Delirium: a Challenge in Prevention Summer School of Neuroscience and Aging Venice, Italy 10-14 June, 2013 Richard W. Besdine, MD,FACP Professor of Medicine Greer Professor of Geriatric Medicine Director, Division of Geriatrics and Palliative Medicine Director, Center for Gerontology and Health Care Research A L P E R T M E D I C A L S C H O O L

OBJECTIVES Know and understand: What is delirium? How to recognize and diagnose delirium Predisposing and precipitating risk factors How to evaluate and treat elders with delirium Interventions to prevent and treat delirium

Other Names for Delirium (AKA) Acute confusional state Acute mental status change Altered mental status Organic brain syndrome Reversible dementia Toxic or metabolic encephalopathy

Morbidity/Consequences of Delirium A 10-fold risk of death in hospital A 3-5 fold  risk of nosocomial complications, post- acute NH placement ↑ Length of stay, morbidity, mortality, costs Poor functional recovery, mortality for 2 years Acceleration of decline of dementia symptoms Persistence of delirium, poor long-term outcomes Decreased physical function Institutionalization, prolonged rehabilitation Delirium

Epidemiology, Detection of Delirium 1/3 of older patients presenting to the ED 1/3 of inpatients aged 70+ on general medical units, half of whom are delirious on admission Under-recognition - nurses recognize, document < 50%; MDs recognize, document only 20% DSM-IV criteria precise, difficult to apply Confusion Assessment Method (CAM) performs better clinically: >95% sensitivity, specificity

Detecting Delirium Nurses recognize, document <50% of cases Recognized by MDs Recognized by nurses Not recognized Not recognized Nurses recognize, document <50% of cases Physicians recognize, document only 20%

DSM-IV Diagnostic Criteria Disturbance of consciousness, reduced ability to focus, sustain, or shift attention Change in cognition (e.g., memory, disorientation, language disturbance) or a perceptual disturbance not better accounted for by existing dementia Develops quickly (hours to days) and fluctuates Evidence from history, physical or labs of direct physiologic consequence of a medical condition SOURCE: Data from the American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000;143. Delirium

Confusion Assessment Method Requires features 1 and 2, and either 3 or 4: Acute change in mental status and fluctuating clinical course Inattention by testing Disorganized thinking Altered level of consciousness

Varieties of Delirium Hyperactive or agitated delirium - 25% of all cases Hypoactive delirium - less recognized or appropriately treated Mixed Additional features include emotional symptoms, psychotic symptoms, “sundowning”

Neuropathophysiology: Cholinergic Deficiency Hypothesis Acetylcholine is an important neurotransmitter for cognition Delirium can be caused by anti-cholinergic drug overdose, and can be reversed by physostigmine Delirium is associated with  serum anti- cholinergic activity Anti-cholinergic activity is found in delirious patients taking no anti-cholinergic drugs

Neuropathophysiology: Inflammation Especially important in postoperative, cancer and infected patients Delirium associated with ↑ C-reactive protein, ↑ interleukin-1β, and ↑ tumor necrosis factor Inflammation can break down blood-brain barrier, allowing toxic medications and cytokines access to CNS

Delirium as a Geriatrics Syndrome Delirium, as with falls, is a result of the cumulative sum of predisposing (already present) and precipitating (new) factors The more predisposing factors present, the fewer precipitating factors required to cause delirium, and vice versa The more risk factors present, the more likely it is that delirium will occur Intervening to modify or eliminate risk factors will reduce the likelihood of delirium

Relationship Between Predisposing and Precipitating Risk Factors The chart demonstrates the interplay between predisposing or baseline risk factors and precipitating or hospital-related risk factors. Young healthy individuals with a low vulnerability will require a greater noxious insult to develop delirium whereas an older person with dementia, many comorbidities and sensory impairments will require a smaller insult, such as a UTI, to develop delirium.

Risk Factors for Delirium Predisposing Dementia Co-morbidity Sensory loss Advanced Age Functional loss Malnutrition Male, alcohol Precipitating Psychoactive Meds Restraints, Catheter, Bed rest Acute Illness Fecal impaction, Retention Surgery, Anesthesia Pain Sleep Deprivation Sensory Deprivation Fluid/electrolyte disorder The chart demonstrates the interplay between predisposing or baseline risk factors and precipitating or hospital-related risk factors. Young healthy individuals with a low vulnerability will require a greater noxious insult to develop delirium whereas an older person with dementia, many comorbidities and sensory impairments will require a smaller insult, such as a UTI, to develop delirium.

Identification of Risk Factors Initial Evaluation: History, physical exam, vital signs Targeted lab tests, search for infections Review medications: Prescription, PRN, OTC, herbal Lower, stop or change any dangerous drugs Further options: Laboratory tests: thyroid, B12, drug levels, toxicology screen, ammonia, cortisol, ABG Brain imaging, LP, EEG Address all risks identified

One-Year Mortality of Delirium 919 patients enrolled in a delirium prevention intervention in 1995 100% follow-up one year following hospitalization with telephone interviews and review of death certificates Those with delirium had ~50 days (0.13 of a year) of life lost, controlling for clinical covariates (p<0.001) Leslie DL, Arch Int Med 2005;165:1657

Fitted Survival Curves With and Without Delirium Survival Estimate 919 Discharged patients, 1year follow up; delirious patients averaged 50 fewer days of life Leslie DL, Arch Int Med 2005;165:1657

___ Not delirious ED _ _ _ Delirious Discharge Survival Probability Days 105 ED patients discharged, 30 with delirium. After adjusting for age, sex, function, cognition, co-morbid conditions and # meds, delirious patients were 7 times more likely to be dead at 6 months Kakuma R et al..  JAGS 2003;51:443

Delirium Prevention Targets (High Risk) Baseline cognitive impairment – orientation, avoid drugs, therapeutic activities Sleep – non-pharmacologic intervention, environmental changes Immobility – PT, maximum mobilization Vision – aids (glasses, magnifiers), equipment (large print, touch pads) Hearing – amplification, ear wax removal Dehydration - early recognition, volume repletion Inouye S, et al. NEJM 1999;340:669-676

Delirium Prevention Aim: reduce rate of incident delirium using a targeted multiple component intervention in high risk patients Intervention: nurse/volunteer-based protocols for addressing identified risk factors in 852 medical in- patients aged >65, 1995-98 Incident delirium reduced from 15% in control group to 9.9% in intervention group (34% risk reduction, P=0.02) Hospital days reduced by one-third (P=0.02) But delirium that did occur in intervention group was not attenuated Inouye S, et al. NEJM 1999;340:669-676

Intervention to Reduce Delirium Inouye S, et al. NEJM 1999;340:669-676

Management – No Drugs Adequate stimulation – hearing, vision Mobility – avoid bed rest, mobilize ASAP, avoid restraints (including catheters) Vision and hearing Nutrition – dentures, feeding help Orientation - day, time, place, people, tests Sleep hygiene

No-Drug Sleep Protocol Warm drink, relaxing music, quiet dark room, back rub, minimize awakenings Quality of sleep correlated with the # of parts of the protocol received Decreased sedative use from 54% to 31% Sleep protocol had a higher association with quality of sleep than a sedative Not as effective in chronic users of sedatives McDowell et al. JAGS 1998;46:700

Guideline for Delirium Prevention Assessment and modification of key clinical factors that may precipitate delirium, including Cognitive impairment Dehydration Constipation Hypoxia Infection Immobility Limited mobility Multiple medications Pain Poor nutrition Sensory impairment Sleep disturbance O'Mahony R et al. Ann Intern Med. 2011;154:746-51

Management - Drugs Drugs increase severity and duration of delirium All neuroleptics produce extrapyramidal disorders, over-sedation, increased risk of stroke and death Haloperidol only drug in randomized trials that was better than others (or better than placebo) in reducing dangerous behavior If severe agitation is a danger to self or others, or interferes with essential therapy, haloperidol, 0.25- 1.0mg IV/PO every 30 minutes until sedated (max 3-5mg/24 hours), then ½ loading dose each 24 hours in divided doses – taper in DAYS

Pharmacologic Treatment of Delirium Table 4. Pharmacologic Treatment of Delirium. Inouye S. N Engl J Med 2006;354:1157-1165

Post-Operative Delirium1

Post-Operative Delirium2 Pre-operative risk factors: Age 70 and older Cognitive impairment Physical functional impairment History of alcohol abuse Abnormal serum chemistries Intra-thoracic or aortic aneurysm surgery

Summary Delirium is common, major morbidity for older persons High sensitivity and specificity for detection by CAM Careful Hx, PE, focused labs will detect cause Careful medication review mandatory; D/C possible contributory agents Managing delirium requires Rx of primary disease, avoiding complications, managing behavioral problems, providing rehabilitation The best treatment for delirium is prevention

Case 11 A 72-year-old man is evaluated because nurses are concerned about his agitation, which increases markedly in the evenings He underwent emergency hip replacement 3 days ago after he fell and fractured his hip He gets antipsychotic agents to control agitation at night; he yells “help me” constantly, and is determined to get out of bed alone and walk In the year before his fall, he had stopped working and driving, but we don’t know why

Case 12 The patient’s history includes hypertension, benign prostatic hyperplasia, and osteoarthritis; there is no history of dementia On examination, he appears confused and is disoriented to place and time He has some pain with hip movement Neurologic examination reveals no focal abnormalities

Case 13 Which of the following is most helpful in establishing the diagnosis of delirium? Order electrolytes, BUN, glucose, and thyrotropin Determine why the patient stopped working and driving Perform the digit-span memory test Order CT of the brain Review the patient’s medication list

DSM-IV Diagnostic Criteria Disturbance of consciousness, reduced ability to focus, sustain, or shift attention Change in cognition (e.g., memory, disorientation, language disturbance) or a perceptual disturbance not better accounted for by existing dementia Develops quickly (hours to days) and fluctuates Evidence from history, physical or labs of direct physiologic consequence of a medical condition SOURCE: Data from the American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000;143. Delirium

Confusion Assessment Method Requires features 1 and 2, and either 3 or 4: Acute change in mental status and fluctuating clinical course Inattention by testing Disorganized thinking Altered level of consciousness

Case 14 Which of the following is most helpful in establishing the diagnosis of delirium? Order electrolytes, BUN, glucose, and thyrotropin Determine why the patient stopped working and driving Perform the digit-span memory test Order CT of the brain Review the patient’s medication list

Case 21 An 89-year-old man is admitted to a nursing home for rehabilitation after being hospitalized for pneumonia; he is anxious and fidgety He is widowed and lives in the community History includes hypertension, benign prostatic hyperplasia, major depressive disorder and chronic back pain Medications on transfer to the nursing home include metoprolol, oxybutynin, paroxetine, acetaminophen with codeine and amitriptyline

Case 22 Which of the following medications is least likely to contribute to delirium? Amitriptyline Acetaminophen with codeine Oxybutynin Paroxetine Metoprolol

Case 22 Which of the following medications is least likely to contribute to delirium? Amitriptyline Acetaminophen with codeine Oxybutynin Paroxetine Metoprolol

Case 31 A 90-year-old man is brought to the emergency department by his family because he has had an abrupt change in behavior The patient moved into his daughter and son-in-law’s house a few months ago, because he was no longer able to manage living alone A few days ago he became aggressive and angry, and hit his son-in-law for no apparent reason He has also become incontinent in the last 2 days

Case 32 He has multiple bruises, which the family suspects are from falling The patient’s history includes moderate dementia and benign prostatic hyperplasia Blood pressure is 160/90 mmHg; all other vital signs are normal, and the physical exam is unremarkable He is demanding to be released from “prison” and is aggressive with the staff He is uncooperative with the neurologic exam, but he appears to be moving all extremities well

Case 33 What is the most appropriate next step? Bladder scan Lumbar puncture Electroencephalography CT of the brain Basic metabolic panel, CBC, and pulse oximetry

Case 33 What is the most appropriate next step? Bladder scan Lumbar puncture Electroencephalography CT of the brain Basic metabolic panel, CBC, and pulse oximetry