Haloperidol vs Olanzapine for the Management of ICU Delirium - Full Text View

Purpose

The purpose of this randomized clinical trial is to determine whether haloperidol is superior to olanzapine for the treatment of ICU acquired delirium. The hypothesis is that haloperidol is in fact superior to olanzapine in treating ICU acquired delirium and sustaining delirium free time.

Condition	Intervention
Delirium Agitation	Drug: Haloperidol Drug: Olanzapine

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Subject) Primary Purpose: Treatment
Official Title:	Haloperidol vs Olanzapine for the Management of ICU Delirium: A Randomized Clinical Trial

Resource links provided by NLM:

MedlinePlus related topics: Delirium

Drug Information available for: Haloperidol Haloperidol decanoate Olanzapine Olanzapine pamoate

U.S. FDA Resources

Further study details as provided by Capital District Health Authority, Canada:

Primary Outcome Measures:

Resolution of delirium as indicated by an Intensive Care Delirium Screening Checklist score of less than 4 [ Time Frame: Every 24 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Delirium free days (i.e. time from resolution of delirium to ICU discharge) [ Time Frame: Every 24 hours ] [ Designated as safety issue: No ]
Incidence of treatment failure at 48 hours [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
Requirement for rescue medication [ Time Frame: Every 24 hours ] [ Designated as safety issue: No ]
Type of rescue medication [ Time Frame: Every 24 hours ] [ Designated as safety issue: No ]
Mortality [ Time Frame: Time of death ] [ Designated as safety issue: No ]
If on mechanical ventilation at time delirium develops, duration of mechanical ventilation [ Time Frame: Every 24 hours ] [ Designated as safety issue: No ]

Estimated Enrollment:	200
Study Start Date:	June 2008
Study Completion Date:	November 2011
Primary Completion Date:	November 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 Haloperidol	Drug: Haloperidol 2.5 mg-10 mg IV q6h for 24 hours and 2.5 mg-5 mg IV prn, up to 40mg in 24 hours. Reassess in 24 hours. Delirium absent - Continue dose for 24 hours then discontinue. Delirium present - Increase dose 5 mg-10 mg IV q6h for 24 hours and 2.5 mg-5 mg IV prn, up to 40 mg in 24 hours. Reassess in 24 hours. Delirium absent - Continue dose for 24 hours then discontinue. Delirium present - Discontinue current drug therapy and select one of: Quetiapine up to 100 mg/day Risperidone up to 6 mg/day Loxapine up to 50 mg/day Methotrimeprazine up to 75 mg/day Reassess in 24 hours. Delirium absent - Continue for 24 hours then discontinue. Delirium present - Treatment at discretion of attending physician. Other Name: Haldol
Active Comparator: 2 Olanzapine	Drug: Olanzapine 2.5 mg-10 mg po/ng/og bid and 2.5 mg po/ng/og prn, up to 20 mg in 24 hours. Reassess in 24 hours. Delirium absent - Continue dose for 24 hours then discontinue. Delirium present - Increase dose 5 mg-10 mg bid and 2.5 mg po/ng/og prn, up to 20 mg in 24 hours. Reassess in 24 hours. Delirium absent - Continue dose for 24 hours then discontinue. Delirium present - Discontinue current drug therapy and select one of: Quetiapine up to 100 mg/day Risperidone up to 6 mg/day Loxapine up to 50 mg/day Methotrimeprazine up to 75 mg/day Reassess in 24 hours. Delirium absent - Continue for 24 hours then discontinue. Delirium present - Treatment at discretion of attending physician. Other Names: Zyprexa Zyprexa Zydis Novo-Olanzapine PMS-Olanzapine

Arms

Assigned Interventions

Active Comparator: 1

Haloperidol

Drug: Haloperidol

2.5 mg-10 mg IV q6h for 24 hours and 2.5 mg-5 mg IV prn, up to 40mg in 24 hours.
Reassess in 24 hours.
Delirium absent - Continue dose for 24 hours then discontinue.
Delirium present - Increase dose 5 mg-10 mg IV q6h for 24 hours and 2.5 mg-5 mg IV prn, up to 40 mg in 24 hours.
Reassess in 24 hours.
Delirium absent - Continue dose for 24 hours then discontinue.
Delirium present - Discontinue current drug therapy and select one of:
1. Quetiapine up to 100 mg/day
2. Risperidone up to 6 mg/day
3. Loxapine up to 50 mg/day
4. Methotrimeprazine up to 75 mg/day
Reassess in 24 hours.
Delirium absent - Continue for 24 hours then discontinue.
Delirium present - Treatment at discretion of attending physician.

Other Name: Haldol

Active Comparator: 2

Olanzapine

Drug: Olanzapine

2.5 mg-10 mg po/ng/og bid and 2.5 mg po/ng/og prn, up to 20 mg in 24 hours.
Reassess in 24 hours.
Delirium absent - Continue dose for 24 hours then discontinue.
Delirium present - Increase dose 5 mg-10 mg bid and 2.5 mg po/ng/og prn, up to 20 mg in 24 hours.
Reassess in 24 hours.
Delirium absent - Continue dose for 24 hours then discontinue.
Delirium present - Discontinue current drug therapy and select one of:
1. Quetiapine up to 100 mg/day
2. Risperidone up to 6 mg/day
3. Loxapine up to 50 mg/day
4. Methotrimeprazine up to 75 mg/day
Reassess in 24 hours.
Delirium absent - Continue for 24 hours then discontinue.
Delirium present - Treatment at discretion of attending physician.

Other Names:

Zyprexa
Zyprexa Zydis
Novo-Olanzapine
PMS-Olanzapine

Detailed Description:

Delirium is defined as a disturbance of consciousness characterized by an acute onset of impaired cognitive function. Although delirium is thought to be common in the Intensive Care Unit (ICU) there are few studies that have evaluated its incidences, risks and outcomes. It has been associated with increased morbidity, and mortality and increased cost to the healthcare system. In addition to the uncertainty of the incidence of ICU delirium, there is a lack of information about the effects that certain pharmacological treatments have on delirious patients.

The standard pharmacological treatments for ICU acquired delirium are haloperidol and olanzapine as they have been shown to be equivalent in reducing its incidence. However, optimal dose and regimen have not been well defined.

The rationale for this study is to determine whether haloperidol is superior to olanzapine in the treatment of ICU acquired delirium. A secondary objective is to determine the most appropriate dosing regimen for the treatmet. The role of alternative agents quetiapine, risperidone, loxapine and methotrimeprazine will also be examined in a preliminary analysis.

Patients who develop agitation or delirium as defined by an Intensive Care Delirium Checklist (ICDSC) score of greater than or equal to 4 meeting all the inclusion criteria and no exclusion criteria will be eligible for randomization. Once randomized they will be screened for ongoing agitation and delirium as well prolongation of the QTc interval greater than 440 msec, development of extrapyramidal symptoms and development of a seizure disorder.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

All patients who are 18 years or older who are admitted for more than 24 hours to the ICU.
Patients screened for delirium using the ICDSC with a score greater than or equal to 4 or with clinical manifestations of delirium.

Exclusion Criteria:

Patients unlikely to survive 24 hours.
Patients with a primary neurologic reason (i.e. stroke, dementia-related psychosis) for ICU admission.
Patients with QTc interval greater than 440 msec.
Pregnant patients.
Patients who are breast feeding.
Patients in whom haloperidol, or olanzapine is contraindicated.
Patients allergic to haloperidol, olanzapine, quetiapine, risperidone, loxapine or methotrimeprazine.
Patients who do not have a urinary catheter.
Patients who have received haloperidol, olanzapine, quetiapine, risperidone, loxapine or methotrimeprazine within 14 days.
Patients unable to undergo assessment (i.e. patients with developmental disability or mental incapacity prior to ICU admission).
Prolonged (greather than 24 hours) comatose patients who have a defined structural reason for their decreased level of consciousness.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00833300

Locations

Canada, Nova Scotia
Halifax Infirmary; Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, Canada
Victoria General Hospital; Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, Canada

Sponsors and Collaborators

Richard Hall

Dalhousie University

Investigators

Principal Investigator:

Richard Hall, MD, FRCPC, FCCP

Capital District Health Authority, Canada

More Information

Publications:

Bergeron N, Skrobik Y, Dubois MJ. Delirium in critically ill patients. Crit Care. 2002 Jun;6(3):181-2. Epub 2002 Apr 5.

Lacasse H, Perreault MM, Williamson DR. Systematic review of antipsychotics for the treatment of hospital-associated delirium in medically or surgically ill patients. Ann Pharmacother. 2006 Nov;40(11):1966-73. Epub 2006 Oct 17. Review.

Jaber S, Chanques G, Altairac C, Sebbane M, Vergne C, Perrigault PF, Eledjam JJ. A prospective study of agitation in a medical-surgical ICU: incidence, risk factors, and outcomes. Chest. 2005 Oct;128(4):2749-57.

Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007 Jan;33(1):66-73. Epub 2006 Nov 11.

Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM, Crippen DW, Fuchs BD, Kelleher RM, Marik PE, Nasraway SA Jr, Murray MJ, Peruzzi WT, Lumb PD; Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002 Jan;30(1):119-41. No abstract available. Erratum in: Crit Care Med 2002 Mar;30(3):726.

Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, Truman B, Bernard GR, Dittus RS, Ely EW. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004 Apr;32(4):955-62.

Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard GR, Ely EW. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006 Jan;104(1):21-6.

Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004 Mar;30(3):444-9. Epub 2003 Dec 19.

Plaschke K, von Haken R, Scholz M, Engelhardt R, Brobeil A, Martin E, Weigand MA. Comparison of the confusion assessment method for the intensive care unit (CAM-ICU) with the Intensive Care Delirium Screening Checklist (ICDSC) for delirium in critical care patients gives high agreement rate(s). Intensive Care Med. 2008 Mar;34(3):431-6. Epub 2007 Nov 9.

Devlin JW, Fong JJ, Schumaker G, O'Connor H, Ruthazer R, Garpestad E. Use of a validated delirium assessment tool improves the ability of physicians to identify delirium in medical intensive care unit patients. Crit Care Med. 2007 Dec;35(12):2721-4; quiz 2725.

Rea RS, Battistone S, Fong JJ, Devlin JW. Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients. Pharmacotherapy. 2007 Apr;27(4):588-94. Review.

Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001 May;27(5):859-64.

Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus RS, Bernard GR. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003 Jun 11;289(22):2983-91.

Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974 Jul 13;2(7872):81-4. No abstract available.

Dubois MJ, Bergeron N, Dumont M, Dial S, Skrobik Y. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med. 2001 Aug;27(8):1297-304.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985 Oct;13(10):818-29.

Bucerius J, Gummert JF, Borger MA, Walther T, Doll N, Falk V, Schmitt DV, Mohr FW. Predictors of delirium after cardiac surgery delirium: effect of beating-heart (off-pump) surgery. J Thorac Cardiovasc Surg. 2004 Jan;127(1):57-64.

Korevaar JC, van Munster BC, de Rooij SE. Risk factors for delirium in acutely admitted elderly patients: a prospective cohort study. BMC Geriatr. 2005 Apr 13;5:6.

Stein LM, Thienhaus OJ. Hearing impairment and psychosis. Int Psychogeriatr. 1993 Spring;5(1):49-56.

Brust JC. Acute neurologic complications of drug and alcohol abuse. Neurol Clin. 1998 May;16(2):503-19. Review.

Vincent FM. The neuropsychiatric complications of corticosteroid therapy. Compr Ther. 1995 Sep;21(9):524-8. Review.

Responsible Party:	Richard Hall, Dr. Richard Hall MD FRCPC FCCP, Capital District Health Authority, Canada
ClinicalTrials.gov Identifier:	NCT00833300 History of Changes
Other Study ID Numbers:	CDHA-RS/2009-001, Control No.:121747, File No.: 9427-C2659-22C
Study First Received:	January 30, 2009
Last Updated:	August 2, 2012
Health Authority:	Canada: Health Canada

Keywords provided by Capital District Health Authority, Canada:

Delirium
Agitation
Intensive Care
Critical Care

Antipsychotics
Olanzapine
Haloperidol

Additional relevant MeSH terms:

Delirium
Psychomotor Agitation
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Dyskinesias
Psychomotor Disorders
Haloperidol
Olanzapine
Haloperidol decanoate
Antiemetics

Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Gastrointestinal Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 19, 2013