Table 1.

Summary of the Studies that have Recorded Perioperative Drug use in Relation to Delirium after Cardiac Surgery

Reference	Sample Description	Surgeries	Assessment and Rate of Delirium	Drugs Studied	P-Valuesab		Odds
Prospective Observational Studies
Santos et al., [5]	Average age = 71 yrs n = 220	Non-emergency CABG on CPB	DSM-IV, 33.6%	Collected data on preoperative use of diuretics, CCBs, b-blockers, ACEIs, nitrates, PPIs; anesthetic premedication with either diazepam or midazolam	Diuretics CCBs b-blockers ACEIs Nitrates PPIs Diazepam	0.080 0.518 0.179 0.088 0.632 0.865 <0.05	NA
Objective: To determine risk factors for delirium after CABG
Rudolph et al., [7]	Average age = 74 yrs n = 42	CABG, valve replacement, combined CABG-valve surgery on CPB	MMSE, DSI, MDAS, CAM, 29%	Collected data on preoperative use of aspirin, NSAIDs, steroids, b-blockers, ACEIs, ARBs, CCBs, nitrates, diuretics	NA (but reported no significant differences in preoperative medication use between patients with and without delirium)		NA
Objective: To compare changes in the levels of inflammatory markers in patients with and without delirium after cardiac surgery
Afonso et al., [10]	Average age = 66 yrs n = 112	Cardiac or thoracic aortic surgeries on CPB	RASS, CAM-ICU, 34%	Collected data on preoperative use of nitratesc, benzodiazepines, SSRIs and ACEIs	ACEI	0.91	NA
Objective: To produce a predictive model for delirium after cardiac surgery
Katznelson et al., [22]	Average age = NA (36% were < 60 yrs old, and 64% were ³ 60 yrs old) n = 1,059	CABG, valve replacements, combined CABG-valve replacement surgery on CPB	CAM-ICU, 11.5%	Looked at preoperative use of statins and perioperative benzodiazepine and opioid use	Statin	<0.01	Statin	Odds Ratiod (95% CI) 0.54 (0.35-0.84)
Objective: To demonstrate an association between preoperative statin use and delirium after cardiac surgery
Tan et al., [25]	Average age = 63 yrs  n = 53	CABG, valve replacements, combined CABG-valve surgery on CPB	CAM, MDAS, MMSE, 23%	Collected data on preoperative ‘chemical dependency’; and use of ‘other’; anticholinergic medications (neither variable was defined); also recorded postoperative morphine equivalents over POD 1-3	Chemical dependency ‘Other’; anti-cholinergic agents Morphine equivalents, POD 1-3	0.18 0.10 0.76	‘Other’; anticholinergic agents Morphine equivalents, POD 1-3	Risk Ratio (95% CI) 2.31 (0.85-6.31) 1.00 (0.99-1.01)
Objective: To determine factors associated with and rate of delirium after cardiac surgery
Prospective Observational Studies
Tully et al., [27]	Average age = 65 yrs n = 158	Elective CABG, combined CABG-valve surgery on CPB	DSI, DSM-IV-TR, 31%	Collected data on preoperative use of anticholinergic drugs, SSRIs, tricyclic antidepressants	Anticholinergic drugs SSRI Tricyclic antidepressant Composite of drugs (anticholinergics, SSRIs, and/or tricyclics)	0.31 0.01 0.65 0.01	Composite of drugs	Odds Ratio (95% CI) 5.12 (1.46-17.94)
Objective: To determine an association between preoperative affective disorders or Type D personality with delirium after cardiac surgery
Koster et al., [29]	Average age = 70 yrs n = 112	Elective cardiac surgery with or without CPB	DOS, DSM-IV, 21%	Collected data on preoperative opioid use	Opioids	1.00	NA
Objective: To determine the predictive validity of a risk checklist for delirium after cardiac surgery
Norkiene et al., [51]	Average age = 71 yrs n = 1,367	CABG on CPB	DSM-IV, 3.1%	Collected data on postoperative use of inotropes for more than 12 hours	Inotropes > 12hrs	0.002	Inotropes > 12hrs	Odds Ratio (95% CI) 8.04 (1.1-60.6)
Objective: To identify the incidence and risk factors for delirium after cardiac surgery
Retrospective Chart Review
Redelmeier et al., [24]	Average age = 74 yrs n = 284,158	Elective cardiac, thoracic, neurosurgical, vascular, musculoskeletal, abdominal, retroperitoneal, lower urogenital, breast and skin, external head and neck, ophthalmologic, and unclassified surgeries	ICD, 1.1%	Outpatient use of two or more of: atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, and/or cerivastatin, with at least one having been prescribed within 90-days before surgery; also preoperative neuropsychiatric agents, nonstatin lipid-lowering agents, antihypertensives, loop diuretics, cardiovascular agents, anticoagulants, vascular agents, other common drugs	Statins Cholinesterase inhibitor Antipsychotic Antidepressant Benzodiazepine ACEI ARB Thiazide diuretic CCB Furosemide Digoxin Spironolactone Nonstatin lipid-lowering agent Anticoagulant Antiplatelet Pentoxifylline Hypoglycemics Insulin Bronchodilator Allopurinol Levothyroxine Glucocorticoid Gastric acid suppressant Anti-osteoporosis Glaucoma eye drops	< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.43 0.77 0.29 0.21 0.71 0.60 0.59 0.21 0.16 0.95 0.44 0.57 0.59 0.34 0.10 0.99 0.56 0.80 0.89 0.39	Statins Cholinesterase inhibitor Antipsychotic Antidepressant Benzodiazepine ACEI ARB Thiazide diuretic CCB Furosemide Digoxin Spironolactone Nonstatin lipid-lowering agent Anticoagulant Antiplatelet Pentoxifylline Hypoglycemic Insulin Bronchodilator Allopurinol Levothyroxine Glucocorticoid Gastric acid suppressant Anti-osteoporosis Glaucoma eye drops	Odds Ratioe (95% CI) 1.28 (1.12-1.46)f 3.99 (2.26-7.05) 1.57 (1.26-1.95) 2.01 (1.75-2.25) 1.40 (1.28-1.53) 0.96 (0.87-1.06) 1.05 (0.73-1.52) 0.92 (0.79-1.07) 0.94 (0.85-1.04) 1.03 (0.89-1.18) 0.96 (0.83-1.11) 1.09 (0.80-1.47) 0.80 (0.56-1.14) 1.14 (0.95-1.38) 1.01 (0.68-1.52) 1.16 (0.80-1.69) 0.96 (0.83-1.11) 0.93 (0.73-1.20) 1.06 (0.94-1.20) 0.83 (0.67-1.03) 1.00 (0.88-1.14) 0.94 (0.77-1.15) 0.99 (0.90-1.08) 1.01 (0.86-1.18) 0.94 (0.80-1.09)
Objective: To determine if the use of statins was associated with a higher rate of delirium after cardiac and non-cardiac surgeries
Post-Hoc Analysis of a Randomized Controlled Trial
Burkhart et al., [11]	Average age = 74 yrs  n = 113	Elective cardiac surgery with CPB	CAM, 30%	Collected data on preoperative use of statins; intraoperative amount of fentanyl; postoperative use of metoclopramide and tropisteron, and postoperative amount of opioids received per kilogram of body weight	Statins Fentanyl dose, per 10-µg/kg increase Opioid dose, per 1-mg/kg increase	0.8 0.006 0.6	Statins Fentanyl dose, per 10-µ>g/kg increase Opioid dose, per 1-mg/kg increase	Odds Ratio (95% CI) 1.1 (0.49-2.48) 3.4 (1.41-8.14) 1.5 (0.29-8.18)
Objective: To identify modifiable risk factors for delirium after cardiac surgery
Randomized Controlled Trial (Open-Label, Treatment-Controlled)
Maldonado et al., [3]	Average age = 58 yrs n = 90	Elective valve procedures on CPB	DSM-IV-TR, Overall rate, 34% Dexmedeto-midine cohort, 3% Propofol cohort, 50% Midazolam cohort, 50%	Compared rate of delirium with postoperative sedation by dexmedetomidine to sedation by propofol, or midazolam (in each sedation 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)	Dexmedetomidine/propofol/midazolam Midazolam/dexmedetomidine Propofol/dexmedetomidine	< 0.001 <0.001 <0.001	Midazolam (vs. dexmedetomidine) Propofol (vs.dexmedetomidine)	Odds Ratiog (95% CI) 28.6 (4.7-262.5) 29.6 (4.8-280.6)
Objective: To determine the effects of postoperative sedation on delirium after cardiac surgery
Randomized Controlled Trial (Double-Blind, Treatment-Controlled)
Shehabi et al., [26]	Average age = 71 yrs n = 299	CABG, valve replace- ments, combined CABG-valve surgery on pump	CAM-ICU, Overall rate, 11.7% Dexmedetomidine cohort, 8.6% Morphine cohort, 15%	Compared rate of delirium with postoperative sedation by dexmedetomidine to sedation by morphine (used open-label morphine in dexmedetomidine group to titrate for analgesia and open-label propofol in morphine group to titrate for sedation)	Dexmedetomidine/ morphine	0.088	Dexmedetomidine (vs. morphine)	Risk Ratio (95% CI) 0.57 (0.26-1.1)h
Objective: To compare the incidence of delirium in patients postoperatively sedated with dexmedeto- midine or morphine after cardiac surgery
Randomized Controlled Trials (Double-Blind, Placebo-Controlled)
Prakanrattana and Prapaitrakool, [6]	Average age = 61 yrs n = 126	Elective cardiac surgery on CPB	CAM-ICU, Risperidone cohort, 11.1% Placebo cohort, 31.7%	Investigated the effectiveness of postoperative risperidone prophylaxis (one dose of 1 mg risperidone or placebo immediately upon awakening from sedation in the ICU)	Risperidone/ placebo	0.009	Risperidone (vs. placebo)	Risk Ratio (95% CI) 0.35 (0.16-0.77)
Objective: To evaluate the efficacy of immediate postoperative risperidone for prevention of delirium after cardiac surgery
Gamberini et al., [8]	Average age = 74 yrs n = 113	CABG, valve replace- ments, with or without CPB	CAM, Rivastigmine cohort, 32% Placebo cohort, 30%	Investigated the effectiveness of a rivastigmine prophylaxis regimen (3 doses of 1.5 mg o.d. rivastigmine or placebo starting on evening before surgery until POD 6)	Rivastigmine/ placebo	0.8	Rivastigmine (vs. placebo)	Risk Ratio (95% CI) 1.08 (0.62 -1.90)
Objective: To evaluate the efficacy of rivastigmine prophylaxis regimen for the prevention of delirium after cardiac surgery
Hudetz et al., [9]	Average age = 64 yrs n = 58	Elective CABG, valve replacements, valve repairs on CPB	Intensive Care Delirium Screening Checklist (based on DSM-IV), Ketamine cohort, 3% Placebo cohort, 31%	Investigated the effectiveness of intraoperative ketamine for prophylaxis (0.5 mg/kg i.v. ketamine or 0.9% saline placebo during anesthetic induction along with fentanyl and etomidate)	Ketamine/placebo	0.01	Placebo (vs. ketamine)	Odds Ratio (95% CI) 12.6 (1.5-107.5)
Objective: To evaluate the efficacy of intraoperative ketamine for the prevention of delirium after cardiac surgery

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).