TVN Webinar Series Wednesday, December 2, 2015 and our webinar format • Welcome to today’s...
Transcript of TVN Webinar Series Wednesday, December 2, 2015 and our webinar format • Welcome to today’s...
Cochrane systematic review of antipsychotics for management of delirium in hospitalized patients –
Results of TVN-funded Knowledge Synthesis Grant
Lisa Burry, BScPharm, PharmDMount Sinai Hospital
TVN Webinar SeriesWednesday, December 2, 2015
Welcome and our webinar format
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• TVN webinar series is a regular forum where Canadian and international experts share research and insights on advancements in assessing and caring for frail elderly Canadians.
• In recent months, we have been highlighting the outcomes of TVN-funded Knowledge Synthesis grants, and today’s presentation is no exception.
Carol Barrie, Bcomm, CPA, CAExecutive Director
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Presenter: Cochrane systematic review of antipsychotics for managing delirium in hospitalized patients –
Results of TVN-funded Knowledge Synthesis Grant
Lisa Burry, BScPharm, PharmD• Clinical Scientist and Clinical Pharmacy Specialist at Mount Sinai Hospital
and University of Toronto• Peer-reviews for multiple journals including Canadian Medical Association
Journal, Critical Care Medicine, CHEST Journal, Annals of Pharmacotherapy, among others
• Chair of Emergency and Trauma Medicine Editorial Board, Annals of Pharmacotherapy, and Board member of Intensive Care Medicine
• Clinical preceptor to BSc, MSc, Doctor of Pharmacy students and pharmacy residents
• Research interests relate to patient and drug safety, in particular sedation, neuromuscular blockade, delirium and pain
Antipsychotics for Management of Delirium in Hospitalized
Patients: A Cochrane Systematic Review
Lisa Burry, PharmD
Objectives1. To review the syndrome of delirium & gain
understanding of its impact on hospitalized patients 2. To review the available data to support or refute the
use of antipsychotics for treatment of delirium in hospitalized patients
3. To review the available data to support or refute safety of antipsychotics for treatment of delirium in hospitalized patients
Delirium
• Neuropsychiatric syndrome typically precipitated by an acute illness such as surgery, infection, or critical illness
• Core features of DSM criteria:• Disturbance of consciousness with reduced ability to sustain,
or shift attention
• Change in cognition or development of a perceptual disturbance not better explained by a preexisting condition
• Disturbance develops over a short period of time and fluctuates during course of the day
Clinical Features
• May be a prodromal phase (sub-syndromal)
• Psychomotor disturbance– restless/agitated or lethargic/inactive
• Disturbance of consciousness– Hyperalert, alert (normal), lethargic, comatose
• Inattention– Reduced ability to focus/sustain/shift attention– Easily distractible
• External stimuli interfere with cognition
Clinical Features
• Disorders of thought
– Abnormalities in form and content of thinking are prominent
• Impaired organization and utilization of information• Thinking may become bizarre or illogical• Content may be impoverished or psychotic
– Delusions of persecution are common• Judgment and insight may be poor
Clinical Features
• Disorders of memory and orientation– Poor registration– Impaired recent and remote memory– Confabulation can occur
• Perceptual disturbances– Distortions (derealization/depersonalization)– Illusions (misinterpretation of external sensory stimuli)– Hallucinations
• May respond as if they are real
Clinical Features
• Disturbances of language
• Emotional disturbance– Fear– Anxiety
• Disruption of sleep and wakefulness– Fragmentation/disruption of sleep– Vivid dreams and nightmares
• Difficulty distinguishing dreams from real perceptions– Somnolent daytime experiences are “dreamlike”
Delirium is common in hospitals
• Low incidence in community 1 - 2%
• Medical/geriatric wards 29 - 64%
• Surgical wards 11 - 51%
• Critical care units 18 – 82%
Delirium is often ‘invisible’(unless you look for it…)
• Delirium is primarily hypoactive “quiet”subtype (35%) or mixed (64%)
• Hyperactive subtype is uncommon (1%)• Hypoactive delirium common in elderly
patients• Onset: ICU day 2 (+/- 1.7 days)• Duration: 4.2 days (+/- 2)
Inouye Lancet 2014
• Associated with poor outcomes –Increased mortality (3 fold ICU mortality)–prolonged hospitalization (~10 extra days)–increased likelihood of transfer to a chronic care facility–long-term cognitive impairment (1/3 delirium survivors–prolonged mechanical ventilation & ICU length of stay
• Caregiver burden (described for non-ICU patients)
• Estimated to cost > $164 billion/ year in the USA and > $182 billion/year in 18 European countries combined (2011)
Impact of delirium
Pathophysiology
• Multi-factorial and poorly understood• Neuroinflammation• Neuroendocrine imbalance• Neurotransmitter imbalance
– Dopamine (excess) & acetlycholine (depletion)– GABA, serotonin, endorphins and glutamate
• First line of treatment - Identification and reversal of underlying medical and environmental causes
• Guidelines – suggest drug intervention at MD’s discretion when – non-drug attempts have failed– behavioural symptoms pose risk to patient and staff
• Possible drug interventions– alpha2 agonists, antipsychotics, benzodiazepines, cholinesterase
inhibitors, opioids– Note: No drug currently approved for treatment of delirium
Delirium Management
Antipsychotic drugs use
Antipsychotics – Black Box Warning
• Considerable consequences and costs for delirium
• Efficacy and safety of antipsychotics for treatment of in-hospital delirium unclear– Cochrane review published 2007 (search conducted in2006)
• Surveys and observational data show exceedingly high use of antipsychotics
Rationale for this review
• Synthesize evidence to elucidate effect of antipsychotics on delirium outcomes (compared to placebo or other drug classes)
• Examine incidence and types of adverse events
• Determine if efficacy and safety are influenced by age
• Compare antipsychotics in terms of efficacy
• Identify evidence gaps for future research
Project Objectives
Methods: PICO
Study type: RCT
Population: – Hospitalized patients
(adults and children) in any ward (not psychiatry)
– Positive screen for delirium (validated tool) or defined high risk
Intervention: any antipsychotic drug
Comparator: – Any non-antipsychotic drug– Placebo– Non-pharmacological
treatment option
Outcomes: – Duration of delirium– Severity of symptoms– Mortality– Length of stay– Adverse events– Use of rescue medications
for agitation or sedation
Methods: Database Queries
Add search terms related to Intervention/Comparator using OR 1.Antipsychotic drugs/ or (antipsychotic* or neuroleptic* or (major adj2 (tranquilizer* or tranquiliser*))).mp. 2.Haloperidol/ or (haloperidol or alased or aloperidin* or (…) or pericate or "r 13,672" or "r 13672" or senorm.mp.
Add search terms related to Condition using OR 1. ("icu syndrome" or (intensive adj2 care adj2 unit adj2syndrome)).ti,ab. 2. delirium, dementia, amnestic, cognitive disorders/ or psychotic disorders/ or delirium/ 3. ("acute brain dysfunction" or (acute adj2 brain adj2dysfunction*) or "septic encephalopath*").ti,ab.4. brain diseases/ and critical illness/
Antipsychotics and other treatment alternatives for delirium
Patients diagnosed with deliriumand
RCTsandand
• HQP with assistance of Librarian with Cochrane review experience• Searched: MEDLINE, EMBASE, CENTRAL, DARE, HTA, CINAHL, LILACS, gray-literature
Additional records identified through other sources
(N = 4)
Unique records after duplicates removed
(N = 16,927)
Abstracts assessed for eligibility
(N = 1012)
Full-text records assessed for eligibility(N = 128)
Records excluded first round (based on title)(N = 15,915)
Included studies(N = 9)
Ongoing eligible studies(N = 3)
Intervention(N = 30)
Comparator(N = 19)
Population(N = 13)
Published abstracts/methods (included studies)
(N = 7)
Screening tool(N = 1)
Number of full-text records excluded with reasons
(N = 119)
Study Type(N = 48)
Records excluded second round (based on abstract)
(N = 880)
Records identified through database search
(N = 19,584)
Sub-analysis of included study
(N = 1)
High risk of delirium at enrollment
(N = 3)
Confirmed delirious at enrollment
(N = 5)
Unconfirmed study status(N = 2)
Early termination(N = 1)
PRISMA – Version 1.0
Sept 25 2014
PRISMA – Version 2.0
October 28, 2015
Study Antipsychotic(s) Age Dx Tool Dementia Included
Co-intervention
?Population
Breitbart 1996
Haldol (N=11)Chlorpromazine (N=13)
Lorazepam (N=6)All: 39.2 (±8.8) DSM Y U Hospitalized medical AIDS;
AIDS dementia included
Hu 2004Olanzapine (N=74)
Haldol (N=72)Placebo (N=29)
O: 74 (±8)H: 74 (±7)M: 73 (±7)
DSM U U Any hospitalized patients > 65 year
Tahir 2010
Quetiapine (N=21)Placebo (N=21)
Q: 84.1 (±9.5)P: 84.3 (±7.2) DSM N U
Medical, surgical, or orthopedic ward patients.Trial terminated
Atalan 2013
Haldol (N=26)Morphine (N=27)
H: 66.00 (±8.39)M: 65.74 (±9.67)
CAM-ICU N U Cardiac surgery, +/_ CABG
Agar 2015
Risperidone (N=82)Haldol (N=81)
Placebo (N=84) U DSM U Y Palliative care
Reade 2009
Haldol (N=10)Dexmedetomidine
(N=10)
H: 68.5 [43-78]D: 52 [42-69] ICDSC U U Mixed ICU
Devlin 2010
Quetiapine (N=18)Placebo (N=18)
Q: 62.4 (±14.0)P: 63.6 (±15.3) ICDSC N U Medical-surgical ICU
Girard 2010
Haloperidol (N=35)Ziprasidone (N=30)
Placebo (N=36)
H: 51 [35-59] Z: 54 [47-66]P: 56 [43-68]
CAM-ICU N N Mechanically ventilated
Medical-surgical ICU
Page 2013
Haldol (N=71)Placebo (N=70)
H: 67.9 (±16.5)P: 68.7 (±14.9)
CAM-ICU N Y Mechanical ventilation
Mixed ICU
Risk of bias summary
Results: Duration of Delirium
Results: Severity of DeliriumStudy Agents Severity
ScaleBaseline
Mean (SD)End PointMean (SD)
Improved?
Breitbart1996
Haloperidol (N=11)
DRS
20.45 (5.87) 11.64 (6.10) Y
Chlorpromazine (N=13) 20.62 (3.88) 11.85 (6.74) Y
Lorazepam (N=6) 18.33 (2.58) 17.00 (4.98) N
Hu 2004
Olanzapine (N=74)
DRS
23.6 (2.7) 6.5 (1.9) Y
Haloperidol (N=72) 24.3 (2.5) 7.2 (4.6) Y
Placebo (N=29) 24.7 (3.5) 17.6 (9.3) N
Tahir2010
Quetiapine (N=21)DRS-R-98
22.736 (3.098) 8.192 (4.223) Y
Placebo (N=21) 22.736 (=3.098) 8.456 (4.133) Y
Agar 2015
Risperidone (N=82)NuDESC
More symptoms than placebo 0.52 (95% CI 0.14, 0.91, p=0.008) N
Haloperidol (N=81) More symptoms than placebo0.26 (95% CI 0.09, 0.46, p=0.004) N
Results: Lengths of Stay
Results: Mortality
Results: Dosing and Rescue Drugs
Study Antipsychotic Comparator Rescue Drug Comments
Breitbart 1996
Haldol – titration Mean: 2.8 mgChlorpromazine – titration Mean 50mg
Lorazepam –titrationMean: 3.0 mg
Hu 2004 Olanzapine - 1.25 – 20 mg/dayHaldol - 2.5 – 10 mg/day IM Placebo Not
permitted
Tahir 2010
Quetiapine - flexible dosing regime 25 mg once daily, dose titration of 25 mg/day to a max 175 mg/day
Placebo same schedule Lorazepam More lorazepam use
in Q group
Atalan 2013
Haldol 5 mg/hr until target RASSMean: 10.96 mg
Morphine 5 mg/hour until target RASSMean: 9.81 mg
Lorazepam Sig more lorazepam use for H group
Agar 2015
Risperidone & haldol titrated based on symptomsMax 4 mg
Placebo MidazolamConsumption of midazolam not reported yet
Results: Adverse Events
Additional analysis
• Insufficient information for any planned subgroup analysis.
Summary• > 2/3 of delirious hospital patients are given antipsychotics.
• Yet, remarkably small body of work addressing a key pharmacotherapy issue.
• The fluctuating nature of delirium, frequent occurrence of spontaneous recovery, & the need to account for impact of medical treatments make placebo-controlled studies essential to the evaluation of efficacy.– Newer studies are including placebo group & indicate greater response in
antipsychotic group vs. placebo, as well as less severe symptoms.
Summary
• However, the challenge of managing delirium in our everyday hospital practice involves applying imperfect evidence and recognizing potential adverse effects.
• As a consequence, clinical practice continues to be guided by empirical knowledge rather than well-designed efficacy studies.
• Clearly greater research effort is warranted!
Research Assistant: Melane Guenette
Co-investigators: Sangeeta Mehta MD (ICU), Marc Perreault PharmD, Jay Luxenberg MD (Geriatrics), Chaim Bell MD (Internal Medicine), Dean Fergusson PhD (stats), Louise Rose PhD (ICU Nursing)
HQP: Anjuli Little MD, Barbara Sneyers PhD
Knowledge users: Wes Ely MD (ICU), Neil Adhikari MD (ICU), Camilla Wong MD (Geriatrics), Leslie Wiesenfeld MD (Psychiatry), Samir Sinha (Geriatrics)
Acknowledgments
Thank you for supporting our research dedicated to improving patient care.
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Scoping review of communication technologies for engaging patients, families and caregivers in the health care system – results of TVN-funded 2014 Knowledge Synthesis Grant – Anthony Lombardo, University of Toronto
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