Management of Agitation: A New Era Horacio Preval MD

Comprehensive PsychiatricEmergency Program

SUNY Stony Brook

“Treatment of Behavioral Emergencies”

• Defining a Behavioral Emergency, often a.k.a. ‘agitation’

• Always: Threatening or Assaultive to Persons• Usually: SEVERAL of: Uncooperative, Restless,

Labile, Shouting, Intimidating, Demeaning, Property destruction

• Sometimes: FEW of: Uncooperative, Restless, Labile, Shouting, Intimidating, Demeaning, Property destruction

Causes of Agitation• Acute Psychotic Illness• Intense Mood shifts, Affective Disorders• Cognitive impairment [dementia, delirium,

mental retardation]• Severe stress• Substances [Intoxication, Withdrawal]• Acute physical illness/injury• Traumatic brain injury

Behavioral Treatment of Agitation

• Examiner’s fear: reflects violence potential • Show concern, allow Pt some choices• Develop rapport• Offer help to stay in control• Offer sedatives• Set limits• May need physical restraints

Rx’s for Agitation

• Barbiturates [Amytal] IM• Benzodiazepines IM, PO, IV• Antihistamines IM, PO• Conventional antipsychotics IM, PO, IV• Droperidol IM, IV• Atypical antipsychotics PO, IM

Limitations of Benzodiazepines as Rx for agitation

• Nonspecific treatment response• Don’t address frequent underlying

psychosis• May potentiate unrecognized intoxication• ?Excessive sedation• ?Respiratory depression• ?Paradoxical behavioral disinhibition• ?Abuse potential

Limitations of Conventional Antipsychotics for agitation

• Acute dystonia• Akathisia, other EPS• ?Prolonged sedation• Anticholinergic effects• EKG effects• Neuroleptic malignant syndrome• Droperidol- FDA new labeling

Ideal IM Rx for Agitation

• Rapid onset• Effective in single dose, w/o excess

sedation• Favorable safety profile

– low risk acute EPS, akathisia– low incidence EKG, medical abnormalities– low risk adverse drug interactions

“Consumer Preferences”

• TYPE of intervention

• Most acceptable: PO medication• Second line: IM medication, seclusion• Least acceptable: Physical restraints

“Consumer Preferences”

• CLASS of medication

• Most acceptable: benzodiazepines• Second line: atypical neuroleptics• Least acceptable: conventional

neuroleptics, droperidol

Droperidol

• Brief Review of studies 1970’s-1990’s• Favorable use for agitation• Off-Label • 2002: Black Box Warning

Droperidol 2002: 1

WARNING: Cases of QT prolongation and/or torsades de pointes have been reported in patients receiving droperidol at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.

Liquid Risperidone: ER StudyDesign

• J Clin Psychiat March 2001• USC Psychiatric ER• Prospective, 60 Cases requiring sedation• N=30 2 mg Liq Risperidone + 2 mg oral LZ• N=30 5 mg IM Haloper + 2 mg IM LZ• Baseline and f/u PANSS, CGI ratings• Pt choice to take oral vs. IM• Toxicol done in 17/60, 2/17cocaine

BASELINE 30 MIN 60 MIN0

5

10

15

20

25

30

IM HALO + IM LZ

PO RISP + PO LZ

RISPERIDONE VS. HALOPERIDOL ER STUDY

Liquid Risperidone: ER StudyCritique

• Does show major effect of Rx’s• Small study, un-restrained pts• Voluntary participation for PO Rx

[although PANSS scores were similar]• Confound of LZ: Better study HALOPER

vs. RISP w/o LZ• Prior studies show LZ+Halo better than

either alone• Unanswered here: Is LZ needed with

atypicals?

PUBLISHED IM ZIPRASIDONE STUDIES10 MG STUDY AND 20 MG STUDY

[CHANGE IN BASELINE BARS SCALE]

IM Ziprasidone StudiesCritique

• 10 mg study shows very modest clinical change on rating scales

• ?generalizable to usual ER pts• Voluntary participation for PO Rx• Unlike risperidone, ziprasidone does show

effect of monotherapy without lorazepam• Onset of clinical effect in reducing

agitation scores seems delayed

SUNY Stony Brook2002 PES STUDY-Rationale

• Droperidol abandoned• Published Ziprasidone studies [e.g., Daniel et al.]

show promise, but excluded severe agitation, ETOH/substance intoxication

• Published study [20 mg]: 50% drop in agitation scores in 2 hr [?rapid enough]

• Ziprasidone IM untested in routine PES cases• Ziprasidone more costly that conventional

alternatives [Halo/LZ] but ?? if Advantages>>Cost

SUNY Stony BrookPES STUDY-Background

• NOT Pfizer Sponsored• Droperidol abandoned June 2002• Advent of IM Ziprasidone • Initially, CQI [QA] project for internal use: ?safe, ?effective, ?

cost-benefit• Pharmacy restricted use to CPEP, Inpatient Psych [Not Med

ER!]• CQI project• Not “research” [I.e., not planned for publication]• IRB approval later obtained for retrospective reporting,

publishing [convert QA data to research data]

SUNY Stony BrookPES STUDY- Investigators

• Steven Klotz, MD- PGY-4 resident• Horacio Preval, MD- Director CPEP• Robert Southard, RNP- CPEP and P-K Day

Treatment Center• Andrew Francis, MD PhD- Director Inpatient

Psychiatric Unit

SUNY Stony BrookPES STUDY-Design 1

• Naturalistic outcome- not random• Predominant sedative for Oct-Dec 2002• Typical PES cases: severe agitation, ETOH,

substances• Data: BARS scale at baseline and over 120 min [non-

obtrusive, practical time limit]• Data: Duration of restraints• Data: Post-Hoc Disposition time from CPEP

SUNY Stony BrookPES STUDY-Design 2

• Compare to conventional sedatives-- mostly HALO +/or LZ

• Routine clinical monitoring, 17/69 EKG, • Categorize cases as PSYCH agitation [toxicology

negative], ETOH agitation [BAL range 50-460, median 285], SUBS agitation [miscellaneous including cocaine, MJ, barbiturates, opiates, or combined with ETOH]

BARS Agitation Scale

• Simple, one-item 7 point scale• Used in published Ziprasidone studies• Validated against PANSS-agitation and CGI-

S• Entirely observational, not obtrusive• High inter-rater reliability

BARS Agitation Scale • 1= difficult to arouse• 2=asleep, responds normally• 3=drowsy, appears sedated• 4=quiet/awake [normal activity level]• 5=overt physical/verbal activity, calms

w/command***• 6=extremely/continuously active, not requiring

restraint• 7=violent, requiring restraint***

Restrained: Yes NoTime entering restraint: _________Time leaving restraint: __________

BARS Agitation Score [1 to 7 numerical score] Baseline Time [at or immediately prior to injection] _____Baseline Score __________Score at 15 min _________Score at 30 min _________Score at 45 min _________Score at 60 min _________Score at 90 min _________Score at 120 min _________

Was a second IM/PO sedative required? Yes NoSpecify agent, route, and time ____________________

SUNY PES STUDY- Data Worksheet

IM ZIPRASIDONE STUDYN=69

• MALES• N=43• MEAN=33.4• SEM=11.7• MEDIAN=34• RANGE 18-67

• FEMALES• N=26• MEAN=43.1• SEM=11.7• MEDIAN=43• RANGE 19-68

QTc IM ZIPRASIDONE

• N=17/69, ~30 min post Rx• MEAN= 0.418• SEM= 0.026• MEDIAN=0.410• RANGE= 0.370-0.462

SUNY Stony BrookPES STUDY-Results

• Routine PES cases more agitated that in published study [BARS 6.6 vs. 5.0]

• ~50 % drop in BARS scores in 30-45 minutes with Ziprasidone 20 mg, clinically significant

• Preliminary data for reduced restraint times• Equally effective for intoxicated cases• Safe, well-tolerated• One dystonic Reaction; 17 EKG’s no QTc changes• ??More prompt interview and disposition

General Conclusions

• Ziprasidone is safe and effective for acute agitation

• Equally effective for agitation of all types• Use of IM preparation fosters easy

conversion to PO Ziprasidone