Search
Close this search box.

RCT: Trazodone vs Quetiapine vs Placebo for Treating ICU Delirium (TraQ)

Studies

Study First Submitted Date 2021-09-27
Study First Posted Date 2021-10-20
Last Update Posted Date 2023-04-19
Start Month Year March 1, 2024
Primary Completion Month Year July 1, 2024
Verification Month Year April 2023
Verification Date 2023-04-30
Last Update Posted Date 2023-04-19

Detailed Descriptions

Sequence: 20824243
Description This is a single-center, double-blind randomized, placebo-controlled pilot trial comparing trazodone, quetiapine, and placebo for the treatment of ICU delirium in adult patients admitted to the surgical ICU at Keck Hospital of the University of Southern California. The purpose of this study is to determine the effectiveness of several medications (trazodone, quetiapine and placebo) used for the treatment of ICU delirium, and their effects on patient outcomes. Since the incidence of ICU delirium is high and has profound negative ramifications on survival, long-term outcomes, cognitive function, in addition to placing a heavy burden on the healthcare system resources and costs, effective delirium treatment strategies are desperately needed. Trazodone is a medication that has promise in delirium treatment, but there is currently insufficient literature to recommend its routine use. The investigators' main objective is to determine if trazodone is an effective and safe treatment option for the management of ICU delirium, and if it results in shorter delirium duration and improved outcomes compared to participants receiving quetiapine and placebo. Subject screening: All patients will be screened for study eligibility daily on rounds throughout the study period. Patients eligible for the study will be asked for written informed consent (signed by either the patient or the surrogate decision maker) after admission (even if the patient does not have delirium), or at any point during the ICU course (patient may or may not have a delirium diagnosis at the time of consent). ICU nurses will assess all patients for delirium at least every 12 hours, using the CAM-ICU tool , in accordance with the standard of care in the surgical ICU (that is, this assessment would be performed regardless of the study). Patients who have written informed consent, have a diagnosis of delirium (CAM-ICU positive) that requires pharmacological intervention as determined by the attending intensivist, and meet all inclusion criteria and have no exclusion criteria, will be randomized to receive either trazodone, quetiapine, or placebo. Stratification/Randomization Scheme: Patients who are enrolled in the study, meet randomization inclusion criteria, and have no exclusion criteria, and require a medication intervention for the treatment of ICU delirium, as determined by the attending ICU physician, will be randomized to one of three study arms: 1. Trazodone; 2. Quetiapine or; 3. placebo. Enrolled patients will be randomized in a 1:1:1 ratio to the Trazodone, Quetiapine, or placebo groups. Randomization will be stratified on age (< vs. ≥65) and delirium severity and occur in blocks, with block size not revealed to investigators. An independent statistician from the USC Clinical and Translational Science Institute (CTSI), will generate a randomization list and import it to REDCap prior to study initiation. Upon confirmation of informed consent, trial eligibility and completion of the baseline assessment, the patient will be randomized to one of the study arms using the REDCap randomization module. Upon randomization, an automated email notification will be sent to the un-blinded pharmacist (who is not part of the study team), who securely accesses the randomization module on REDCap and will prepare numbered supplement bottles according to the randomization list. The pharmacist will assign and dispense the drug to the ICU nurse who is administering the drug (and is blinded to the medication). The rest of the study team (PIs, co-PIs, research assistants, ICU nurses) will be blinded to the therapy being received and they will be blinded to the randomization and allocation process on REDCap as well, as the allocation and randomization files will be blinded and securely kept under passcode protection by the independent pharmacist. The patients will not know which study medication they are receiving. USC Plaza Pharmacy will prepare the study medications and packaging prior to study initiation. Study Medication Administration: There will be standardized method delineating how to begin dosing the study medication, and how to adjust the dose and frequency as needed. Additionally, there will be standardized tapering protocol, so there is consistency among all participants. Furthermore, there will be a standardized rescue medication protocol in place, should patients who are receiving placebo, or having break through delirium despite intervention. Statistics/Analysis Plan: -Determination of sample size: As this is a pilot study, a total sample size of 30 (10 per treatment group) over an enrollment period of 1 year is estimated to be recruited based on feasibility. As the primary goal of this pilot study is to identify a signal for treatment efficacy, sample size considerations are based on the precision (i.e., 95% confidence interval) with which key trial parameters can be estimated. -Baseline descriptive statistics: Baseline characteristics of the study population will be presented by treatment group using conventional descriptive statistics methods, including proportions for categorical variables and means and standard deviations or medians and interquartile ranges for continuous variables, as appropriate based on the data distribution. Comparisons of baseline variables will be performed between treatment groups by one-way Analysis of Variance (ANOVA) for continuous variables and chi-square or Fisher's exact tests for categorical variables, as appropriate. If a statistically significant difference is found (p<0.05) in the ANOVA models, pairwise treatment comparisons will be performed using Tukey's multiple comparison adjustment. Assumptions of the ANOVA model will be tested including 1) normality of model residuals, 2) homogeneity of variance, and 3) independence of observations and if not met, the non-parametric equivalent Kruskal-Wallis test will be used. -Analysis of primary endpoints: The primary outcome is the duration of ICU delirium measured in days. Differences in the duration of delirium between treatment groups will be analyzed by Poisson regression or negative binomial regression if there is evidence of over-dispersion. Patients with delirium episodes lasting less than one day will be classified as zero days. All models will include the randomized group and randomization stratification variables as independent variables. Model coefficients for each treatment group will be exponentiated to give the estimated rate ratio of each treatment comparison, with 95% confidence intervals. The referent group for treatment group comparisons will be the placebo group (i.e., comparing trazodone to placebo, and quetiapine to placebo). The pairwise comparison of trazodone to quetiapine will also be conducted. -Analysis of secondary endpoints: Binary secondary endpoints include the proportion of patients with in-hospital mortality, 28-day mortality, who experience complications, and who use rescue medications. The proportion in each treatment group will be compared univariately by the chi-square or Fisher's exact test and in a multivariable model by binary logistic regression. Additional secondary endpoints include the length of hospital stay, length of ICU stay, and duration of mechanical ventilation (if applicable). These outcomes will be analyzed as described in the "analysis of primary endpoint". Trial outcomes that are measured daily (delirium severity measured by CAM-S, nightly sleep duration (hours), number of times awoken at night, and sleep quality (Richards Campbell Sleep Questionnaire) will be compared among treatment groups using generalized linear mixed effects models (GLMMs). Normally distributed continuous outcomes will use a normal random outcome with an identify link function; count outcomes (e.g., number of times awoken) will use a Poisson random variable with a log link function. For each model, the primary independent variables will be randomized treatment group and randomization stratification variables. Assessment time (day of assessment, from day 0 to 14) will be treated as indicator variables. The main effect of treatment will estimate the mean of the outcome among treatment groups over the treatment period. An interaction term of treatment-by-day will be used to estimate treatment group means (with SEs and confidence intervals) by intervention day. -Analysis of safety measures: Numbers and percentages of adverse events and serious adverse events will be cross-tabulated and summarized descriptively by treatment group. No formal statistical analysis will be conducted. -Populations for analysis: The full analysis dataset will be based on an intention-to-treat (ITT) principle and will be comprised of all study participants who have been randomized to any of the 3 treatment groups. Analysis will be based on the original intervention, regardless of actual intervention received.

Facilities

Sequence: 201050348
Name Keck Hospital of the University of Southern California
City Los Angeles
State California
Zip 90033
Country United States

Facility Contacts

Sequence: 28252487
Facility Id 201050348
Contact Type primary
Name Catherine M Kuza, MD, FASA
Email catherine.kuza@med.usc.edu
Phone 323-442-8843

Browse Interventions

Sequence: 96468963 Sequence: 96468964 Sequence: 96468965 Sequence: 96468966 Sequence: 96468967 Sequence: 96468968 Sequence: 96468969 Sequence: 96468970 Sequence: 96468971 Sequence: 96468972 Sequence: 96468973 Sequence: 96468974 Sequence: 96468975 Sequence: 96468976 Sequence: 96468977 Sequence: 96468978
Mesh Term Quetiapine Fumarate Mesh Term Trazodone Mesh Term Antidepressive Agents Mesh Term Psychotropic Drugs Mesh Term Antipsychotic Agents Mesh Term Tranquilizing Agents Mesh Term Central Nervous System Depressants Mesh Term Physiological Effects of Drugs Mesh Term Anti-Anxiety Agents Mesh Term Selective Serotonin Reuptake Inhibitors Mesh Term Neurotransmitter Uptake Inhibitors Mesh Term Membrane Transport Modulators Mesh Term Molecular Mechanisms of Pharmacological Action Mesh Term Neurotransmitter Agents Mesh Term Serotonin Agents Mesh Term Antidepressive Agents, Second-Generation
Downcase Mesh Term quetiapine fumarate Downcase Mesh Term trazodone Downcase Mesh Term antidepressive agents Downcase Mesh Term psychotropic drugs Downcase Mesh Term antipsychotic agents Downcase Mesh Term tranquilizing agents Downcase Mesh Term central nervous system depressants Downcase Mesh Term physiological effects of drugs Downcase Mesh Term anti-anxiety agents Downcase Mesh Term selective serotonin reuptake inhibitors Downcase Mesh Term neurotransmitter uptake inhibitors Downcase Mesh Term membrane transport modulators Downcase Mesh Term molecular mechanisms of pharmacological action Downcase Mesh Term neurotransmitter agents Downcase Mesh Term serotonin agents Downcase Mesh Term antidepressive agents, second-generation
Mesh Type mesh-list Mesh Type mesh-list Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor

Conditions

Sequence: 52434983 Sequence: 52434984 Sequence: 52434985 Sequence: 52434986 Sequence: 52434987
Name Delirium Name Morality Name Quality of Life Name Psych Name Treatment Side Effects
Downcase Name delirium Downcase Name morality Downcase Name quality of life Downcase Name psych Downcase Name treatment side effects

Id Information

Sequence: 40346365
Id Source org_study_id
Id Value APP-20-01962

Countries

Sequence: 42778897
Name United States
Removed False

Design Groups

Sequence: 55885713 Sequence: 55885714 Sequence: 55885715
Group Type Active Comparator Group Type Experimental Group Type Placebo Comparator
Title Quetiapine Title Trazodone Title Placebo
Description Start study medication at 25 mg daily PO ; may increase to BID or TID if RASS>=2 or rescue medication must be given; thereafter, if med is TID, dose can be increased by increment of 50 mg q12 hr if RASS>=2 and/or >1 dose of rescue medication is given within 24 hours [max dose 200 mg/day] dose can be reduced/discontinued per discretion of ICU attending if delirium improving, patient experiences AE likely related to study drug, after 14 days of treatment, or patient is discharged from ICU dose should be held if RASS is -3 to -5/comatose/unresponsive or sudden acute change in mental status Description Start study medication at 25 mg daily PO ; may increase to BID or TID if RASS>=2 or rescue medication must be given; thereafter, if med is TID, dose can be increased by increment of 50 mg q12 hr if RASS>=2 and/or >1 dose of rescue medication is given within 24 hours [max dose 200 mg/day] dose can be reduced/discontinued per discretion of ICU attending if delirium improving, patient experiences AE likely related to study drug, after 14 days of treatment, or patient is discharged from ICU dose should be held if RASS is -3 to -5/comatose/unresponsive or sudden acute change in mental status Description Start study medication at 25 mg daily PO ; may increase to BID or TID if RASS>=2 or rescue medication must be given; thereafter, if med is TID, dose can be increased by increment of 50 mg q12 hr if RASS>=2 and/or >1 dose of rescue medication is given within 24 hours [max dose 200 mg/day] dose can be reduced/discontinued per discretion of ICU attending if delirium improving, patient experiences AE likely related to study drug, after 14 days of treatment, or patient is discharged from ICU dose should be held if RASS is -3 to -5/comatose/unresponsive or sudden acute change in mental status

Interventions

Sequence: 52744311 Sequence: 52744312 Sequence: 52744313
Intervention Type Drug Intervention Type Drug Intervention Type Drug
Name Trazodone Name Quetiapine Name Placebo
Description Trazodone will be administered to ICU patients who need pharmacological intervention for delirium, if they are randomized to the trazodone arm. Description Quetiapine will be administered to ICU patients who need pharmacological intervention for delirium, if they are randomized to the quetiapine arm. Description Placebo will be administered to ICU patients who need pharmacological intervention for delirium, if they are randomized to the placebo arm.

Keywords

Sequence: 80225221 Sequence: 80225222 Sequence: 80225223 Sequence: 80225224 Sequence: 80225225
Name delirium Name quetiapine Name trazodone Name critical care Name ICU delirium
Downcase Name delirium Downcase Name quetiapine Downcase Name trazodone Downcase Name critical care Downcase Name icu delirium

Design Outcomes

Sequence: 178370744 Sequence: 178370745 Sequence: 178370746 Sequence: 178370747 Sequence: 178370748 Sequence: 178370749 Sequence: 178370750 Sequence: 178370751 Sequence: 178370752 Sequence: 178370753 Sequence: 178370754 Sequence: 178370755 Sequence: 178370756 Sequence: 178370757 Sequence: 178370758 Sequence: 178370759 Sequence: 178370760
Outcome Type primary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary
Measure Delirium duration using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) tool Measure ICU length of stay Measure hospital length of stay Measure mechanical ventilator duration Measure in-hospital mortality Measure 28-day mortality Measure complications Measure adverse study drug-related reactions Measure Use of rescue medications Measure Delirium severity Measure sleep quality Measure discharge disposition Measure Long-term cognitive function Measure Long-term depression Measure Long-term anixety Measure Long-term PTSD Measure Long-term quality of life
Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame 28 days Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame 14 days Time Frame up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization) Time Frame up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization) Time Frame up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization) Time Frame up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization) Time Frame up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization)
Description days Description days Description days Description days Description yes or no Description yes or no Description yes or no Description yes or no Description yes or no Description 0-19 points using the CAM-S long form Description using Richards Campbell Sleep Questionnaire Description home, acute facility, rehabilitation, death, etc. Description using MoCA questionnaire Description using HADS Description using HADS Description using IES-R Description using SF-36 questionnaire

Browse Conditions

Sequence: 194489987 Sequence: 194489988 Sequence: 194489989 Sequence: 194489990 Sequence: 194489991 Sequence: 194489992 Sequence: 194489993
Mesh Term Delirium Mesh Term Confusion Mesh Term Neurobehavioral Manifestations Mesh Term Neurologic Manifestations Mesh Term Nervous System Diseases Mesh Term Neurocognitive Disorders Mesh Term Mental Disorders
Downcase Mesh Term delirium Downcase Mesh Term confusion Downcase Mesh Term neurobehavioral manifestations Downcase Mesh Term neurologic manifestations Downcase Mesh Term nervous system diseases Downcase Mesh Term neurocognitive disorders Downcase Mesh Term mental disorders
Mesh Type mesh-list Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor

Sponsors

Sequence: 48563392
Agency Class OTHER
Lead Or Collaborator lead
Name University of Southern California

Overall Officials

Sequence: 29422383
Role Principal Investigator
Name Catherine M Kuza, MD, FASA
Affiliation University of Southern California

Central Contacts

Sequence: 12077976
Contact Type primary
Name Catherine M Kuza, MD, FASA
Phone 9089176330
Email catherine.kuza@med.usc.edu
Role Contact

Design Group Interventions

Sequence: 68509880 Sequence: 68509881 Sequence: 68509882
Design Group Id 55885714 Design Group Id 55885713 Design Group Id 55885715
Intervention Id 52744311 Intervention Id 52744312 Intervention Id 52744313

Eligibilities

Sequence: 30916445
Gender All
Minimum Age 18 Years
Maximum Age N/A
Healthy Volunteers No
Criteria Inclusion Criteria: >=18-years-old Admitted to the surgical ICU for >24 hours Written informed consent obtained from the patient or their surrogate decision maker. Diagnosis of ICU delirium defined by positive CAM-ICU score AND exhibiting symptomatic delirium (i.e., combative, pulling at lines, a danger to self or others, inability to sleep, hallucinations, etc.), thus, requiring the need for pharmacologic intervention as determined by the attending intensivist Exclusion Criteria: Acute alcohol or substance abuse withdrawal symptoms/syndrome (i.e., delirium tremens) requiring treatment/intervention (i.e., implementation of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) protocol, benzodiazepines, alpha-2 agonist, etc.) Recent torsade de pointes or ventricular arrhythmia Prolonged QTc syndrome AND/OR prolonged QT-interval (QTc>500 ms on baseline EKG, performed on the day of randomization) Active psychosis Patients taking medications with known interactions with either trazodone and/or quetiapine Acute encephalopathy (i.e., hepatic, uremic, etc.) Seizure disorder myocardial infarction (MI) within the past 30 days Tardive dyskinesia Hyponatremia Terminal state Diagnosis of liver disease Patients who are strict NPO, are a high aspiration risk (defined as frequent nausea/vomiting, ileus, gastric dysmotility disorder, uncontrolled GERD, weakness/deconditioning, diabetes with gastroparesis, not tolerating full tube feeds if being enterally fed (high residual gastric volume >500 cc), elderly patients with waxing/waning mental status), have dysphagia, and/or have difficulty swallowing capsules as determined by speech therapist Patients who have enteral access such as a small-bore feeding tube, nasogastric or orogastric tube, or gastrostomy/gastrojejunostomy tube (as these patients will need medications crushed in order to administer via the tube, and the capsules used in this study cannot be crushed) Presence of an acute neurologic condition (i.e., acute cerebrovascular accident, intracranial tumor, traumatic brain injury, etc.) on ICU admission. History of stroke or other neurological condition(s) without cognitive impairment is not an exclusion criterion. Pregnancy/lactation History of ventricular arrhythmia including torsade de pointes Allergy/hypersensitivity reaction to trazodone and/or quetiapine Diagnosis of dementia History of neuroleptic malignant syndrome and/or serotonin syndrome Diagnosis of Parkinson's disease or parkinsonism (also referred to as hypokinetic rigidity syndrome) Schizophrenia or other psychotic disorder Patients in whom CAM-ICU cannot be performed to screen for delirium (i.e., acute encephalopathy, mental retardation, vegetative state/coma, deaf, blind, etc.) Inability to speak or understand English Expected to die or transfer out of the ICU within 24 hours Currently enrolled and participating in another interventional study No signed written informed consent by patient or their surrogate decision maker.
Adult True
Child False
Older Adult True

Calculated Values

Sequence: 254182130
Number Of Facilities 1
Registered In Calendar Year 2021
Were Results Reported False
Has Us Facility True
Has Single Facility True
Minimum Age Num 18
Minimum Age Unit Years
Number Of Primary Outcomes To Measure 1
Number Of Secondary Outcomes To Measure 16

Designs

Sequence: 30662130
Allocation Randomized
Intervention Model Parallel Assignment
Observational Model
Primary Purpose Treatment
Time Perspective
Masking Quadruple
Masking Description The only unmasked participant will be the pharmacist (who is not part of the study) who will be preparing and packaging the 3 different study medications. The intensivist, ICU RN, patients, patient's family members/legal representative, and additional study personnel will be masked to the intervention.
Subject Masked True
Caregiver Masked True
Investigator Masked True
Outcomes Assessor Masked True

Intervention Other Names

Sequence: 26804106 Sequence: 26804107
Intervention Id 52744311 Intervention Id 52744312
Name Desyrel Name Seroquel

Responsible Parties

Sequence: 29028814
Responsible Party Type Principal Investigator
Name Catherine Kuza, MD
Title Assistant Professor of Anesthesiology and Critical Care
Affiliation University of Southern California

Study References

Sequence: 52344255 Sequence: 52344256 Sequence: 52344257 Sequence: 52344258 Sequence: 52344259 Sequence: 52344260 Sequence: 52344261 Sequence: 52344262 Sequence: 52344263 Sequence: 52344264 Sequence: 52344265 Sequence: 52344266 Sequence: 52344267 Sequence: 52344268 Sequence: 52344269 Sequence: 52344270 Sequence: 52344271 Sequence: 52344272 Sequence: 52344273 Sequence: 52344274 Sequence: 52344275 Sequence: 52344276 Sequence: 52344277 Sequence: 52344278 Sequence: 52344279 Sequence: 52344280 Sequence: 52344281 Sequence: 52344282 Sequence: 52344283 Sequence: 52344284 Sequence: 52344285 Sequence: 52344286 Sequence: 52344287 Sequence: 52344288 Sequence: 52344289 Sequence: 52344290 Sequence: 52344291 Sequence: 52344292 Sequence: 52344293 Sequence: 52344294
Pmid 24088092 Pmid 23314584 Pmid 31724092 Pmid 28284292 Pmid 26975647 Pmid 30113379 Pmid 26238778 Pmid 30005303 Pmid 19915454 Pmid 21923923 Pmid 26304279 Pmid 26144941 Pmid 24916753 Pmid 10350040 Pmid 21748745 Pmid 29216606 Pmid 33577386 Pmid 23983836 Pmid 31523132 Pmid 11227580 Pmid 24373338 Pmid 11373423 Pmid 26118922 Pmid 19347026 Pmid 23182527 Pmid 15082703 Pmid 26077062 Pmid 23506796 Pmid 22301509 Pmid 19865006 Pmid 25348864 Pmid 21926597 Pmid 19687169 Pmid 12075033 Pmid 15817019 Pmid 6880820 Pmid 1593914
Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type background Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result Reference Type result
Citation Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013 Oct 3;369(14):1306-16. doi: 10.1056/NEJMoa1301372. Citation Kamdar BB, King LM, Collop NA, Sakamuri S, Colantuoni E, Neufeld KJ, Bienvenu OJ, Rowden AM, Touradji P, Brower RG, Needham DM. The effect of a quality improvement intervention on perceived sleep quality and cognition in a medical ICU. Crit Care Med. 2013 Mar;41(3):800-9. doi: 10.1097/CCM.0b013e3182746442. Citation Reznik ME, Slooter AJC. Delirium Management in the ICU. Curr Treat Options Neurol. 2019 Nov 14;21(11):59. doi: 10.1007/s11940-019-0599-5. Citation Marra A, Ely EW, Pandharipande PP, Patel MB. The ABCDEF Bundle in Critical Care. Crit Care Clin. 2017 Apr;33(2):225-243. doi: 10.1016/j.ccc.2016.12.005. Citation Reade MC, Eastwood GM, Bellomo R, Bailey M, Bersten A, Cheung B, Davies A, Delaney A, Ghosh A, van Haren F, Harley N, Knight D, McGuiness S, Mulder J, O'Donoghue S, Simpson N, Young P; DahLIA Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA. 2016 Apr 12;315(14):1460-8. doi: 10.1001/jama.2016.2707. Erratum In: JAMA. 2016 Aug 16;316(7):775. Citation Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299. Citation Michaud CJ, Bullard HM, Harris SA, Thomas WL. Impact of Quetiapine Treatment on Duration of Hypoactive Delirium in Critically Ill Adults: A Retrospective Analysis. Pharmacotherapy. 2015 Aug;35(8):731-9. doi: 10.1002/phar.1619. Epub 2015 Aug 4. Citation Mangan KC, McKinzie BP, Deloney LP, Leon SM, Eriksson EA. Evaluating the risk profile of quetiapine in treating delirium in the intensive care adult population: A retrospective review. J Crit Care. 2018 Oct;47:169-172. doi: 10.1016/j.jcrc.2018.07.005. Epub 2018 Jul 5. Citation Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, Robbins T, Garpestad E. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010 Feb;38(2):419-27. doi: 10.1097/CCM.0b013e3181b9e302. Citation Devlin JW, Skrobik Y, Riker RR, Hinderleider E, Roberts RJ, Fong JJ, Ruthazer R, Hill NS, Garpestad E. Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post-hoc analysis of a double-blind, randomized, placebo-controlled study. Crit Care. 2011;15(5):R215. doi: 10.1186/cc10450. Epub 2011 Sep 17. Citation Knauert MP, Haspel JA, Pisani MA. Sleep Loss and Circadian Rhythm Disruption in the Intensive Care Unit. Clin Chest Med. 2015 Sep;36(3):419-29. doi: 10.1016/j.ccm.2015.05.008. Epub 2015 Jun 29. Citation Madrid-Navarro CJ, Sanchez-Galvez R, Martinez-Nicolas A, Marina R, Garcia JA, Madrid JA, Rol MA. Disruption of Circadian Rhythms and Delirium, Sleep Impairment and Sepsis in Critically ill Patients. Potential Therapeutic Implications for Increased Light-Dark Contrast and Melatonin Therapy in an ICU Environment. Curr Pharm Des. 2015;21(24):3453-68. doi: 10.2174/1381612821666150706105602. Citation Pulak LM, Jensen L. Sleep in the Intensive Care Unit: A Review. J Intensive Care Med. 2016 Jan;31(1):14-23. doi: 10.1177/0885066614538749. Epub 2014 Jun 10. Citation Ishii T et al. Retrospective Study of Trazodone Monotherapy Compared with Ramelteon and Trazodone Combination Therapy for the Management of Delirium. J Psychiatry. 2018; 21(3):1-5 Citation Okamoto Y, Matsuoka Y, Sasaki T, Jitsuiki H, Horiguchi J, Yamawaki S. Trazodone in the treatment of delirium. J Clin Psychopharmacol. 1999 Jun;19(3):280-2. doi: 10.1097/00004714-199906000-00018. No abstract available. Citation Ospina JP et al. Epidemiology, Mechanisms, Diagnosis, and Treatment of Delirium: A Narrative Review. Clinical Medicine and Therapuetics. 2018;1(1):3-9. Citation Popeo DM. Delirium in older adults. Mt Sinai J Med. 2011 Jul-Aug;78(4):571-82. doi: 10.1002/msj.20267. Citation Wada K, Morita Y, Iwamoto T, Mifune Y, Nojima S. First- and second-line pharmacological treatment for delirium in general hospital setting-Retrospective analysis. Asian J Psychiatr. 2018 Feb;32:50-53. doi: 10.1016/j.ajp.2017.11.028. Epub 2017 Dec 5. Citation Maeda I, Inoue S, Uemura K, Tanimukai H, Hatano Y, Yokomichi N, Amano K, Tagami K, Yoshiuchi K, Ogawa A, Iwase S; Phase-R Delirium Study Group. Low-Dose Trazodone for Delirium in Patients with Cancer Who Received Specialist Palliative Care: A Multicenter Prospective Study. J Palliat Med. 2021 Jun;24(6):914-918. doi: 10.1089/jpm.2020.0610. Epub 2021 Feb 11. Citation Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011 Jan;1(1):41-7. doi: 10.1177/1941875210386491. Citation Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. Int J Tryptophan Res. 2019 Sep 9;12:1178646919873925. doi: 10.1177/1178646919873925. eCollection 2019. Citation Richards KC, O'Sullivan PS, Phillips RL. Measurement of sleep in critically ill patients. J Nurs Meas. 2000 Fall-Winter;8(2):131-44. Citation Hodgson C, Needham D, Haines K, Bailey M, Ward A, Harrold M, Young P, Zanni J, Buhr H, Higgins A, Presneill J, Berney S. Feasibility and inter-rater reliability of the ICU Mobility Scale. Heart Lung. 2014 Jan-Feb;43(1):19-24. doi: 10.1016/j.hrtlng.2013.11.003. Epub 2013 Nov 19. Erratum In: Heart Lung. 2014 Jul-Aug;43(4):388. Citation Jones C, Griffiths RD, Humphris G, Skirrow PM. Memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. Crit Care Med. 2001 Mar;29(3):573-80. doi: 10.1097/00003246-200103000-00019. Citation Jackson P, Khan A. Delirium in critically ill patients. Crit Care Clin. 2015 Jul;31(3):589-603. doi: 10.1016/j.ccc.2015.03.011. Epub 2015 May 4. Citation Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol. 2009 Apr;5(4):210-20. doi: 10.1038/nrneurol.2009.24. Citation Brummel NE, Girard TD. Preventing delirium in the intensive care unit. Crit Care Clin. 2013 Jan;29(1):51-65. doi: 10.1016/j.ccc.2012.10.007. Citation Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. doi: 10.1001/jama.291.14.1753. Citation Salluh JI, Latronico N. Making advances in delirium research: coupling delirium outcomes research and data sharing. Intensive Care Med. 2015 Jul;41(7):1327-9. doi: 10.1007/s00134-015-3864-4. Epub 2015 Jun 3. No abstract available. Citation Zhang H, Lu Y, Liu M, Zou Z, Wang L, Xu FY, Shi XY. Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials. Crit Care. 2013 Mar 18;17(2):R47. doi: 10.1186/cc12566. Citation Ringdal GI, Ringdal K, Juliebo V, Wyller TB, Hjermstad MJ, Loge JH. Using the Mini-Mental State Examination to screen for delirium in elderly patients with hip fracture. Dement Geriatr Cogn Disord. 2011;32(6):394-400. doi: 10.1159/000335743. Epub 2012 Feb 1. Citation Roberts DJ, Goralski KB, Renton KW, Julien LC, Webber AM, Sleno L, Volmer DA, Hall RI. Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain. Crit Care Med. 2009 Oct;37(10):2767-74. doi: 10.1097/CCM.0b013e3181b755d5. Citation Collinsworth AW, Priest EL, Campbell CR, Vasilevskis EE, Masica AL. A Review of Multifaceted Care Approaches for the Prevention and Mitigation of Delirium in Intensive Care Units. J Intensive Care Med. 2016 Feb;31(2):127-41. doi: 10.1177/0885066614553925. Epub 2014 Oct 27. Citation van den Boogaard M, Schoonhoven L, Evers AW, van der Hoeven JG, van Achterberg T, Pickkers P. Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning. Crit Care Med. 2012 Jan;40(1):112-8. doi: 10.1097/CCM.0b013e31822e9fc9. Citation Davydow DS. Symptoms of depression and anxiety after delirium. Psychosomatics. 2009 Jul-Aug;50(4):309-16. doi: 10.1176/appi.psy.50.4.309. Citation Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses. Psychosomatics. 2002 May-Jun;43(3):183-94. doi: 10.1176/appi.psy.43.3.183. Citation Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x. Erratum In: J Am Geriatr Soc. 2019 Sep;67(9):1991. Citation Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x. Citation Weiss DS, Marmar CR, Wilson JP, et al. Assessing psychological trauma and PTSD. The Impact of Events Scale. 1997;19:399-411. Citation Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83.