Management of Agitation: A New Era

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Management of Agitation A New Era Horacio
Preval MD Comprehensive Psychiatric Emergency
Program SUNY Stony Brook
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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

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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

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Behavioral Treatment of Agitation

• Examiners 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

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Rxs for Agitation

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

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Limitations of Benzodiazepines as Rx for
agitation

• Nonspecific treatment response
• Dont address frequent underlying psychosis
• May potentiate unrecognized intoxication
• ?Excessive sedation
• ?Respiratory depression
• ?Paradoxical behavioral disinhibition
• ?Abuse potential

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Limitations of Conventional Antipsychotics for
agitation

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

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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

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Consumer Preferences

• TYPE of intervention
• Most acceptable PO medication
• Second line IM medication, seclusion
• Least acceptable Physical restraints

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Consumer Preferences

• CLASS of medication
• Most acceptable benzodiazepines
• Second line atypical neuroleptics
• Least acceptable conventional neuroleptics,
  droperidol

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Droperidol

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

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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.
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Liquid Risperidone ER StudyDesign

• J Clin Psychiat March 2001
• USC Psychiatric ER
• Prospective, 60 Cases requiring sedation
• N30 2 mg Liq Risperidone 2 mg oral LZ
• N30 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

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Liquid Risperidone ER StudyCritique

• Does show major effect of Rxs
• 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 LZHalo better than either
  alone
• Unanswered here Is LZ needed with atypicals?

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PUBLISHED IM ZIPRASIDONE STUDIES 10 MG STUDY AND
20 MG STUDY CHANGE IN BASELINE BARS SCALE
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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

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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 AdvantagesgtgtCost

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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

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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

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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

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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

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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

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BARS Agitation Scale

• 1 difficult to arouse
• 2asleep, responds normally
• 3drowsy, appears sedated
• 4quiet/awake normal activity level
• 5overt physical/verbal activity, calms
  w/command
• 6extremely/continuously active, not requiring
  restraint
• 7violent, requiring restraint

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SUNY PES STUDY- Data Worksheet
Restrained Yes No Time 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 No Specify
agent, route, and time ____________________
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IM ZIPRASIDONE STUDYN69

• MALES
• N43
• MEAN33.4
• SEM11.7
• MEDIAN34
• RANGE 18-67

• FEMALES
• N26
• MEAN43.1
• SEM11.7
• MEDIAN43
• RANGE 19-68

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QTc IM ZIPRASIDONE

• N17/69, 30 min post Rx
• MEAN 0.418
• SEM 0.026
• MEDIAN0.410
• RANGE 0.370-0.462

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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 EKGs no QTc changes
• ??More prompt interview and disposition

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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