Learning Objectives Delirium Defined in DSM‐5

• Key clinical features of delirium • Essential elements of the bedside assessment and work‐up • Causes of delirium • Pathoetiologic models • Treatment strategies

Patient Case 1: Presentation to Urgent Care Clinic DELIRIUM KNOWN BY ANY OTHER NAME IS • 61 year‐old man with schizophrenia & epilepsy brought to urgent care by sister for “ 2 days of confusion & fever.” STILL DELIRIUM . . . • Takes quetiapine XR 600mg daily (x 24 months) & • carbamazepine XR 400mg BID (x 6 weeks). Altered Mental Status • Smokes 1.5 ppd; no illicit drugs or ETOH • Acute Brain Syndrome • Physical Exam: BP 95/52, HR 115, temp 101.7 F • Acute Confusional State • Agitated; diffuse rash on trunk, face, extremities. • “ICU Psychosis” • Reports small girl he sees in the room carrying a black • Toxic‐Metabolic Encephalopathy bag & oriented to “apartment” and “May 1917.” • Sundowning https://www.brainyquote.com/quotes/keywords/rose.html • Can barely repeat 3 words without getting sleepy • 0/3 recall at even one minute • No other psychiatric diagnosis can be made in the presence of delirium • Counts down from 20 by saying “20, 100, 17…”

Patient Transported to Emergency Center via 911 Motor Subtypes of Delirium • WORK UP in EC & on admission Hyperactive • ABG: no hypercarbia or hypoxia • Agitated, pacing, fidgeting, wandering, restless, violent • Labs: WBC 18,000 mg/dL with hypereosinophilia, atypical lymphocytes & (don’t give benzodiazepines!!) platelet count of 97,000 • Comprehensive Metabolic Panel: Hypoactive • Creatinine 1.7 mg/dL & AST 278 U/L and ALT 298 U/L • Few spontaneous movements, slower movements, less awareness of • TSH, UA, urine toxicology, RPR, HIV, CK, folate, B12, ammonia– unremarkable surroundings, less speech, slower speech, listless • CSF: WBC 3; protein 40 mg/dL glucose 65 mg/dL • Often missed • Carbamazepine level: within therapeutic range • Common in metabolic disorder, organ failure delirium, ICU & palliative care & • CT head: “mild cortical atrophy with mild subcortical white matter ischemic associated with poorer prognosis changes” Mixed • EEG: “diffuse slowing; no epileptiform activity” • Combination of features ANTICHOLINERGIC MEDICATION BURDEN

Some BIG Neuropsychiatric/Cognitive Features of Delirium OFFENDERS TCAs Incontinence “A complex neuropsychiatric syndrome that includes a wide range of cognitive Paroxetine Quetiapine and non‐cognitive disturbances.” Olanzapine H1 blockers DEFICITS in the following domains: Anti‐emetics Attention 97‐100% Visuospatial ability 87‐96% Orientation 76‐96% Motor control 24‐94% Short‐term memory 88‐92% Language 57‐67% Long‐term memory 89‐96% Perception 50‐63% Sleep‐wake cycle 92‐97% Delusions 21‐31% Thought process 54‐79% Mood/affect 43‐86%

COMMON CAUSES OF DELIRIUM HOW COMMON IS DELIRIUM • 0.4% >18 in general population False Positives and Negatives on Urine Drug • 1.1% >55 in general population \ Screens Emerg Med Clin N Am 33 (2015) 753–764 • 10‐30% of medically ill in the hospital • 30% in surgical intensive care • 30‐40% hospitalized with AIDS • 28‐42% terminal cancer patients on admission • 40‐50% s/p surgery for hip fractures • 60% nursing home pts >75 have episodes • 80‐88% terminally ill in palliative care • 90% post‐cardiac surgery

Emerg Med Clin N Am 33 (2015) 753–764

WHO GETS DELIRIOUS? Pathologies to Consider with Vital Sign Mental Status & Physical Signs of Toxic Abnormalities in DeliriumEmerg Med Clin N Am 33 (2015) 753– 764 Syndromes Emerg Med Clin N Am 33 (2015) 753–764

Am Fam Physician. 2014;90(3):150‐158. Delirium Work‐Up STARTS WITH. . . EEG in Delirium A GOOD H&P • Oxygen saturation, ABG • CT head (faster & better for agitated • EEG –not necessary but can help confirm dx • Serum glucose patient): good to r/o acute hemorrhage • CBC w/ differential • MRI brain more sensitive & specific for • shows diffuse slowing (most common) or triphasic waves (esp. in hepatic CNS lesion presence & type encephalopathy or uremia) • Serum chemistry • EKG • LFTs, ammonia • EEG • delirium tremens: may be normal or fast • Thyroid function tests • CXR • Urinalysis with micro & culture • LP & CSF analysis • Urine drug screen • may be useful for confirmation of diagnosis (no EEG changes in • Blood cultures primary psych disorders) • B12, RPR, HIV, hepatitis panel • Autoimmune & paraneoplastic work‐up in the right setting but not routine • useful if seizures – convulsive or non‐convulsive‐ are suspected as cause of delirium

Examining the Patient In Order to Diagnose Delirium Pathophysiology of Delirium Bedside cognitive assessment is critical to diagnosis • Level of consciousness • Neurotransmitter Hypothesis • Can use Glasgow Coma Scale • ↓ACh and ↑DA, NE, Glutamate • • Orientation: person, place, time, situation GABA and 5HT dysregulated • Impaired oxidative metabolism • Attention/concentration • Inflammatory: ↑ cytokines • count down from 20 • Physiologic stress: • months of year backwards • faulty blood‐brain barrier • digit span (should be able to to do 2 less backwards than can be done • Sick euthyroid syndrome forward) • Hypothalamic/pituitary/adrenal axis hyperactivity • Immediate recall: repeat 3 words • Intraneuronal cellular signaling • Delayed recall: test 3 word recall after a few minutes dysfunction

Specific Assessment Instruments for Delirium Risk factors for Delirium

• Age‐related brain changes, i.e. “reduced cerebral reserve” • Prior CNS disorders: stroke, tumor, traumatic brain injury, cognitive impairment/dementia • Malnutrition: • Thiamine deficiency: not just alcoholics: hyperemesis gravidarum, s/p bariatric surgery, s/p chemotherapy • Low serum albumin –a risk factor at any age (may signify poor nutrition, chronic disease, liver or renal insufficiency, and results in greater bioavailability of many drugs) • Medication/toxin/alcohol exposure/intoxication/withdrawal – benzodiazepines, opioids, drugs with anticholinergic activity • Surgery & anesthesia – age, duration of anesthesia, lower education, second operation, post‐op infection, respiratory bCAM (~0.9 sens & spec) complications = predictors of post‐op delirium Consequences of Delirium

• Increased Length of Stay • 100% in general medical patients; 300% in critical care • Why? Persistent cognitive & behavioral changes + more iatrogenic complications • Decreased independent living/increased institutionalization • Persistent cognitive deficits • 25% elderly delirious with symptoms lasting months • Rate of cognitive decline in patients with Alzheimer’s disease who develop delirium is accelerated 3 fold • Increased Mortality even when controlling for comorbidities, demographics, dementia • Index hospitalization for delirium = mortality range from 4‐65% • Longer the delirium ‐‐ the higher the mortality risk

Am Fam Physician. 2014;90(3):150‐158.

DISTINGUISHING DELIRIUM FROM OTHER CONDITIONS FIRST, PREVENT DELIRIUM FROM OCCURING Delirium vs. Schizophrenia vs. Depression SECOND, TREAT UNDERLYING CAUSE Delirium Schizophrenia Depression • Impaired awareness/attention Unimpaired; clear Unimpaired PREVENTION & MANAGEMENT OF DELIRIUM Am Fam Physician. 2014;90(3):150‐158. • Orient patient (pictures, consistent staff, • Poor attention Poor attention Diurnal attention variation windows, calendars, appropriate lighting) • Impaired memory Memory intact +/‐ memory complaints • Promote regular routines, day –night • VH most common AH most common AH most common cycle • Avoid complete sensory deprivation / • Fleeting delusions Complex, systematized Complex, mood overstimulation often paranoid delusions congruent delusions • Avoid restraints; use Posey vest (velcro, • Sleep‐wake disturbance No characteristic pattern Initial insomnia, early zippers) wakening or hypersomnia • Treat pain, constipation, dehydration • Avoid delirium inducing medications • Ensure glasses & hearing aids are working & in proper condition • Mobilize early • Avoid urinary catheterization

AFTER DIAGNOSING & TREATING UNDERLYING CONDITION… PHARMACOLOGIC TREATMENT OF DELIRIUM DISTINGUISHING DELIRIUM FROM OTHER CONDITIONS • Benzodiazepines: Use ONLY for Delirium vs. Dementia delirium due to ETOH, benzodiazepine Delirium Dementia Do not use in Lewy Body Dementia withdrawal or • Impaired consciousness Unimpaired consciousness* or Parkinson disease patients catatonia • Even low doses, • Poor attention Attention varies by dementia** lorazepam= • VH most common VH more more common than AH independent delirium risk factor • Fleeting delusions Paranoid often fixed delusions • Older & sicker: • Sleep‐wake disturbance Nocturnal insomnia increased risk of lorazepam induced delirium • Delirium superimposed on dementia: delirium can accelerate the progression of dementia and may never fully resolve in this setting • * Exception: Lewy Body Dementia (LBD): fluctuation in levels of alertness is one of the cardinal features • ** Vascular dementia, LBD, Frontotemporal dementia, HIV dementia, NPH, etc.

Am Fam Physician. 2014;90(3):150‐158. PATIENT 2: PRESENTATION TO URGENT CARE CLINIC MANIFESTATIONS OF SEROTONIN SYNDROME & RELATED SYNDROMES • 47 year‐old woman with hypertension, depression, DM type II, seasonal allergies & sciatica • Confusion, restlessness, and tremulousness beginning “a couple days ago.” • Patient is an accountant but couldn’t write a check this morning. • Medications: duloxetine, lisinopril, tramadol, HCTZ, glyburide, trazadone, prn diphenhydramine, and metformin. • No illicit drug or alcohol use per husband. • HR 105, BP 147/92, RR 20, Temp 100.8 F • Awake, agitated, diaphoretic, restless. • Oriented to “clinic and 2017.” • Exam: Tremor, myoclonic jerks x 4 extremities. Pupils dilated; no focal weakness but diffuse hyperreflexia with sustained clonus at the knees and

ankles The Serotonin Syndrome N Engl J Med 2005; 352:1112-1120 • Labs: Blood glucose 450 mg/dL, WBC 14,000 mg/dL with left shift; Na 147 mg/dL

SEROTONIN SYNDROME AS EXAMPLE OF Delirium: Take Home Messages DRUG-DRUG INTERACTION CAUSING • DELIRIUM = acute change resulting in fluctuating level of attention & awareness LIFE THREATENING DELIRIUM with additional cognitive changes due to some physiologic perturbation in homeostasis • No other psychiatric diagnosis can be made during delirium • Resolution can take weeks to months • Prevent: implement QI plan to reduce anti‐cholinergic burden and improve environment in hospitalized patients • Recognize Early: all forms: hypoactive, hyperactive, mixed • Treat: 1. Remove offending agents (anti‐cholinergic & other drugs) 2. Identify and treat underlying cause 3. Implement non‐pharmacologic measures 4. May low‐dose haloperidol for symptom control BUT NOT in PD or LBD patients

The Serotonin Syndrome Edward W. Boyer, M.D., Ph.D., and Michael Shannon, M.D., M.P.H. 5. Benzodiazepines: generally worsen & prolong delirium (only ETOH/benzo withdrawal) N Engl J Med 2005; 352:1112-1120March 17, 2005DOI: 10.1056/NEJMra041867

SELECTED DRUG ASSOCIATED SEROTONIN SYNDROME ALGORITHM FOR DIAGNOSING SEROTONIN SYNDROME Selected References:

• Boyer EW, Shannon M. The Serotonin Syndrome N Engl J Med 2005; 352:1112‐1120 • Delirium. The American Psychiatric Publishing Textbook of Psychosomatic Medicine, Psychiatric Care of the Medically III, Second Edition, Edited by James L. Levenson, M.D. 2011 • Caplan JP, Cassem NH, Murray GB. Chapter 18: Delirium. Massachusetts General Hospital Comprehensive Clinical Psychiatry (2008) • Kalish VB, Gillham JE, Unwin BK. Delirium in Older Adults: Evaluation and Management. Am Fam Physician. 2014;90(3):150‐158. • Maldonado JR. Pathoetiological Model of Delirium: a Comprehensive Understanding of the Neurobiology of Delirium and an evidence‐Based Approach to Prevention and Treatment. Crit Care Clin 24 (2008) 789–856 • Odiari EA, Sekhon N, Han JY, David EH. Stabiling and Manging Patients with Altered Mental Status and Delirium. Emerg Med Clin N Am 33 (2015) 753–764

The Serotonin Syndrome N Engl J Med 2005; 352:1112‐1120 http://epmonthly.com/article/serotonin-syndrome-and-the-libby-zion-affair/