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

Sponsor:	Capital District Health Authority, Canada
Collaborator:	Dalhousie University
Information provided by:	Capital District Health Authority, Canada
ClinicalTrials.gov Identifier:	NCT00833300

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:	Treatment, Randomized, Single Blind (Subject), Parallel Assignment, Efficacy Study
Official Title:	Haloperidol vs Olanzapine for the Management of ICU Delirium: A Randomized Clinical Trial

Resource links provided by NLM:

Drug Information available for: Haloperidol Haloperidol decanoate Haloperidol lactate Olanzapine

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
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator 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.
2: Active Comparator 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.

Arms

Assigned Interventions

1: Active Comparator

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.

2: Active Comparator

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.

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

Contacts

Contact: Kristi Abraham, BSc.Phm, ACPR	902-473-2057	kristi.abraham@cdha.nshealth.ca
Contact: Leah Morrison, BSc.Pharm	902-473-2057	leah.morrison@cdha.nshealth.ca

Locations

Canada, Nova Scotia
Halifax Infirmary; Queen Elizabeth II Health Sciences Centre	Recruiting
Halifax, Nova Scotia, Canada
Contact: Kristi Abraham, BSc.Phm, ACPR 902-473-2057 kristi.abraham@cdha.nshealth.ca
Contact: Leah Morrison, BSc.Pharm 902-473-2057 leah.morrison@cdha.nshealth.ca
Sub-Investigator: Pauwlina McGrath, BSc.Biochem
Sub-Investigator: Charles MacLean, BBA, BSc.Pharm
Sub-Investigator: Kristi Abraham, BSc Chem, BSc Phm
Sub-Investigator: Julie McNeil, BA, BSc.Bio, BSc.Pharm
Sub-Investigator: Leah Morrison, BScPharm
Sub-Investigator: Hoan Linh Banh, BScPharm, PharmD
Sub-Investigator: Philippe Boilard
Victoria General Hospital; Queen Elizabeth II Health Sciences Centre	Recruiting
Halifax, Nova Scotia, Canada
Contact: Kristi Abraham, BScPhm, ACPR 902-473-2057 kristi.abraham@cdha.nshealth.ca
Contact: Leah Morrison, BScPharm 902-473-2057 leah.morrison@cdha.nshealth.ca
Sub-Investigator: Pauwlina McGrath, BScBiochem
Sub-Investigator: Charles MacLean, BBA, BSc.Pharm
Sub-Investigator: Kristi Abraham, BScChem, BScPhm
Sub-Investigator: Julie McNeil, BA, BSc.Bio, BSc.Pharm
Sub-Investigator: Leah Morrison
Sub-Investigator: Hoan Linh Banh, BScPharm, PharmD

Sponsors and Collaborators

Capital District Health Authority, Canada

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.

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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.

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Responsible Party:	Capital District Health Authority, Canada ( Richard Hall, MD, FRCPC, FCCP )
Study ID Numbers:	CDHA-RS/2009-001, Control No.:121747, File No.: 9427-C2659-22C
Study First Received:	January 30, 2009
Last Updated:	September 10, 2009
ClinicalTrials.gov Identifier:	NCT00833300 History of Changes
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:

Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Physiological Effects of Drugs
Psychotropic Drugs
Olanzapine
Antiemetics
Psychomotor Agitation
Haloperidol
Signs and Symptoms
Mental Disorders
Therapeutic Uses
Psychomotor Disorders
Neurobehavioral Manifestations

Delirium
Tranquilizing Agents
Nervous System Diseases
Gastrointestinal Agents
Central Nervous System Depressants
Dopamine Antagonists
Confusion
Antipsychotic Agents
Serotonin Uptake Inhibitors
Dyskinesias
Pharmacologic Actions
Haloperidol decanoate
Serotonin Agents
Delirium, Dementia, Amnestic, Cognitive Disorders
Autonomic Agents

ClinicalTrials.gov processed this record on February 08, 2010