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

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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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