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Item Drugs of Abuse Can Entrain Circadian Rhythms(Hindawi Publishing Corporation, 2007-11-02) Kosobud, Ann E.K.; Gillman, Andrea G.; Leffel, Joseph K., II; Pecoraro, Norman C.; Rebec, G.V.; Timberlake, William; Neurology, School of MedicineCircadian rhythms prepare organisms for predictable events during the Earth's 24-h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.Item Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness(Massachusetts Medical Society., 2018-12-27) Girard, T.D.; Exline, M.C.; Carson, S.S.; Hough, C.L.; Rock, P.; Gong, M.N.; Douglas, I.S.; Malhotra, A.; Owens, R.L.; Feinstein, D.J.; Khan, B.; Pisani, M.A.; Hyzy, R.C.; Schmidt, G.A.; Schweickert, W.D.; Hite, R.D.; Bowton, D.L.; Masica, A.L.; Thompson, J.L.; Chandrasekhar, R.; Pun, B.T.; Strength, C.; Boehm, L.M.; Jackson, J.C.; Pandharipande, P.P.; Brummel, N.E.; Hughes, C.G.; Patel, M.B.; Stollings, J.L.; Bernard, G.R.; Dittus, R.S.; Ely, E.W.; Medicine, School of MedicineBACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).Item Pharmacological Management of Delirium in the Intensive Care Unit: A Randomized Pragmatic Clinical Trial(Wiley, 2019-05) Khan, Babar A.; Perkins, Anthony J.; Campbell, Noll L.; Gao, Sujuan; Farber, Mark O.; Wang, Sophia; Khan, Sikandar H.; Zarzaur, Ben L.; Boustani, Malaz A.; Biostatistics, School of Public HealthBACKGROUND/OBJECTIVE: Delirium in the intensive care units (ICUs) is prevalent, with both delirium duration and delirium severity associated with adverse outcomes. We designed a pragmatic trial to test the efficacy of a pharmacological management of delirium (PMD) bundle in improving delirium/coma-free days and reducing delirium severity among ICU patients. DESIGN: A randomized pragmatic clinical trial. SETTING: Medical, surgical, and progressive ICUs of three tertiary care hospitals. PARTICIPANTS: A total of 351 critically ill patients. INTERVENTION: A multicomponent PMD bundle consisting of reducing the exposure to 20 definite anticholinergic medications and benzodiazepines and prescribing low-dose haloperidol. MEASUREMENTS: The primary outcomes were delirium/coma-free days, measured through the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the ICU (CAM-ICU), and delirium severity, measured through Delirium Rating Scale-Revised-98 and the CAM-ICU-7. Secondary outcomes were in-hospital and posthospital discharge 30-day mortality, ICU and hospital lengths of stay, and delirium-related hospital complications. RESULTS: We randomized 351 critically ill delirious patients (mean age = 59.3 years [SD = 16.9 years]; 52% female, 42% African Americans) to receive the PMD bundle or usual care. There were no significant differences in median delirium/coma-free days at day 8 (PMD vs usual care = 4 [interquartile range {IQR} = 2-7] days vs 5 [IQR = 1-7] days; P = .888) or at day 30 (PMD vs usual care = 26 [IQR 19-29] days vs 26 [IQR, 14-29] days; P = .991). There were no significant differences for decrease in delirium severity at day 8, but at hospital discharge, the intervention group showed a greater reduction in delirium severity (mean decrease in CAM-ICU-7 score for PMD vs usual care = 3.2 [SD = 3.3] vs 2.5 [SD = 3.2]; P = .046). No differences were observed between groups for ICU and hospital lengths of stay, mortality, and delirium-related hospital complications. Similar results were observed when analyses were limited to patients 65 years or older and 75 years or older. CONCLUSION AND RELEVANCE: Implementing the PMD bundle in the ICU did not reduce delirium duration or severity among critically ill patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00842608. J Am Geriatr Soc 67:1057-1065, 2019.Item Preventing Postoperative Delirium After Major Noncardiac Thoracic Surgery—A Randomized Clinical Trial(Wiley, 2018) Khan, Babar A.; Perkins, Anthony J.; Campbell, Noll L.; Gao, Sujuan; Khan, Sikandar H.; Wang, Sophia; Fuchita, Mikita; Weber, Daniel J.; Zarzaur, Ben L.; Boustani, Malaz A.; Kesler, Kenneth; Medicine, School of MedicineObjectives: To assess the efficacy of haloperidol in reducing postoperative delirium in individuals undergoing thoracic surgery. Design: Randomized double-blind placebo-controlled trial. Setting: Surgical intensive care unit (ICU) of tertiary care center. Participants: Individuals undergoing thoracic surgery (N=135). Intervention: Low-dose intravenous haloperidol (0.5 mg three times daily for a total of 11 doses) administered postoperatively. Measurements: The primary outcome was delirium incidence during hospitalization. Secondary outcomes were time to delirium, delirium duration, delirium severity, and ICU and hospital length of stay. Delirium was assessed using the Confusion Assessment Method for the ICU and delirium severity using the Delirium Rating Scale-Revised. Results: Sixty-eight participants were randomized to receive haloperidol and 67 placebo. No significant differences were observed between those receiving haloperidol and those receiving placebo in incident delirium (n=15 (22.1%) vs n=19 (28.4%); p = .43), time to delirium (p = .43), delirium duration (median 1 day, interquartile range (IQR) 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, ICU length of stay (median 2.2 days, IQR 1-3.3 days vs median 2.3 days, IQR 1-4 days; p = .29), or hospital length of stay (median 10 days, IQR 8-11.5 days vs median 10 days, IQR 8-12 days; p = .41). In the esophagectomy subgroup (n = 84), the haloperidol group was less likely to experience incident delirium (n=10 (23.8%) vs n=17 (40.5%); p = .16). There were no differences in time to delirium (p = .14), delirium duration (median 1 day, IQR 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, or hospital length of stay (median 11 days, IQR 10-12 days vs median days 11, IQR 10-15 days; p = .26). ICU length of stay was significantly shorter in the haloperidol group (median 2.8 days, IQR 1.1-3.8 days vs median 3.1 days, IQR 2.1-5.1 days; p = .03). Safety events were comparable between the groups. Conclusion: Low-dose postoperative haloperidol did not reduce delirium in individuals undergoing thoracic surgery but may be efficacious in those undergoing esophagectomy.