The Medical Management of Acute Agitation

1. The Medical Management of Acute Agitation APM Resident Education Curriculum Revised 2019: Ariadna Forray, MD, Naomi Schmelzer, MD Original version: R. Scott Babe, M.D., Clinical Assistant Professor of Psychiatry, Western University of Health Sciences, Samaritan Mental Health, Corvallis, Oregon Thomas W. Heinrich, MD, Associate Professor of Psychiatry & Family Medicine, Chief, Psychiatric Consult Service at Froedtert Hospital, Department of Psychiatry & Behavioral Medicine, Medical College of Wisconsin Version of March 15, 2019

2. Objectives Identify the behavioral spectrum of agitation Describe the broad differential diagnosis behind the symptoms of agitation and aggression. Apply non-pharmacologic and pharmacologic approaches to management of the agitated patient in the general medical setting.

3. The Case A 47 year-old male with a history of substance use disorder and bipolar disorder along with morbid obesity, DM and COPD presents to the ED at 0200 after calling 911 and reporting chest pain. He is cooperative in the ED, but observed to be mumbling to himself and staring at staff suspiciously. He is given lorazepam 1mg PO to calm him. Since arriving to the floor to rule out an MI, he has become increasingly restless, irritable, and confrontational. He is increasingly uncooperative with medical care, then becomes verbally and physically threatening to the staff. His primary team calls a psychiatry consult for help managing these behaviors.

4. Definitions • Agitation • Excessive motor or verbal activity • “an emergent situation that is temporary, breaks the therapeutic alliance, and is in need of a prompt and immediate intervention” (Garriga et al. 2016) • Aggression • Hostile, injurious, or destructive behavior. Can be verbal or physical. • Violence • Denotes physical aggression by people against other people • 2 general types: • Impulsive/reactive • Instrumental/premeditated –goal-oriented violence (Siever L. (2008) Neurobiology of aggression and violence. Am J Psychiatry 165: 429-42. Garriga M., Pacchiarotti, I., Kasper, S. et al. (2016) Assessment and Management of Agitation in Psychiatry: Expert consensus. World J Biol Psychiatry. 17, 170-185.)

5. Component Behaviors of Agitation • Nonaggressive behaviors • Restlessness (akathisia, fidgeting) • Wandering • Loud, excited speech • Pacing or frequently changing body positions • Inappropriate behavior (disrobing, intrusive, repetitive questioning) • Aggressive behaviors • Physical • Combativeness, punching walls • Throwing or grabbing objects, destroying items • Clenching hands into fists, posturing • Self-injury (repeatedly banging one’s head) • Verbal • Cursing • Screaming

6. Larkin GL. et al. Trends in US Emergency Department Visits for Mental Health Conditions, 1992-2001. Psychiatric Services, June 2005. 56; 671-677.Marco, C. A., & Vaughan, J. (2005). Emergency management of agitation in schizophrenia. The American journal of emergency medicine, 23(6), 767-776. Epidemiology • There is little direct data on the prevalence, clinical impact, or financial consequences of agitation • Behavioral emergencies responsible for 6% of all ED visits (Larkin et al 2005) • 4.3 million psychiatric emergency visits/year (Marco and Vaughan, 2005) • 21% (900,000) agitated patients with schizophrenia • 13% (560,000) agitated patients with bipolar disorder • 5% (210,000) agitated patients with dementia

7. Epidemiology Peek-Asa, C., Howard, J., Vargas, L., & Kraus, J. F. (1997). Incidence of non-fatal workplace assault injuries determined from employer's reports in California. Journal of Occupational and Environmental Medicine, 39(1), 44-50. Gerberich, S. G., Church, T. R., McGovern, P. M., Hansen, H. E., Nachreiner, N. M., Geisser, M. S., ... & Watt, G. D. (2004). An epidemiological study of the magnitude and consequences of work related violence: the Minnesota Nurses’ Study. Occupational and environmental medicine, 61(6), 495-503. • Studies for health care workers • California: • 465 assaults per 100,000 hospital workers vs. 82.5 assaults per 100,000 for all workers (Peek-Asa et al 1997) • Minnesota Nurses Study (Gerberich et al 2004): • 13.2 per 100 persons per year for physical assaults • 38.8 per 100 persons per year for non-physical assaults • Greatest risk for persons working in/with: • Long term care facility • Intensive care • Psychiatric unit • Emergency department • Geriatric patients

8. Etiology of Agitation • A. Disease-related: three major categories • Psychiatric manifestations of general medical conditions • Substance intoxication/withdrawal • Primary psychiatric illness • B. Instrumental: unlikely to benefit from medical intervention (e.g., criminal behavior) • Consider short trial of verbal de-escalation • Depending on severity, consider involving security or law enforcement These are not mutually exclusive

9. Etiology of Agitation: A Sample of the Varied Conditions that may Present with Pathologic Agitation • Substance intoxication or withdrawal • Bipolar disorder • Major Depressive Disorder • Psychosis • PTSD • Anxiety Disorders • Personality Disorders • Autism • Intellectual Disability Dementia Huntington's disease Brain injury or trauma Delirium (Organic Brain Syndrome) Korsakoff’s psychosis Brain tumors Seizure Hypoglycemia Stroke Thyroid disease Antisocial behavior

10. Etiology of Agitation: Medical Causes • Hypoxia • Thyroid disease • Seizure (including post-ictal state) • Toxic levels of medications Nordstrom, K., Zun, L. S., Wilson, M. P., Stiebel, V., Ng, A. T., Bregman, B., & Anderson, E. L. (2012). Medical evaluation and triage of the agitated patient: consensus statement of the American Association for Emergency Psychiatry Project BETA Medical Evaluation Workgroup. Western Journal of Emergency Medicine, 13(1), 3. Head trauma Encephalitis, meningitis, other infection Encephalopathy (e.g., liver or renal failure) Environmental toxins Metabolic abnormalities (sodium, calcium, glucose)

11. Etiology of Agitation: Delirium Diagnostic Features • Disturbance of consciousness • A change in cognition or development of perceptual disturbance • Not accounted for by a dementia • Disturbance develops over a short period of time and tends to fluctuate (“waxing and waning”) • Caused by a general medical condition

12. Etiology of Agitation: Substances • Substance intoxication – • Alcohol, cocaine, amphetamines, cannabis, ketamine, ecstasy, bath salts, inhalants • Substance withdrawal – • Alcohol withdrawal delirium/DTs • CNS effects of non-psychiatric medications (steroids)

13. Etiology of Agitation: Primary Psychiatric disorders • Schizophrenia • Bipolar Disorder • Neurocognitive Disorder (Dementia) • Personality Disorders • Agitated depression • Anxiety disorder • Autism spectrum disorder

14. Etiology of Agitation: Common Triggers Garriga, M., Pacchiarotti, I., Bernardo, M., & Vieta, E. (2017). Psychiatric Causes of Agitation: Exacerbation of Mood and Psychotic Disorders. The Diagnosis and Management of Agitation, 126.. Akathisia from antipsychotic or antidepressant use Comorbid substance use or intoxication Poor impulse control or other comorbid cognitive deficits Chaotic or disruptive environment Medical illness Exacerbation of symptoms of primary illness Psychosocial trigger

15. Etiology of Agitation: Schizophrenia • Patients may present to the ED with acute psychosis • Hallucinations • Delusions • Disorganized speech and/or behavior • Lack of insight • Bizarre behavior • Fertile conditions for the development of agitation • Psychosis and agitation have a reciprocal relationship

16. Etiology of Agitation: Schizophrenia Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. The Journal of clinical psychiatry, 67, 5-12. • Patients at highest risk for violence • More suspicious and hostile • More severe hallucinations • Less insight into delusions • Greater thought disorder • Poor impulse control • Risk factors for being targeted for violence by person with schizophrenia • Parent or immediate family member • Cohabitation • Patient financially dependent on you

17. Etiology of Agitation: Personality Disorders Some personality disorders are more prone to agitation • Decreased stress tolerance • Poor impulse control E.g., Borderline personality disorder, Antisocial personality disorder

18. Etiology of Agitation: Major Neurocognitive Disorder Bartels, S. J., Horn, S. D., Smout, R. J., Dums, A. R., Flaherty, E., Jones, J. K., ... & Voss, A. C. (2003). Agitation and depression in frail nursing home elderly patients with dementia: treatment characteristics and service use. The American journal of geriatric psychiatry, 11(2), 231-238. Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. The Journal of clinical psychiatry, 67, 5-12 • Overall, the incidence of agitation is estimated to be between 60-80% (median 44%) (Bartels et al 2003) • 50% become frankly physically aggressive • 24% become verbally aggressive • Burden of institutionalization • Residents with dementia complicated by agitation have the highest 3-month rate of ED visits and greatest use of restraints (Sachs, 2006) • Despite use of restraints, over 40% receive no psychiatric medications

19. Etiology of Agitation: Dementia Madhusoodanan, S. (2001). Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients. The American Journal of Geriatric Psychiatry, 9(3), 283-288. • Agitation may be a final common pathway for the expression of… • Depression • Anxiety • Psychosis • Pain • Delirium • While agitation may be of multifactorial etiology in patients with dementia, it is also true that many patients have only agitation as a target symptom for treatment (Madhusoodanan, 2001)

20. Etiology of Agitation: Psychodynamic Perspectives Yakeley, J. (2018). Psychodynamic approaches to violence. BJPsych Advances, 24(2), 83-92. • A Psychodynamic framework can be used to complement treatment strategies - Helps temper counter-transference • Psychodynamic perspectives of agitation and violence • In contemporary psychoanalytic thought, “the capacity for aggression is innate and universal, aggressive behavior occurs in response to threats that the self perceives in relation to internal and external objects.” • Crisis can be defined as an assault on the person’s sense of self (Bernstein 2007)

21. Back to the Case (continued) • Potential etiologies for our gentleman’s growing agitation • Substance intoxication or withdrawal • Delirium • Bipolar disorder • Personality disorder

22. Assessment of Agitation • Decisions regarding diagnostic tests must be made in the context of available history and physical examination • Goal is to evaluate patient’s risk for medical comorbidities • Many questions involve forced decisions based on… • Assumptions • Information available • Diagnostic confidence • Patient’s individual risk factors

23. Assessment of Agitation • For a patient with known diagnosis of schizophrenia presenting with behavioral features of typical decompensation: • Expectant management is appropriate • For patients with atypical features additional diagnostic tests may be required • Atypical presentations • Delirium • History of trauma • Overdose • Headache • Fever • Diagnostic tests to consider • Toxicology screens • CT of brain • BMP, CBC, and LFTs • Urinalysis • Endocrine tests • Lumbar puncture

24. The Case (continued) • Examination of the patient • The patient is febrile with normal vitals • Disheveled and malodorous • Heart, lungs and abdomen are benign • No tremor, diaphoresis, nystagmus or asterixis • Mental status examination reveals: • Appearance/behavior: middle-aged unkempt male in hospital johnny and socks, uncooperative, pacing the room, poor eye contact, posturing with fists • Speech: spontaneous, loud, nonpressured, use of profane language • Mood: “I’m lousy!”, Affect: labile, irritable • TP: tangential, TC: paranoia towards hospital staff, no SI/HI, no perceptual disturbances. Does not participate in formal cognitive exam questions.

25. The Case (continued) • Laboratory evaluation of the patient • CBC, BMP are normal except for a glucose of 211 • LFTs are normal except for a low albumin • TSH, B12, Folate, and RPR are also normal • U/A is positive for glucose and trace ketones • CT of head is read as “negative” • EKG shows QTc < 400msec • UDS and serum toxicology are negative • Valproate, carbamazepine, and lithium levels are all negative

26. Before the Acute Intervention • The staff on Med/Surg units are often less informed about what feelings and behaviors their actions may elicit in patients • Studies indicate that staff training and education can change this lack of appreciation • Psychiatric consultants should provide education about • Establishing goals from the patient’s perspective • Interventions that support a structured setting • Private or semi-private room • Establish clear set of expectations with a written schedule • Identify staff that are responsible for the patient’s care • Attempting to enlist the patient in the treatment, i.e. which route of medication has worked the best in the past as a “choice” which retains some patient control

27. Goals of Intervention • Acute agitation or a violent patient modifies the normal caregiver-patient relationship • The first goal of treatment is to do only what is necessary to assure the safety of the patient and others while facilitating the resumption of more normal interpersonal relations • Calming without over-sedation

28. Agitation Management Holloman Jr, G. H., & Zeller, S. L. (2012). Overview of Project BETA: best practices in evaluation and treatment of agitation. Western Journal of Emergency Medicine, 13(1), 1. Medical evaluation and triage Psychiatric evaluation Verbal de-escalation Environmental intervetions Psychopharmacologic interventions Use of seclusion/restraint

29. Environmental Interventions • Examples of effective non-pharmacological treatments • Clearing the room • Removing dangerous objects • Having staff available as a “show of force” • Close observation • Calm conversation • Decreasing sensorial stimulation

30. Communication/Behavioral Interventions Onyike, C., & Lyketsos, C. (2011). Aggression and violence. Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically, 101, 153-174.. • Nonverbal • Maintain a safe distance • Maintain a neutral posture • Do not stare; eye contact should convey sincerity • Do not touch the patient • Stay at the same height as the patient • Avoid sudden movements • Verbal • Speak in calm, clear tone • Personalize yourself • Avoid confrontation; offer to solve the problem

31. Communication/Behavioral Interventions Onyike, C., & Lyketsos, C. (2011). Aggression and violence. Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically Ill, 101, 153-174.. • Aligning Goals of Care • Acknowledge the patient’s grievance • Acknowledge the patient’s frustration • Shift the focus to discussion of how to solve the problem • Emphasize common ground • Focus on the big picture • Find ways to make small concessions • Monitoring Intervention Progress • Be acutely aware of progress • Know when to disengage • Do not insist on having the last word

32. Back to the Case (continued) • You assist the team and the nursing staff: • Clear the room • Keep dangerous objects out of reach • Call security • You approach the patient using verbal de-escalation techniques that you have learned and practiced • Despite these interventions the patient makes further threats, rips-off telemetry lines, and starts to pace with clenched fists while mumbling incoherently

33. A little bit of history…

34. Serotonin Serotonin-Dopamine Model of Regulation of Agitation Provides a basis for the response to certain medications Amygdala activation Nucleus Accumbens Suppression Dopamine Released Prefrontal Cortex agitation Ryding et al. The role of dopamine and serotonin in suicidal behavior and aggression. Prog Brain Res 2008;172:307-15 Dynamic interaction between the amygdala, nucleus accumbens, and the prefrontal cortex

35. Goals of Intervention • Ideally pharmacotherapy for acute agitation should: • Be easy to administer, non-traumatic • Provide rapid tranquilization without excessive sedation • Have a fast onset of action and a sufficient duration of action • Have a low risk for significant adverse events and drug interactions

36. Goals of Intervention Vieta et al. Protocol for the management of psychiatric patients with psychomotor agitation. BMC Psychiatry2017;17:328 • Definition of psychopharmacologic treatment endpoint: rapid tranquilization • Calming process separate from total sleep induction • Allows patient to participate in care • Enables clinician to gather history, initiate a work-up, and begin treatment of unidentified conditions • Better therapeutic endpoint • Sleep is not the desired outcome • It conflicts with goal of patient participation • Has not been found to be essential to improvement in agitation or decrease in psychotic symptoms

37. Pharmacologic Considerations Zeller et al. Systematic Reviews of Assessment Measures and Pharmacologic Treatments for Agitation. Clin Therapeutics 2010; 32:405-425 • Ease of preparation/administration • Rapid onset of action: IV > IM > PO • Sufficient duration of effect • Low risk of adverse reactions or drug interactions • What is known about the patient’s underlying condition(s)? • Age • Comorbid conditions • Medication/other substance exposure

38. Pharmacologic Treatment Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry 2006;67:13-21 • Most important factors in medication selection • Etiology of agitation • Acute effect on behavioral symptoms • Multiple means of administration • Limited side effects • Ease of administration • Patient preference • History of response • Goal is a balance between effectiveness and tolerability

39. Pharmacologic Treatment • Route of administration • Oral (PO) administration • Preferred if patient accepts • Liquid or orally dissolving tablets • Intramuscular (IM) administration • Rapid elevation of plasma level • Higher transient concentration • Faster reduction in agitated behavior

40. Pharmacologic Treatment • Route of administration (continued) • Intravenous (IV) administration • Similar to IM but more rapid elevation of plasma level • Should be limited to when immediate tranquilization is essential • Requires appropriate monitoring of vital signs for respiratory depression and cardiovascular compromise

41. Pharmacologic Treatment • Most studies of pharmacologic treatment in agitation were done in patients with KNOWN psychiatric diagnosis • No randomized, controlled studies have examined the use of medications in populations with… • Severe agitation • Drug-induced agitation • Significant medical comorbidity • Results difficult to extrapolate to the undifferentiated agitated patient in the general ED or medical/surgical unit

42. Association for Emergency Psychiatry Recommendations Wilson M.P. et al. The Psychopharmacology of Agitation. Consensus Statement of the American Association for Emergency Psychiatry, Western J Emerg Med. 2012;13(1):26-34.  • Undifferentiated Agitation/Suspected intoxication with stimulant or withdrawal from alcohol/benzodiazepine • Oral benzodiazepines (e.g. lorazepam 1-2 mg) • Parenteral benzodiazepines (e.g. lorazepam 1-2 mg IM or IV) • Acute intoxication with CNS depressant (e.g., alcohol) • Avoid benzodiazepine if possible • Oral 1st generation antipsychotic (e.g. haloperidol 2-10 mg ) • Parenteral 1st generation antipsychotic (e.g. haloperidol 2-10 mg IM) • Delirium (not associated with alcohol or benzodiazepine withdrawal) • Oral 2nd generation antipsychotic (e.g. risperidone 2 mg, olanzapine 5-10 mg) • Oral 1st generation antipsychotic (e.g. low dose haloperidol) • Parenteral 2nd generation antipsychotic (e.g. olanzapine 10 mg IM) • Parenteral 1st generation antipsychotic (e.g. haloperidol low dose IM or IV) • Schizophrenia or Mania • Oral 2nd generation antipsychotic alone (e.g. risperidone 2 mg, olanzapine 5-10 mg) • Oral 1st generation antipsychotic (e.g. haloperidol 2-10 mg with benzodiazepine) • Parenteral 2nd generation antipsychotic (e.g. olanzapine 10 mg IM) • Parenteral 1st generation antipsychotic (e.g. haloperidol 2-10 mg IM) along with benzodiazepine (e.g. lorazepam 1-2 mg)

43. Benzodiazepines Zaman et al. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2017;12:Cd003079 • Benzodiazepines (BZDs) act by facilitating the activity of GABA • GABA is a major inhibitory neurotransmitter • Therapeutic effects appears linked to decreased arousal • Little benefit for psychiatric symptoms other than anxiety • Long history of use in the management of acute agitation • Individually • Combination with antipsychotics (except IM olanzapine) • Preferred in a patient in whom agitation is secondary to alcohol or sedative withdrawal

44. Benzodiazepines 1Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry 2000;61(S14):S1-S20 2Battaglia et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 1997;15:335–340 • Lorazepam • Only BZD with complete and rapid IM absorption • No involvement of P450 system • IM or sublingual administration • 60-90 minutes until peak plasma concentration • 8-10 hour duration of effect • 12-15 hour elimination half-life • Studies suggest that lorazepam 2 mg is at least as effective as haloperidol in controlling acute agitation1-2

45. Benzodiazepines • Side effects • Excessive sedation • Additive with other CNS depressants • Respiratory depression • BZDs avoided in patients at risk for CO2 retention • Paradoxical disinhibition • More likely with high doses in patients with structure brain damage, mental retardation or dementia • Ataxia

46. Typical Antipsychotics • Dopamine antagonist • Positive • Antipsychotic • Anti-agitation • Negative • Extrapyramidal symptoms (EPS) • Neuroleptic Malignant Syndrome (NMS) • Many authors consider typical antipsychotics the treatment of choice in acute agitation, especially in the setting of delirium

47. TypicalAntipsychotics Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377 • Low potency • Not recommended • High potency - Haloperidol • Virtually no anticholinergic properties • Little risk of hypotension • Does not suppress respiration • Can be given IV • Not FDA approved • Fast acting • Onset of action: 30 minutes • Duration of action up to 12-24 hours

48. TypicalAntipsychotics Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377 • Side effects • Extrapyramidal symptoms • Dystonia • Akathisia • Parkinson-like effects • QTc prolongation • Rare at low doses • Haloperidol and droperidol with “Black Box” warnings • Lower seizure threshold • Low-potency > high-potency antipsychotics

49. Typical Antipsychotics Owen RT. Inhaled loxapine: a new treatment for agitation in schizophrenia or bipolar disorder. Drugs of Today. 49(3):195-201, 2013 Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128 • Loxapine • 5 – 10 mg, inhaled • Inhaled Loxapine has been recently endorsed by FDA for treatment for agitation in Bipolar I disorder • Efficacy supported in multiple trials when compared to placebo, has not been compared to other active medication • Need to monitor for bronchospasm, especially in patients with asthma

50. Atypical Antipsychotics • Major advance in psychiatry • Broader spectrum of response • Different side effect profile • Less EPS and akathisia • QTc concern remains • Metabolic syndrome • No randomized, controlled studies have examined the use of medications in populations with… • Severe agitation • Drug-induced agitation • Significant medical comorbidity