Send Orders of Reprints at [email protected] Current Neuropharmacology, 2012, 10, 181-196 181 Pharmacological Risk Factors for Delirium after Cardiac Surgery: A Review Lurdes Tsea, Stephan K.W. Schwarza, John B. Boweringa, Randell L. Moorea, Kyle D. Burnsb, Carole M. Richfordb, Jill A. Osborna and Alasdair M. Barra,* aDepartment of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, B.C., Canada, V6T 1Z3; bDepartment of Psychiatry, The University of British Columbia, Canada Abstract: Purpose: The objective of this review is to evaluate the literature on medications associated with delirium after cardiac surgery and potential prophylactic agents for preventing it. Source: Articles were searched in MEDLINE, Cumulative Index to Nursing and Allied Health, and EMBASE with the MeSH headings: delirium, cardiac surgical procedures, and risk factors, and the keywords: delirium, cardiac surgery, risk factors, and drugs. Principle inclusion criteria include having patient samples receiving cardiac procedures on cardiopulmonary bypass, and using DSM-IV-TR criteria or a standardized tool for the diagnosis of delirium. Principal Findings: Fifteen studies were reviewed. Two single drugs (intraoperative fentanyl and ketamine), and two classes of drugs (preoperative antipsychotics and postoperative inotropes) were identified in the literature as being independently associated with delirium after cardiac surgery. Another seven classes of drugs (preoperative antihypertensives, anticholinergics, antidepressants, benzodiazepines, opioids, and statins, and postoperative opioids) and three single drugs (intraoperative diazepam, and postoperative dexmedetomidine and rivastigmine) have mixed findings. One drug (risperidone) has been shown to prevent delirium when taken immediately upon awakening from cardiac surgery. None of these findings was replicated in the studies reviewed. Conclusion: These studies have shown that drugs taken perioperatively by cardiac surgery patients need to be considered in delirium risk management strategies. While medications with direct neurological actions are clearly important, this review has shown that specific cardiovascular drugs may also require attention. Future studies that are methodologically consistent are required to further validate these findings and improve their utility. Keywords: Cardiac surgery, delirium, drugs, medications, prevent, risk factors. INTRODUCTION recently has been on identifying risk factors that can be modified so that the incidence or severity of postoperative Delirium after cardiac surgery is associated with serious delirium may be reduced. A focus of such modifiable risk long-term medical consequences [1, 2] and high costs [3]. It factors includes medications that cardiac surgery patients affects approximately 30% of cardiac surgery patients, consume before, during, and after surgery. Interestingly, it although reported incidences are variable [4-11]. Delirium is seems that while some medications may be associated with a an acute and fluctuating state of confusion and disorientation, higher rate of delirium, others may be associated with a characterized by changes in attention, cognition, consciousness, significantly reduced rate of delirium. Despite a growing and perception, and is often associated with changes in sleep number of studies that include perioperative drug use in their patterns. Diagnosis is typically based on clinical assessments investigations, the influence of drugs on the development of of patient symptoms, which are defined by the Diagnostic delirium after cardiac surgery has not been the subject of and Statistical Manual fourth, text-revised (DSM-IV TR) critical review. edition [12]. Critical examination of perioperative drugs is important Factors that have previously been identified as key, because these agents may have pharmacological actions independent predictors of delirium after cardiac surgery (particularly within neural tissues) that can greatly influence include advanced age, pre-operative cognitive decline, atrial the etiology of postoperative delirium. One popular theory fibrillation, previous delirium as well as a sizeable list for delirium etiology is the neurotransmitter hypothesis. This of other conditions and co-morbidities [13-15]. Given theory postulates that decreased neuronal metabolism from that many of these risk factors are non-modifiable, emphasis oxygen deprivation during cardiac surgery alters neuro- transmitter function and causes generalized dysfunction in the brain [16, 17]. In particular, the neurologically ubiquitous *Address correspondence to this author at the Department of cholinergic system is believed to be deficient in the delirious Anesthesiology, Pharmacology & Therapeutics, The University of British patient [18, 19]; additionally, there may also be excesses of Columbia, 2176 Health Sciences Mall, Vancouver, B.C., Canada, V6T 1Z3; dopamine, norepinephrine, and glutamate, while serotonin Tel: 604-875-2000 (x4728); Fax: 604-822-6012; E-mail: [email protected] and GABA levels may be increased or decreased [16, 19]. 1875-6190/12 $58.00+.00 ©2012 Bentham Science Publishers 182 Current Neuropharmacology, 2012, Vol. 10, No. 3 Tse et al. Therefore, cardiac medications such as digoxin, furosemide medications like dexmedetomidine or rivastigmine to prevent or nifedipine (which have relatively significant anticholinergic delirium in vulnerable individuals. Unlike observational properties), and other medications like selective serotonin studies, well-controlled RCTs can suggest that any observed reuptake inhibitors (SSRIs), antipsychotics, or benzo- differences in the rates of delirium are due to differences in diazepines, may pay important contributions to delirium drug administration. etiology through these neurotransmitter pathways. In this review, delirium after cardiac surgery is It is important to emphasize that most studies that have considered distinct from other types of postoperative deliria collected data on perioperative use of medications in for a number of reasons. For one, different surgical delirious patients are prospective or retrospective obser- populations often have different medication profiles and vational studies, and therefore cannot imply direct causal require different anesthesia techniques. Thus, the phar- relationships between the medications that were studied and macological triggers of delirium will vary depending on the outcome of delirium. Even though the majority of these surgery. Secondly, the use of cardiopulmonary bypass (CPB) observational studies use multivariate logistic regression in cardiac surgeries requires special consideration since its analyses to identify drugs that may independently increase or use is associated with postoperative effects on neurological decrease the risk of delirium, such techniques cannot account function and an increase in delirium [13]. Lastly, it is for all the reasons why groups differ in the rates of delirium; unknown if the pathophysiology of different postoperative depending on the covariates that are being controlled for in deliria differs: research has shown that predictors of delirium the regression models, there may be significant cross-study appear to vary depending on surgery type, and levels of differences in the results. certain biomarkers for delirium also appear to vary with different forms [23]. Another challenge of using the observational study design for delirium research is in determining the influence The purpose of this article hence is to synthesize the of intraoperative drugs on delirium. The reason for this is evidence in the literature for drugs that have been shown to because behavioural abnormalities that appear immediately be associated with either a higher or a lower rate of delirium following surgery may be attributed to the residual effects of after cardiac surgery. We also discuss studies that have anesthesia, and patients may experience a form of delirium attempted to use certain drugs for strategic prevention of known as emergence delirium, which is a state of short- postoperative delirium. lived, self-limiting agitation that is attributable to substance METHODS use [20]. In the literature, emergence delirium is not consistently defined, and its etiological and pathological Studies were searched in MEDLINE (January 1948 distinction from postoperative delirium is not consistently through January 2011), Cumulative Index to Nursing and differentiated (compare, for example, [20] to [21]). For this Allied Health (CINAHL; 1982-2011), and EMBASE (1980- reason, a couple of the studies that were reviewed for 2011). MeSH headings that were searched included the this synopsis did not commence their assessments of following: delirium, cardiac surgical procedures, and risk delirium in patients until the second day after surgery factors. Keyword searches included: delirium, cardiac [5, 7]. Nevertheless it has been suggested that intraoperative surgery, risk factors, and drugs. Reference lists of the articles factors reliably contribute to the development of posto- that were retrieved were also searched for relevant citations. perative delirium because the first symptoms almost always Articles were included only if they were published between occur in the period shortly after awakening from sedation January 2000 and December 2010, used DSM-IV-TR criteria [13]. or a standardized assessment tool (e.g., CAM, CAM-ICU, MDAS, ICDSC) for the screening or diagnosis of delirium, Similarly, it is also difficult to establish the role of involved more than one assessment of delirium in the postoperative drugs on delirium with such observational postoperative period, included only adults, were written in designs. Even though delirium is defined by the DSM-IV- English, were prospective, retrospective, or interventional in TR as having multifactorial etiology (which includes their designs, and included cardiac procedures requiring preoperative, intraoperative, and postoperative factors) the CPB, i.e., coronary artery bypass grafting (CABG), valve role of postoperative factors on delirium is frequently replacements, combination CABG-valve replacements, or downplayed in studies because they are not commonly heart transplants1. The DSM-IV-TR, which is the current considered ‘predictors’ of delirium, despite the fact that they edition of the manual as of this publication, was published in are potentially modifiable. For instance, Afonso et al. [10], 2000; therefore, only studies that were published in 2000 Katznelson et al. [22] and Redelmeier et al. [24] did not onward were included in this review. Studies were excluded include any postoperative variables in their investigations, if they took place in a community setting, if delirium was while Tan et al. [25], Shehabi et al. [26], and Tully et al. not a specific outcome, if the diagnosis of delirium was [27] focused primarily on pre- and intraoperative factors in based solely on a clinical diagnosis without the use of DSM their studies. Thus, studies that look at postoperative criteria or a standardized tool, or if they were reviews or case medications as potential factors that influence delirium are reports. limited in number. Other studies that have looked at the influence of drugs on delirium are randomized controlled trials (RCTs). These studies, which are more robust, are typically designed to 1While heart transplants were included for review, only the study by Afonso et al. [10] investigate the prophylactic effectiveness of certain included patients who had received heart transplants (n = 1). For this reason, the effect of heart transplant on delirium is not given considerable weight in this review. Risk Factors for Postoperative Delirium Current Neuropharmacology, 2012, Vol. 10, No. 3 183 It should be mentioned that the study by Redelmeier RESULTS et al. [24] possesses some qualities that should exclude it for See Table 2 for a complete summary of the drugs review; only 3.3% of the patient sample actually received that have been studied in relation to delirium after cardiac cardiac interventions on CPB, with the rest receiving non- surgery. cardiac surgeries. It also used a retrospective diagnosis of delirium based on International Classification of Diseases I. Preoperative Period (ICD) criteria instead of DSM-IV-TR criteria or a standardized assessment tool. However, Redelmeier et al. Psychiatric Drugs [24] did include an impressively large number of patients in Preoperative use of psychiatric medications is frequently their cohort (total n = 284, 158; cardiac patients n = 9,272), cited to be a risk factor for postoperative delirium and this gives the study considerable relevance for cardiac [28]. However, in the studies that met inclusion criteria surgery despite the small proportion of the total sample for this review, only antipsychotics, antidepressants and size that were actually cardiac surgery patients. More benzodiazepines have been studied for their relationship to importantly, when the rate of delirium was analyzed with delirium [10, 24, 27]. respect to their primary factor of interest (i.e., preoperative statin use), they found that the type of surgery received Only one single study included preoperative did not affect the relationship that they found between antipsychotic use as a factor in their analysis. Redelmeier preoperative statin use and postoperative delirium [24] (this et al. [24] found that patients who took preoperative finding is further discussed below). For these reasons, and antipsychotics within the year before surgery were 1.57 given the importance of the findings from the Redelmeier times more likely to develop delirium after surgery than et al. [24] study, it was included for review. patients who were not taking antipsychotics (OR = 1.57, 95% CI 1.26 – 1.95; p < 0.001). This result was obtained by Most studies reviewed were not specifically designed to controlling for age, sex, social status, prior admissions, prior measure the role of drugs on postoperative delirium; in fact, use of medications, all neuropsychiatric, cardiac, vascular this was only the case for 5 of the studies reviewed [3, 8, 9, and miscellaneous medications, and duration and type of 22, 26]. The majority of studies that collected data on surgery in their multivariable logistic regression model [24]. medication administration included only a small number of No other study that was evaluated for this review included specific drugs or general drug classes as variables in their preoperative antipsychotics in their investigations. extensive databases. These drug variables were developed a priori, or were included through naturalistic intake (the only The work on antidepressants and delirium is more exception to this is the report by Burkhart et al. [11], which extensive, but likewise unconvincing due to small sample was a post-hoc analysis of the results from a randomized sizes and conflicting findings. Tully et al. [27] looked at controlled trial performed by Gamberini et al., [8]). For the preoperative tricyclic antidepressant use in a cohort of most part, drug variables in these studies were quantified by prospectively recruited cardiac surgery patients, but found no comparing the proportions of delirious versus non-delirious statistically significant effect of this class of drugs on the individuals who were taking these drugs. The studies by outcome of delirium. However, when individuals taking Burkhart et al., [11] and Hudetz et al. [9] also quantified and SSRIs were analyzed, use of these drugs was significantly compared the doses of certain drugs consumed by delirious associated with an increased rate of postoperative delirium versus non-delirious individuals. compared to individuals who were not taking SSRIs (p = 0.01) [27]. Despite this association, the study faced statistical From the studies that were evaluated, several drugs that issues, as there was only one non-delirious individual in this patients were taking as outpatients prior to surgery, during study who was taking SSRIs. Hence, use of SSRIs was not surgery, and in postoperative intensive care emerged as included as a factor in multivariable logistic regression being either significantly predictive or protective of analyses in this study. To mitigate this issue, the authors postoperative delirium. In most studies, drugs that were formed a composite variable that included SSRIs, tricyclics, identified to be significantly associated with delirium by and drugs with known anticholinergic properties [27]. This univariate analysis were further analyzed by multivariate composite variable not only significantly correlated with logistic regression to identify drugs that were independently delirium (p ≤ 0.01), but also was reported to be highly associated with delirium. One study that took a rather predictive: patients who were taking SSRIs or tricyclic different approach was by Katznelson et al. [22], who antidepressants and/or drugs with known anticholinergic performed stepwise model selection procedures in which effects were 5.12 times more likely to become delirious than statins, their primary factor of interest, was always forced patients who were not taking these drugs (95% CI 1.46- into the models regardless of its association (or lack thereof) 17.94; p = 0.01) [27]. A study by Afonso et al. [10] also with delirium in univariate analysis. Some drugs failed to included preoperative SSRI use in their prospective demonstrate any significant associations with postoperative examination of potential predictors of postoperative delirium delirium in either direction in these studies, and these are in cardiac surgery patients. However, because SSRIs were also discussed. not frequently used in this patient sample (only one patient Eight prospective observational studies, 5 randomized for in this sample was taking an SSRI), this drug was not controlled trials, 1 retrospective observational study and 1 included in univariate analysis and no conclusions could be post-hoc analysis were selected for review, and these are drawn from these results. The study by Redelmeier et al. summarized in Table 1. [24] also investigated the relationship between preoperative 184 Current Neuropharmacology, 2012, Vol. 10, No. 3 Tse et al. Table 1. Summary of the Studies that have Recorded Perioperative Drug use in Relation to Delirium after Cardiac Surgery Reference Sample Surgeries Assessment and Drugs Studied P-Valuesab Odds Description Rate of Delirium Prospective Observational Studies Santos et al., Average Non- DSM-IV, 33.6% Collected data on Diuretics 0.080 NA [5] age = 71 yrs emergency preoperative use of CCBs 0.518 n = 220 CABG on diuretics, CCBs, β- β-blockers 0.179 Objective: CPB blockers, ACEIs, ACEIs 0.088 To determine nitrates, PPIs; anesthetic Nitrates 0.632 risk factors for premedication with PPIs 0.865 delirium after either diazepam or Diazepam <0.05 CABG midazolam Rudolph et al., Average CABG, valve MMSE, DSI, Collected data on NA NA [7] age = 74 yrs replacement, MDAS, CAM, preoperative use of (but reported no significant n = 42 combined 29% aspirin, NSAIDs, differences in preoperative Objective: CABG-valve steroids, β-blockers, medication use between To compare surgery on ACEIs, ARBs, CCBs, patients with and without changes in the CPB nitrates, diuretics delirium) levels of inflammatory markers in patients with and without delirium after cardiac surgery Afonso et al., Average age Cardiac or RASS, CAM- Collected data on ACEI 0.91 NA [10] = 66 yrs thoracic ICU, 34% preoperative use of n = 112 aortic nitratesc, Objective: surgeries on benzodiazepines, To produce a CPB SSRIs and ACEIs predictive model for delirium after cardiac surgery Katznelson Average age CABG, valve CAM-ICU, Looked at preoperative Statin <0.01 Odds Ratiod et al., [22] = NA (36% replacements, 11.5% use of statins and (95% CI) were < 60 combined perioperative Statin 0.54 (0.35-0.84) Objective: yrs old, and CABG-valve benzodiazepine and To demonstrate 64% were replacement opioid use an association ≥ 60 yrs old) surgery on between n = 1,059 CPB preoperative statin use and delirium after cardiac surgery Tan et al., [25] Average age CABG, valve CAM, MDAS, Collected data on Chemical 0.18 Risk Ratio = 63 yrs replacements, MMSE, 23% preoperative ‘chemical dependency (95% CI) Objective: n = 53 combined dependency’ and use of ‘Other’ anti- 0.10 ‘Other’ anticholinergic 2.31 (0.85-6.31) To determine CABG-valve ‘other’ anticholinergic cholinergic agents factors surgery on medications (neither agents Morphine 1.00 (0.99-1.01) associated with CPB variable was defined); Morphine 0.76 equivalents, POD and rate of also recorded equivalents, 1-3 delirium after postoperative morphine POD 1-3 cardiac surgery equivalents over POD 1-3 Risk Factors for Postoperative Delirium Current Neuropharmacology, 2012, Vol. 10, No. 3 185 Table 1. contd…. Reference Sample Surgeries Assessment and Drugs Studied P-Valuesab Odds Description Rate of Delirium Prospective Observational Studies Tully et al., [27] Average age Elective DSI, DSM-IV- Collected data on Anticholinergic drugs 0.31 Odds Ratio = 65 yrs CABG, TR, 31% preoperative use of SSRI 0.01 (95% CI) Objective: n = 158 combined anticholinergic Tricyclic antidepressant 0.65 Composite of drugs 5.12 (1.46-17.94) To determine an CABG-valve drugs, SSRIs, association between surgery on CPB tricyclic Composite of drugs 0.01 preoperative antidepressants (anticholinergics, SSRIs, affective disorders and/or tricyclics) or Type D personality with delirium after cardiac surgery Koster et al., [29] Average age Elective cardiac DOS, DSM-IV, Collected data on Opioids 1.00 NA = 70 yrs surgery with or 21% preoperative opioid Objective: n = 112 without CPB use To determine the predictive validity of a risk checklist for delirium after cardiac surgery Norkiene et al., Average age CABG on CPB DSM-IV, 3.1% Collected data on Inotropes > 12hrs 0.002 Odds Ratio [51] = 71 yrs postoperative use (95% CI) n = 1,367 of inotropes for Inotropes > 12hrs 8.04 (1.1-60.6) Objective: more than 12 hours To identify the incidence and risk factors for delirium after cardiac surgery Retrospective Chart Review Redelmeier et al., Average age Elective ICD, 1.1% Outpatient use of Statins < 0.001 Odds Ratioe [24] = 74 yrs cardiac, two or more of: Cholinesterase inhibitor < 0.001 (95% CI) n = 284,158 thoracic, atorvastatin, Antipsychotic < 0.001 Statins 1.28 (1.12-1.46)f Objective: neurosurgical, simvastatin, Antidepressant < 0.001 Cholinesterase 3.99 (2.26-7.05) To determine if vascular, pravastatin, Benzodiazepine < 0.001 inhibitor the use of statins musculoskeletal, lovastatin, ACEI 0.43 Antipsychotic 1.57 (1.26-1.95) was associated abdominal, fluvastatin, ARB 0.77 Antidepressant 2.01 (1.75-2.25) with a higher rate retroperitoneal, rosuvastatin, and/or Thiazide diuretic 0.29 Benzodiazepine 1.40 (1.28-1.53) of delirium after lower cerivastatin, with at CCB 0.21 ACEI 0.96 (0.87-1.06) cardiac and non- urogenital, least one having Furosemide 0.71 ARB 1.05 (0.73-1.52) cardiac surgeries breast and skin, been prescribed Digoxin 0.60 Thiazide diuretic 0.92 (0.79-1.07) external head within Spironolactone 0.59 CCB 0.94 (0.85-1.04) and neck, 90-days before Nonstatin lipid-lowering 0.21 Furosemide 1.03 (0.89-1.18) ophthalmologic, surgery; also agent Digoxin 0.96 (0.83-1.11) and preoperative Anticoagulant 0.16 Spironolactone 1.09 (0.80-1.47) unclassified neuropsychiatric Antiplatelet 0.95 Nonstatin lipid- 0.80 (0.56-1.14) surgeries agents, nonstatin Pentoxifylline 0.44 lowering agent lipid-lowering Hypoglycemics 0.57 Anticoagulant 1.14 (0.95-1.38) agents, Insulin 0.59 Antiplatelet 1.01 (0.68-1.52) antihypertensives, Bronchodilator 0.34 Pentoxifylline 1.16 (0.80-1.69) loop diuretics, Allopurinol 0.10 Hypoglycemic 0.96 (0.83-1.11) cardiovascular Levothyroxine 0.99 Insulin 0.93 (0.73-1.20) agents, Glucocorticoid 0.56 Bronchodilator 1.06 (0.94-1.20) anticoagulants, Gastric acid 0.80 Allopurinol 0.83 (0.67-1.03) vascular agents, suppressant Levothyroxine 1.00 (0.88-1.14) other common Anti-osteoporosis 0.89 Glucocorticoid 0.94 (0.77-1.15) drugs Glaucoma eye drops 0.39 Gastric acid 0.99 (0.90-1.08) suppressant Anti-osteoporosis 1.01 (0.86-1.18) Glaucoma eye drops 0.94 (0.80-1.09) 186 Current Neuropharmacology, 2012, Vol. 10, No. 3 Tse et al. Table 1. contd…. Reference Sample Surgeries Assessment and Drugs Studied P-Valuesab Odds Description Rate of Delirium Post-Hoc Analysis of a Randomized Controlled Trial Burkhart et al., Average Elective CAM, 30% Collected data on Statins 0.8 Odds Ratio [11] age = 74 yrs cardiac preoperative use of Fentanyl dose, per 0.006 (95% CI) n = 113 surgery statins; 10-µg/kg increase Statins 1.1 (0.49-2.48) Objective: with CPB intraoperative Opioid dose, per 1- 0.6 Fentanyl dose, per 3.4 (1.41-8.14) To identify amount of fentanyl; mg/kg increase 10-µg/kg increase modifiable risk postoperative use Opioid dose, per 1- 1.5 (0.29-8.18) factors for of metoclopramide mg/kg increase delirium after and tropisteron, cardiac surgery and postoperative amount of opioids received per kilogram of body weight Randomized Controlled Trial (Open-Label, Treatment-Controlled) Maldonado et al., Average Elective DSM-IV-TR, Compared rate of Dexmedetomidine/ < 0.001 Odds Ratiog [3] age = 58 yrs valve Overall rate, 34% delirium with propofol/midazolam (95% CI) n = 90 procedures Dexmedeto- postoperative Midazolam/ <0.001 Midazolam (vs. 28.6 (4.7-262.5) Objective: on CPB midine cohort, 3% sedation by dexmedetomidine dexmedetomidine) To determine the Propofol dexmedetomidine Propofol/ <0.001 Propofol (vs. 29.6 (4.8-280.6) effects of cohort, 50% to sedation by dexmedetomidine dexmedetomidine) postoperative Midazolam propofol, or sedation on cohort, 50% midazolam delirium after (in each sedation cardiac surgery protocol, also looked at differences in intraoperative amount of fentanyl and midazolam, postoperative amount of fentanyl and total morphine equivalents, and postoperative use of antiemetics, lorazepam, and haloperidol) Randomized Controlled Trial (Double-Blind, Treatment-Controlled) Shehabi et al., Average CABG, CAM-ICU, Compared rate of Dexmedetomidine/ 0.088 Risk Ratio [26] age = 71 yrs valve Overall rate, delirium with morphine (95% CI) n = 299 replace- 11.7% postoperative Objective: ments, Dexmedetomidine sedation by Dexmedetomidine 0.57 (0.26-1.1)h To compare the combined cohort, 8.6% dexmedetomidine (vs. morphine) incidence of CABG- Morphine cohort, to sedation by delirium in valve 15% morphine patients surgery on (used open-label postoperatively pump morphine in sedated with dexmedetomidine dexmedeto- group to titrate midine or for analgesia morphine after and open-label cardiac surgery propofol in morphine group to titrate for sedation) Risk Factors for Postoperative Delirium Current Neuropharmacology, 2012, Vol. 10, No. 3 187 Table 1. contd…. Reference Sample Surgeries Assessment and Drugs Studied P-Valuesab Odds Description Rate of Delirium Randomized Controlled Trials (Double-Blind, Placebo-Controlled) Prakanrattana and Average Elective CAM-ICU, Investigated the Risperidone/ 0.009 Risk Ratio Prapaitrakool, [6] age = 61 yrs cardiac Risperidone effectiveness of placebo (95% CI) n = 126 surgery on cohort, 11.1% postoperative Risperidone 0.35 (0.16-0.77) Objective: CPB Placebo cohort, risperidone (vs. placebo) To evaluate the 31.7% prophylaxis (one efficacy of dose of 1 mg immediate risperidone or postoperative placebo risperidone for immediately upon prevention of awakening from delirium after sedation in the cardiac surgery ICU) Gamberini et al., Average CABG, CAM, Investigated the Rivastigmine/ 0.8 Risk Ratio [8] age = 74 yrs valve Rivastigmine effectiveness of a placebo (95% CI) n = 113 replace- cohort, 32% rivastigmine Rivastigmine 1.08 (0.62 -1.90) Objective: ments, Placebo cohort, prophylaxis (vs. placebo) To evaluate the with or 30% regimen (3 doses of efficacy of without 1.5 mg o.d. rivastigmine CPB rivastigmine or prophylaxis placebo starting on regimen for the evening before prevention of surgery until delirium after POD 6) cardiac surgery Hudetz et al., [9] Average Elective Intensive Care Investigated the Ketamine/placebo 0.01 Odds Ratio age = 64 yrs CABG, Delirium effectiveness of (95% CI) Objective: n = 58 valve Screening intraoperative Placebo 12.6 (1.5-107.5) To evaluate the replace- Checklist (based ketamine for (vs. ketamine) efficacy of ments, on DSM-IV), prophylaxis intraoperative valve Ketamine cohort, (0.5 mg/kg i.v. ketamine for the repairs on 3% ketamine or 0.9% prevention of CPB Placebo cohort, saline placebo delirium after 31% during anesthetic cardiac surgery induction along with fentanyl and etomidate) CABG, coronary artery bypass graft surgery; CPB, cardiopulmonary bypass; DSM-IV-(TR), diagnostic and statistical manual of mental disorders fourth, (text-revised) edition; CCB, calcium channel blocker; ACEI angiotensin-converting enzyme inhibitor; PPI, proton-pump inhibitor; MMSE, mini-mental state examination; DSI, delirium symptom interview; MDAS, memorial delirium assessment scale; CAM-(ICU), confusion assessment method (intensive care version); NSAID, non-steroidal anti-inflammatory drug; ARB, angiotensin receptor II blocker; RASS, Richmond agitation-sedation scale; SSRI, selective serotonin reuptake inhibitor; CI, confidence interval; POD postoperative day; DOS, delirium observation screening scale; ICD, international classification of diseases; ICU, intensive care unit; o.d., omne in die; i.v., intravenously; NA, not available aWith respect to delirium after surgery bCalculated based on the proportions of patients on these drugs, unless otherwise specified cDid not analyze preoperative nitrates, benzodiazepines or SSRIs because only one patient was taking each of these drugs dAdjusted for age, preoperative depression, preoperative renal dysfunction, complex cardiac surgery, perioperative intra-aortic balloon pump, and massive blood transfusion eAdjusted for age, sex, duration of surgery, individual medications, and type of surgery fAdjusted for age, sex, social status, prior admissions, duration of surgery, individual medications, type of surgery gAdjusted for other sedatives, age, ASA score (American Society of Anesthesiologists Physical Status Classification System score), male sex hWhile Shehabi et al. [26] failed to find a statistically significant difference in the incidence of delirium between morphine- and dexmedetomidine-treated patients, they did find that compared to delirious morphine-treated patients, dexmedetomidine patients who did become delirious had shorter durations of delirium (p = 0.0317), were extubated earlier (p = 0.04), had fewer episodes of systolic hypotension (p=0.006), required less norepinephrine (p = <0.001), but had more bradycardia (p = 0.006). antidepressant use and postoperative delirium. Unlike the antidepressants in the year leading up to surgery doubled the previous two studies, the retrospective design of the odds of developing postoperative delirium in their patient Redelmeier et al. [24] study facilitated the inclusion of a sample (OR = 2.01, 95% CI 1.75 – 2.25; p < 0.001). much larger sample size (n = 287, 353), and they were able Afonso et al. [10] included benzodiazepine use in to acquire a much larger number of patients who were taking their study but similar to their finding on SSRIs, they antidepressants in the preoperative period (n = 266, 519). were unable to draw any conclusions since only one Redelmeier et al. [24] found that taking preoperative 188 Current Neuropharmacology, 2012, Vol. 10, No. 3 Tse et al. Table 2. Summary of Drugs that have been Shown to be Independently Associated with Delirium after Cardiac Surgery (Drug Names are Given as they were Reported in the Original Studies) Drug Effect on Rate of Deliriuma References Preoperative Period Statins Mixed findings [11, 22, 24] Non-statin lipid lowering agents No effect [9, 24] Cholinesterase inhibitors No effect [8, 24] Anticholinergic agents Mixed findings [25, 27] Antipsychotics Increase [24] Antidepressants Mixed findings [24, 27] SSRI Mixed findings [10, 27] Benzodiazepines Mixed findings [10, 24] Opioids No effect [29] Diuretics No effect [5, 7, 9, 24] CCBs No effect [5, 7, 9, 24] β-blockers No effect [5, 7, 9, 24] ACEIs No effect [5, 7, 9, 10, 24] ARBs No effect [7, 24] Nitrates No effect [5, 7, 9, 10, 24] PPIs No effect [5, 24] Digoxin No effect [24] Anticoagulants No effect [24] Antiplatelet agents No effect [24] Pentoxifylline No effect [24] Oral hypoglycemic agents No effect [24] Insulin No effect [24] Bronchodilator No effect [24] Allopurinol No effect [24] Levothyroxine No effect [24] Steroids No effect [7, 24] Anti-osteoporosis agents No effect [24] Glaucoma eye drops No effect [24] Aspirin No effect [7] NSAIDs No effect [7] Intraoperative Period Diazepam No effectb [5] Ketamine Decrease [9] Fentanyl, dose/patient Mixed findings [8, 9] Fentanyl, dose/kg body weight Increase [11] Risk Factors for Postoperative Delirium Current Neuropharmacology, 2012, Vol. 10, No. 3 189 Table 2. contd…. Drug Effect on Rate of Deliriuma References Postoperative Period Dexmedetomidine Mixed findings [3, 26] Morphine, dose/patient No effect [9, 25, 26] Opioids, dose/kg body weight No effect [11] Inotropes > 12 hours Increase [51] Prophylactic Regimens Risperidone Decrease [6] Rivastigmine No effect [8] SSRI, selective serotonin-reuptake inhibitor; CCB, calcium channel blocker; ACEI, angiotensin-converting enzyme inhibitor; PPI, proton-pump inhibitor; ARB, angiotensin receptor blocker; NSAID, non-steroidal anti-inflammatory drug aEffect is based on proportions of delirious and non-delirious patients taking the drug, unless otherwise stated (e.g., the effect of postoperative opioids on delirium was analyzed based on dose/kg body weight) bDiazepam was associated with an increased rate of delirium in univariate analysis, but lost this association with stepwise logistic regression individual in this sample was taking a benzodiazepine in meds”, while Tully et al. [27] included “anticholinergic” the preoperative period. Conversely, Redelmeier et al.’s drugs as a factor, but neither study precisely defined these [24] multivariable logistic regression model showed that variables, nor did they report the specific drugs that were preoperative use of benzodiazepines within the year before included in these broad classes. As there is a wide range of surgery was independently associated with a 1.40 times drugs with direct or indirect anticholinergic activity [30-31], increase in the rate of delirium (OR = 1.40, 95% CI 1.28 – it would have been important for these studies to report 1.53; p < 0.001). Thus, the findings for the influence of exactly which drugs were included under these broad preoperative benzodiazepine use on postoperative delirium are variables. Given this, neither Tan et al. [25] nor Tully et al. inconclusive and further work is required to reveal any [27] found a significant relationship between drugs with relationship that may exist. anticholinergic activity and delirium after cardiac surgery (p = 0.10; p = 0.31 respectively). Though Tan et al. [25] did No studies were found that included preoperative use of have a moderate number of patients who were taking mood stabilizers, stimulants, anxiolytics or any other preoperative anticholinergic medications in their study (n = psychiatric drugs. 20 out of a total n = 53), the broad definition that they Opioids attributed to the variable “ other anticholinergic meds” means that additional studies are required for evidence on the Preoperative opioids have not been thoroughly effects of anticholinergic medications on postoperative investigated for their relationship to delirium. Only one delirium. study meeting inclusion criteria included this as a factor [29]. Koster et al. [29] showed that preoperative use of opioids Interestingly, as noted above, when Tully et al. [27] was not linked to postoperative delirium after cardiac grouped anticholinergic agents, SSRIs, and tricyclic surgery in their study (p = 1.00). However, given that only antidepressants into a single composite variable, they four individuals in the entire cohort of 112 patients were found that patients who were taking any of these drugs taking opioids before surgery [29], this finding bears the preoperatively were approximately 5 times more likely to same limitations of sample size as the studies by Afonso et develop delirium after cardiac surgery than patients who al. [10] and Tully et al. [27]. were not taking these drugs. Considering that SSRIs and tricyclic antidepressants such as paroxetine and nortriptyline Anticholinergics have been demonstrated in vitro to have moderate anti- Two studies evaluated the relationship between cholinergic activity at therapeutic doses [31], it may be preoperative anticholinergic drug use and postoperative justified to regard this composite variable as a crude measure delirium, and neither found an association between anti- of the relationship between anticholinergic activity and the cholinergics and delirium. These studies by Tan et al. [25] occurrence of postoperative delirium. Future studies would and Tully et al. [27] were both prospective, observational benefit from standardized quantification of anticholinergic studies with patient samples of similar mean ages that medication burden (such as the anticholinergic drug scale were undergoing CABG, valve, or combined CABG-valve [32]) to allow for comparisons to be made between delirious surgeries on CPB. Medication consumption data from both and non-delirious patients and to establish consistency across studies were recorded in terms of frequencies of drug use. studies. Tan et al. [25] used the variable “other anticholinergic 190 Current Neuropharmacology, 2012, Vol. 10, No. 3 Tse et al. Statins authors, who have shown statins to be neuroprotective [33] as well as important for stroke prevention [34]. Studies that have looked at the influence of preoperative statin use on the outcome of delirium after cardiac surgery Besides advanced age, one confounding factor that was have produced contrasting findings: of the four studies that not appropriately controlled for in neither the Katznelson focused specifically on preoperative statin use, one study et al. [22] nor the Redelmeier et al. [24] study was the showed that it was protective against delirium [22], another frequency of atherosclerosis in their patient samples. The showed that it was predictive of delirium [24], and two importance of controlling for atherosclerosis arises from two did not find a statistically significant relationship between earlier studies that show that atherosclerosis is a significant, lipid-lowering agents and delirium [9, 11]. Non-statin lipid independent risk factor for delirium after cardiac surgery [35, lowering agents such as fenofibrate were investigated in 36]. The lower rate of delirium associated with the non-statin only one study [24], and no relationship was found between users in Katznelson et al. [22], for example, may also be these drugs and delirium. In evaluating these studies on attributed to a potentially lower rate of atherosclerosis in this statins, it is important to consider the major differences in population, and this could be the more major contributor to methodologies and patient samples that make comparing the pathophysiological state of delirium than the results between these studies difficult. The study by Katznelson pharmacological actions of statins. Although atherosclerosis et al. [22] was a prospective observational study that was as a factor was not accounted for in Redelmeier et al. [24], a performed on patients undergoing cardiac surgery with selection bias analysis was performed and showed that CPB, while Redelmeier et al. [24] performed a retrospective patients in their sample who were taking statins tended to be analysis on patients undergoing either cardiac or non-cardiac healthier than non-statin users. No description was given elective surgeries, and used ICD criteria instead of DSM-IV- about the factors that were controlled for in this selection TR criteria for the diagnosis of delirium. bias analysis; however, they concluded from this that hidden confounders would not explain the significantly independent, Redelmeier et al. [24] found that postoperative delirium detrimental relationship that they found between statin use was more likely to occur amongst patients taking preoperative and delirium [24]. statins than amongst those who were not taking statins (OR = 1.30, 95% CI 1.15 – 1.47; p < 0.001). To control for Other studies that included statins or lipid-lowering the broad range of surgeries that were included in this study, agents as variables in their databases failed to find a surgery type was included as a covariate in the analysis. This significant association with postoperative delirium use in produced an OR = 1.12, with a 95% confidence interval of either direction [9, 11]. This may be due in part to the much 0.99 – 1.27 (p = 0.07), meaning that surgery type had no smaller sample sizes and lower frequency counts of patients effect on the relationship between statin use and delirium who were taking statins in these studies (total n = 58 in [24]. Redelmeier et al. [24] then proceeded to look at the Hudetz et al., [9]; total n = 113 in Burkhart et al., [11]). relative risk of delirium exclusively amongst statin users. In Based on evidence from a systematic review, Kulik and this case, surgery type did significantly affect delirium: Ruel [37] recommended that statins should be used for specifically, statin use was only independently associated CABG patients and should ideally be started before surgery with delirium for patients receiving non-cardiac surgeries because of the beneficial cardiac and medical outcomes (RR = 1.33, 95% CI 1.16 – 1.53), but not for patients associated with perioperative statin use; but considering the receiving cardiac surgeries (RR = 1.26, 95% CI 0.86 – 1.87) current ambiguity regarding conclusions about the effects of [24]. It is pertinent to acknowledge that these results were statins on postoperative delirium, this suggestion should be only obtained when the factors of age, sex, duration of carefully regarded. surgery, and “individual medications” (which was not explicitly defined in this report) were selected as covariates Antihypertensives [24]. Had they picked other appropriate covariates, it is Antihypertensive drugs taken in the preoperative period, likely that they would have found different results. other than drugs with direct cholinergic receptor interactions, Redelmeier et al. [24] also found that the risk of delirium have not been linked to delirium after cardiac surgery in any was increased for both simvastatin and atorvastatin (OR study that was reviewed. Diuretics, calcium channel-blockers 1.46, 95% CI 1.15 – 1.84 for simvastatin; OR 1.68, 95% CI (CCBs), angiotensin-converting enzyme inhibitors (ACE-Is), 1.34 – 2.09 for atorvastatin), but no association was observed β-blockers, angiotensin receptor blockers (ARBs) and for the non-lipophilic pravastatin (OR 1.26, 95% CI 0.96 – nitrates have all failed to show a relationship with delirium 1.64). No other cardiac medications were found to increase in the studies published thus far [5, 7, 9, 10, 24]. It is unclear the risk of developing delirium after cardiac surgery in this whether this is due to a true lack of association, or if these study [24]. results are merely reflecting inappropriate study design or On the other hand, the prospective study by Katznelson insufficient sample sizes. et al. [22] came to the opposite conclusion. Cardiac surgery II. Intraoperative Period patients who were taking preoperative statins (mostly atorvastatin in this sample) had half the risk of developing Diazepam delirium when compared to individuals who were not taking One class of drugs commonly used during surgery that statins (OR = 0.54, 95% CI 0.35-0.84, p < 0.01) [22]. This has been implicated in the development of delirium after relationship, however, was revealed only after ‘age over 60 cardiac surgery is the benzodiazepines and their derivatives. years’ was identified and controlled for as a confounding variable. This result supports similar findings by other Specifically, Santos et al. [5] showed that the use of 5-10 mg