Secondary Logo

Journal Logo

Intraoperative Dexamethasone and Delirium After Cardiac Surgery: A Randomized Clinical Trial

Sauër, Anne-Mette C. MD*; Slooter, Arjen J. C. MD, PhD; Veldhuijzen, Dieuwke S. PhD*; van Eijk, Maarten M. J. MD, PhD; Devlin, John W. PharmD, FCCM, FCCP; van Dijk, Diederik MD, PhD

doi: 10.1213/ANE.0000000000000248
Cardiovascular Anesthesiology: Research Report
Free
SDC

BACKGROUND: Delirium is common after cardiac surgery and may be partly related to the systemic inflammatory response triggered by the surgery and the use of cardiopulmonary bypass. We hypothesized that intraoperative administration of high-dose dexamethasone, a drug with potent anti-inflammatory effects, would reduce the incidence of delirium at any time point during the first 4 postoperative days after cardiac surgery.

METHODS: This was a single-center substudy within a larger, multicenter placebo-controlled randomized clinical trial, the Dexamethasone for Cardiac Surgery (DECS) trial that randomized patients ≥18 years, undergoing cardiac surgery with cardiopulmonary bypass, to receive, in a double-blind fashion, either dexamethasone 1 mg/kg or placebo at the induction of anesthesia. Over the first 4 postoperative days, we compared between groups the incidence of delirium (based on the Confusion Assessment Method adapted for the intensive care unit, or after intensive care unit discharge, by the Confusion Assessment Method, accompanied by chart review), restraint use, and administered haloperidol, benzodiazepines, and opioids. Data were analyzed according to the intention-to-treat principle. The proportion of patients with delirium in the dexamethasone versus the placebo group was compared using the odds ratio (OR) with a 95% confidence interval (CI). The proportion also was compared using logistic regression to adjust for common baseline variables that might confound the presence of delirium between the 2 groups.

RESULTS: Of 768 eligible patients, 737 subjects (96.0%) had complete data. The incidence of delirium was similar between the dexamethasone (14.2%) and placebo (14.9%) groups (crude OR = 0.95, 95% CI, 0.63–1.43; adjusted OR = 0.85, 95% CI, 0.55–1.31). Among patients who developed delirium, the median (interquartile range) duration of delirium was similar between the dexamethasone and placebo groups (2 [1–3] vs 2 [1–2] days, respectively, P = 0.45; WMWodds 0.98, 95% CI, 0.83–1.17). Restraint use and the administration of haloperidol, benzodiazepines, and opioids were also similar between the 2 groups.

CONCLUSIONS: The intraoperative administration of dexamethasone did not reduce the incidence or duration of delirium in the first 4 days after cardiac surgery.

Published ahead of print May 7, 2014.Supplemental Digital Content is available in the text.

From the Departments of *Anesthesiology, and Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; and Department of Pharmacy Practice, Bouve College, Northeastern University, Boston, Massachusetts.

Published ahead of print May 7, 2014.

Maarten M. J. van Eijk, MD, PhD, is currently affiliated with Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.

Accepted for publication January 24, 2014.

Funding: This work was supported by grants 80-82310-98-08607 from the Netherlands Organization for Health Research and Development (ZonMw) and 2007B125 from the Dutch Heart Foundation.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the International Symposium on Intensive Care and Emergency Medicine, Brussles, Belgium, 2013 and at the annual meeting of the European Delirium Association in Leuven, Belgium, 2013.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Anne-Mette C. Sauër, MD, Department of Anesthesiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Address e-mail to a.c.sauer@umcutrecht.nl.

Delirium, defined by an acute change in consciousness, attention, cognition, and perception caused by a general medical condition,1 occurs in up to 52% of patients undergoing cardiac surgery.2–4 Patients who develop delirium have an increased risk of death,5 prolonged hospitalization, and long-term cognitive impairment.6,7 While the precise mechanisms of delirium after cardiac surgery are not fully elucidated, the profound inflammatory response associated with the surgery and the use of cardiopulmonary bypass remain a key potential instigating factor. This inflammatory response8 and an increased embolic load are postulated to increase blood––brain barrier permeability, leading to neuroinflammation and potentially cerebral edema, possibly causing postoperative delirium and cognitive decline.9–11 The role of the hypothalamic-pituitary axis and serum cortisol in the pathogenesis of postoperative delirium is controversial.12–16 While postoperative serum cortisol concentrations are higher in patients who develop delirium,12,14,16 this association has not been consistently found.12 It remains unclear whether this relationship is causally related to delirium or is simply a marker of the inflammatory stress response that develops during surgery.14–16

The inflammatory response during and after cardiac surgery can be suppressed with the administration of high-dose corticosteroids.17 It has been hypothesized that this reduces neuroinflammation and cerebral edema and therefore may prevent the development of postoperative delirium. One small controlled study indeed suggested that postoperative administration of dexamethasone was associated with a reduced delirium prevalence.18 It could also be argued, however, that dexamethasone increases the risk of delirium because delirium is a known complication of long-term and/or high-dose treatment with corticosteroids.19 It is currently unknown whether dexamethasone will increase or decrease the incidence of postoperative delirium.

In a recent multicenter, randomized study, the Dexamethasone for Cardiac Surgery (DECS) trial, intraoperative administration of high-dose dexamethasone (1 mg/kg) bodyweight was associated with less delirium.20 However, in that study, the presence of delirium was defined by the postoperative use of an antipsychotic medication(s), rather than based on delirium screening using a validated instrument, and thus it is likely that delirium was underrecognized.21,22 The objective of the present study was to investigate in detail whether the intraoperative administration of high-dose dexamethasone to patients undergoing cardiac surgery affects the incidence of postoperative delirium during the first 4 postoperative days. We hypothesized that dexamethasone administration would reduce the incidence of delirium at any time point during the first 4 postoperative days.

Back to Top | Article Outline

METHODS

Study Design and Participants

The Medical Ethics Committee of the University Medical Center Utrecht approved this study, and written informed consent was obtained from all patients. This was a single-center substudy within a larger, multicenter placebo-controlled randomized clinical trial, the DECS trial that was registered in ClinicalTrials.gov (NCT00293592). The design of the DECS trial has been published in detail elsewhere.20 Briefly, patients 18 years or older undergoing cardiac surgery with cardiopulmonary bypass at the University Medical Center Utrecht were randomized, in a double-blind fashion, to receive a single 1 mg/kg IV injection of dexamethasone (maximum 100 mg), or placebo at the time of induction of anesthesia. Specifics regarding the randomization, allocation, and implementation of the interventions are described in detail in the DECS trial.20 We excluded patients who required emergency surgery, those who were scheduled for a procedure using an off-pump technique, and patients with a life expectancy ≤6 months.

Back to Top | Article Outline

Delirium Assessment

The primary study outcome was the presence of delirium on any of the first 4 postoperative days. Patients were assessed for delirium 7 days a week at a fixed time point as much as possible by trained research personnel using a previously validated method.23 Briefly, during intensive care unit (ICU) admission, delirium was assessed daily by a research nurse using the Confusion Assessment Method (CAM) adapted for the ICU (CAM-ICU),24 and a chart review over the previous 24 hours that included the results of twice daily CAM-ICU assessments conducted by the bedside nurse, and notation of administration of haloperidol. Patients found to have a Richmond Agitation Sedation Scale25 score of −4 or −5 were deemed to be unarousable and were not evaluated for delirium.26 Patients transferred to the ward were evaluated on a daily basis for the presence of delirium by trained research personnel using the CAM.27 Like the ICU evaluations, each patient’s record over the previous 24-hour period was reviewed to identify key words suggestive of delirium (e.g., confused, agitated, drowsiness, disorientated, and delirious) and the administration of antipsychotic therapy.28

Back to Top | Article Outline

Secondary Outcomes

Restraint use, episodes of patient-initiated device removal (e.g., self-extubation), and the amount of administered benzodiazepines, opioids, and haloperidol were recorded for each postoperative assessment day. Duration of delirium was also considered a secondary study outcome. All benzodiazepine use was converted in diazepam equivalents29 where 1 mg diazepam was equivalent to: 1.5 mg midazolam, 4 mg oxazepam, 0.2 mg lorazepam, 2 mg temazepam,1.3 mg zopiclone, 0.8 mg clonazepam,30 and 1 mg zolpidem.30 All opioid use was converted in morphine equivalents31,32 where 1 mg IV morphine was deemed equivalent to 10 mcg IV fentanyl, 1.5 mg oral oxycodone, 15 mg oral tramadol, and 1.5 mg oral piritramide. Demographic, clinical, and surgical data were obtained from the DECS trial database.20

Back to Top | Article Outline

Statistical Analysis

Given the assumption that the prevalence of delirium in cardiac surgery patients is 16%, that a clinically significant decrease in the incidence of delirium with the use of dexamethasone use would be 50%, and 90% power, and a 2-sided significance level of 5%, we estimated that 345 patients would be required in each group to detect a reduction in delirium from 16% to 8%.

Data were analyzed according to the intention-to-treat principle. The proportion of patients with delirium in the dexamethasone versus the placebo group was compared using the odds ratio (OR) with a 95% confidence interval (CI). The proportion also was compared using logistic regression. We performed logistic regression analysis to adjust for common baseline variables that might confound the presence of delirium between the 2 groups: age, gender, valve surgery, and history of stroke (Supplemental Digital Content, http://links.lww.com/AA/A898). Additional sensitivity analyses were conducted in which deceased patients were assigned to have delirium.

Normally distributed continuous data were presented as means with a 95% CI and compared using a Student t test. Skewed data were presented as medians with interquartile ranges and analyzed with a Mann-Whitney U test and WMWodds with accompanying 95% CI.33,34 Binary data were presented as percentages and analyzed using the Pearson χ2 test.

The analyses were performed using SPSS software, version 15 (SPSS Inc., Chicago, IL). All reported P values were 2-sided, and a significance level of P < 0.05 was used.

Back to Top | Article Outline

RESULTS

Among the 768 enrolled patients in the DECS trial at the University Medical Center Utrecht between June 2009 and November 2011, complete data for this study were obtained for 737 patients (96.0%, Fig. 1). Baseline demographic, clinical, and surgical factors were similar between the dexamethasone (n = 367) and placebo (n = 370) groups (Table 1).

Figure 1

Figure 1

Table 1

Table 1

The incidence of delirium over the first 4 postoperative days was comparable between the dexamethasone and placebo groups (14.2% [n = 52] vs 14.9% [n = 55]; crude OR 0.95, 95% CI, 0.631.43, P = 0.79). After adjusting for the potential confounders described above, the incidence of delirium remained similar between the 2 groups (adjusted OR 0.85, 95% CI, 0.551.31, P = 0.45). The proportion of patients in each group who had delirium on each of the 4 postoperative days was also similar (Fig. 2). Among patients who developed delirium, the median (interquartile range) number of delirium days did not differ between the dexamethasone and placebo groups (2 [13] vs 2 [12]; Mann-Whitney U P = 0.45, WMWodds 0.98, 95% CI, 0.831.17). A sensitivity analysis, where any patient who died during the 4-day postoperative period was assigned to have delirium, did not change these findings.

Figure 2

Figure 2

The daily amount of administered haloperidol, benzodiazepines, and opioids was similar between the 2 groups on each of the 4 assessment days (Table 2). The proportion of patients who received ≥1 dose of haloperidol over the course of the 4-day assessment period did not differ between the dexamethasone (9.3%, n = 34) and placebo (8.9%, n = 33) groups (P = 0.87). Furthermore, restraint use and incidence of patient-initiated device removal were similar between the 2 groups (Table 3). In addition, we found a comparable proportion of patients who experienced deep sedation or coma (Richmond Agitation Sedation Scale of −4 or −5) over the assessment period in the dexamethasone (2.4%) and placebo (3.4%) groups (P = 0.36).

Table 2

Table 2

Table 3

Table 3

Back to Top | Article Outline

DISCUSSION

In this randomized clinical trial in 737 cardiac surgical patients, we did not find a difference in the incidence and duration of delirium over the first 4 postoperative days between patients who received a high dose of intraoperative dexamethasone and those who received placebo, despite controlling for other factors that could have affected delirium incidence. Sensitivity analyses in which deceased patients were assigned to have delirium did not change our findings.

Previous reports on the incidence of delirium in cardiac surgery vary widely ranging from 3% to 50%.2–4,7,16,21,22 The incidence found in this study corresponds closely to a similar, large trial that reported an incidence of 11.9% in 1528 cardiac patients.22 The incidence of postoperative delirium in our Utrecht cohort (14.5%) was higher than in the overall DECS study population (10.4%).20 This most likely resulted from different methods to detect delirium between the 2 cohorts. In Utrecht, delirium was evaluated in detail on a daily basis by trained research personnel. By contrast, patients at the other centers were not screened for delirium using a formalized procedure. Instead, delirium was deemed to have occurred based on a retrospective review of the patient’s record and documentation of antipsychotics use in discharge letters. The results of our study support earlier observations that failure to use a validated delirium screening will miss delirium that is present.21,22

Compared with other assessment methods for delirium in the ICU, the CAM-ICU shows good validity and sensitivity in a research setting35 and is proven to be superior to diagnosis by critical care physicians alone.21 However, it might not capture the fluctuating nature of the disease. To overcome this, we also based our definition of delirium on inspection of the medical records and prescription of antipsychotics.

The anti-inflammatory effects of dexamethasone may lead to a number of potential beneficial effects in patients undergoing cardiac surgery, including potential decrease of cerebral edema and neuroinflammation, improved pulmonary gas exchange, and the reduced need for postoperative inotropic support.17 We hypothesized that dexamethasone would reduce the occurrence of delirium, either directly through its anti-inflammatory effect or indirectly through faster postsurgical recovery that would reduce the risk for delirium. Although there is some evidence that inflammation is an important mechanism for postoperative cognitive dysfunction,10 the results of our investigation suggest that other, not yet identified, factors might play a greater role in the development of delirium in this population, also explaining why (pre) treatment with other drugs with anti-inflammatory properties such as statins36 and haloperidol37,38 does not seem to decrease the incidence of postoperative delirium.

Our study has several strengths including its large sample size compared with that of other studies investigating delirium, the detailed method that was used to identify delirium, and the use of multivariate models to adjust for possible confounding. The potential limitations are, first, that the assessment for delirium was limited to the first 4 postoperative days. While it is possible that patients may have developed delirium after 4 days, previous studies suggest that the vast majority of delirium in this population is clinically apparent over the first 3 postoperative days. The number of patients with later-onset delirium, who may have been missed in the current study, is therefore likely very small.9,39–41 Second, we may also have missed delirium in patients who were transferred before the fourth postoperative day. It is, however, unlikely that this would have influenced our findings, because the number of patients who were transferred before the fourth day was low and similar between the 2 study groups. Third, we did not collect data on some potential risk factors for delirium, including preoperative cognitive status, education level, sensory impairment, and history of psychiatric disease. Although these factors may be relatively rare in a population undergoing elective cardiac surgery, we cannot exclude that there may have been a disbalance between the 2 study groups, despite the randomized, controlled design of the trial. Finally, to obtain full workday and weekend coverage on delirium assessments, 7 individual observers were involved in this study who were thoroughly trained by 2 staff members (AJCS, MMJvE). Despite this extensive training, interindividual differences in assessment may have occurred.

In conclusion, the administration of a single intraoperative injection of high-dose dexamethasone did not influence the incidence or duration of delirium in the first 4 days after cardiac surgery.

Back to Top | Article Outline

DISCLOSURES

Name: Anne-Mette C. Sauër, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Anne-Mette C. Sauër has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Arjen J. C. Slooter, MD, PhD.

Contribution: This author helped design and conduct the study and write the manuscript.

Attestation: Arjen J. C. Slooter has seen the original study data and approved the final manuscript.

Name: Dieuwke S. Veldhuijzen, PhD.

Contribution: This author helped write the manuscript.

Attestation: Dieuwke S. Veldhuijzen approved the final manuscript.

Name: Maarten M. J. van Eijk, MD, PhD.

Contribution: This author helped design and conduct the study and write the manuscript.

Attestation: Maarten M. J. van Eijk has seen the original study data and approved the final manuscript.

Name: John W. Devlin, PharmD, FCCM, FCCP.

Contribution: This author helped analyze the data, and write the manuscript.

Attestation: John Devlin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Diederik van Dijk, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Diederik van Dijk has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Charles W. Hogue Jr, MD

Back to Top | Article Outline

ACKNOWLEDGMENTS

We would like to acknowledge Linda M. Peelen, PhD, biostatistician at the Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands for her support in this revision.

Back to Top | Article Outline

REFERENCES

1. American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders: DSM IV, Fourth Edition, Text Revision. 2000 Washington, DC American Psychiatric Association
2. Lin Y, Chen J, Wang Z. Meta-analysis of factors which influence delirium following cardiac surgery. J Card Surg. 2012;27:481–92
3. Kazmierski J, Kowman M, Banach M, Fendler W, Okonski P, Banys A, Jaszewski R, Rysz J, Mikhailidis DP, Sobow T, Kloszewska IIPDACS Study. . Incidence and predictors of delirium after cardiac surgery: Results from The IPDACS Study. J Psychosom Res. 2010;69:179–85
4. Burkhart CS, Dell-Kuster S, Gamberini M, Moeckli A, Grapow M, Filipovic M, Seeberger MD, Monsch AU, Strebel SP, Steiner LA. Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2010;24:555–9
5. Gottesman RF, Grega MA, Bailey MM, Pham LD, Zeger SL, Baumgartner WA, Selnes OA, McKhann GM. Delirium after coronary artery bypass graft surgery and late mortality. Ann Neurol. 2010;67:338–44
6. Bickel H, Gradinger R, Kochs E, Förstl H. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn Disord. 2008;26:26–31
7. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367:30–9
8. Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB. The neuroinflammatory hypothesis of delirium. Acta Neuropathol. 2010;119:737–54
9. Steiner LA. Postoperative delirium. Part 1: pathophysiology and risk factors. Eur J Anesthesiol. 2011;28:628–36
10. van Harten AE, Scheeren TW, Absalom AR. A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia. Anaesthesia. 2012;67:280–93
11. Hirleman E, Larson DF. Cardiopulmonary bypass and edema: physiology and pathophysiology. Perfusion. 2008;23:311–22
12. Kazmierski J, Banys A, Latek J, Bourke J, Jaszewski R. Cortisol levels and neuropsychiatric diagnosis as markers of postoperative delirium: a prospective cohort study. Crit Care. 2013;17:R38
13. Hauer D, Weis F, Campolongo P, Schopp M, Beiras-Fernandez A, Strewe C, Giehl M, Toth R, Kilger E, Schelling G. Glucocorticoid-endocannabinoid interaction in cardiac surgical patients: relationship to early cognitive dysfunction and late depression. Rev Neurosci. 2012;23:681–90
14. Mu DL, Wang DX, Li LH, Shan GJ, Li J, Yu QJ, Shi CX. High serum cortisol level is associated with increased risk of delirium after coronary artery bypass graft surgery: a prospective cohort study. Crit Care. 2010;14:R238
15. Kazmierski J, Kloszewska I. Is cortisol the key to the pathogenesis of delirium after coronary artery bypass graft surgery? Crit Care. 2011;15:102
16. Plaschke K, Fichtenkamm P, Schramm C, Hauth S, Martin E, Verch M, Karck M, Kopitz J. Early postoperative delirium after open-heart cardiac surgery is associated with decreased bispectral EEG and increased cortisol and interleukin-6. Intensive Care Med. 2010;36:2081–9
17. Dieleman JM, van Paassen J, van Dijk D, Arbous MS, Kalkman CJ, Vandenbroucke JP, van der Heijden GJ, Dekkers OM. Prophylactic corticosteroids for cardiopulmonary bypass in adults.; Cochrane Database Syst Rev. 2011;5:CD005566
18. Mardani D, Bigdelian H. Prophylaxis of dexamethasone protects patients from further post-operative delirium after cardiac surgery: A randomized trial. J Res Med Sci. 2013;18:137–43
19. Kenna HA, Poon AW, de los Angeles CP, Koran LM. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65:549–60
20. Dieleman JM, Nierich AP, Rosseel PM, van der Maaten JM, Hofland J, Diephuis JC, Schepp RM, Boer C, Moons KG, van Herwerden LA, Tijssen JG, Numan SC, Kalkman CJ, van Dijk DDexamethasone for Cardiac Surgery (DECS) Study Group. . Intraoperative high-dose dexamethasone for cardiac surgery: a randomized controlled trial. JAMA. 2012;308:1761–7
21. van Eijk MM, van Marum RJ, Klijn IA, de Wit N, Kesecioglu J, Slooter AJ. Comparison of delirium assessment tools in a mixed intensive care unit. Crit Care Med. 2009;37:1881–5
22. Katznelson R, Djaiani G, Tait G, Wasowicz M, Sutherland AM, Styra R, Lee C, Beattie WS. Hospital administrative database underestimates delirium rate after cardiac surgery. Can J Anesth. 2010;57:898–902
23. Zaal IJ, Peelen LM, van Dijk D, Slooter AJ. Development and validation of an eight-step flowchart based on the CAM-ICU: a quick and highly adaptable tool to determine the presence of delirium in ICU patients. Crit Care. 2011;15:P335
24. Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29:1370–9
25. Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus RS, Bernard GR. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289:2983–91
26. Pisani MA, Araujo KL, Van Ness PH, Zhang Y, Ely EW, Inouye SK. A research algorithm to improve detection of delirium in the intensive care unit. Crit Care. 2006;10:R121
27. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113:941–8
28. Inouye SK, Leo-Summers L, Zhang Y, Bogardus ST Jr, Leslie DL, Agostini JV. A chart-based method for identification of delirium: validation compared with interviewer ratings using the confusion assessment method. J Am Geriatr Soc. 2005;53:312–8
29. Zitman FG, Couvée JE. Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper-off: report on behalf of the Dutch Chronic Benzodiazepine Working Group. Br J Psychiatry. 2001;178:317–24
30. . Stoppen met benzodiazepinen. Geneesmiddelen bulletin. 1994;28:98–101 Available at: http://gebu.artsennet.nl/English.htm. Accessed May 1, 2014
31. Patanwala AE, Duby J, Waters D, Erstad BL. Opioid conversions in acute care. Ann Pharmacother. 2007;41:255–66
32. . Editorial board. palliative care: practice guidelines. Guideline Pain in palliative care 2.0. IKNL [Online]. 2009 [cited 2013 april 15]. Available at: http://www.oncoline.nl/pain. Accessed May 1, 2014
33. Divine G, Norton HJ, Hunt R, Dienemann J. Statistical grand rounds: a review of analysis and sample size calculation considerations for Wilcoxon tests. Anesth Analg. 2013;117:699–710
34. Dexter F. Wilcoxon-Mann-Whitney test used for data that are not normally distributed. Anesth Analg. 2013;117:537–8
35. Luetz A, Heymann A, Radtke FM, Chenitir C, Neuhaus U, Nachtigall I, von Dossow V, Marz S, Eggers V, Heinz A, Wernecke KD, Spies CD. Different assessment tools for intensive care unit delirium: which score to use? Crit Care Med. 2010;38:409–18
36. Mariscalco G, Cottini M, Zanobini M, Salis S, Dominici C, Banach M, Onorati F, Piffaretti G, Covaia G, Realini M, Beghi C. Preoperative statin therapy is not associated with a decrease in the incidence of delirium after cardiac operations. Ann Thorac Surg. 2012;93:1439–47
37. Kalisvaart KJ, de Jonghe JF, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ, Eikelenboom P, van Gool WA. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc. 2005;53:1658–66
38. Moots RJ, Al-Saffar Z, Hutchinson D, Golding SP, Young SP, Bacon PA, McLaughlin PJ. Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines. Ann Rheum Dis. 1999;58:585–7
39. Koster S, Oosterveld FG, Hensens AG, Wijma A, van der Palen J. Delirium after cardiac surgery and predictive validity of a risk checklist. Ann Thorac Surg. 2008;86:1883–7
40. Detroyer E, Dobbels F, Verfaillie E, Meyfroidt G, Sergeant P, Milisen K. Is preoperative anxiety and depression associated with onset of delirium after cardiac surgery in older patients? A prospective cohort study. J Am Geriatr Soc. 2008;56:2278–84
41. Ohki T, Matsushima E, Shibuya M, Sunamori M. An evaluation strategy for the early detection of postoperative delirium. Psychiatry Clin Neurosci. 2006;60:277–82
42. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16:9–13

Supplemental Digital Content

Back to Top | Article Outline
© 2014 International Anesthesia Research Society