1999) 342–344.
