Delirium Disorder and the Great Unlearning

Mark Oldham, MD Assistant Professor of Psychiatry University of Rochester Medical Center Medical Director, PRIME Medicine Lead, URMC Delirium Multidisciplinary Team Treasurer, American Delirium Society Disclosures

No relevant financial conflicts to disclose. No medication is approved for “delirium” • Diazepam for “impending or acute delirium tremens” • Rifaximin for “hepatic encephalopathy” The great unlearning

L. lira delirium PIE leis “furrow” “track” OE. læran learning “instruct” delirium noun \di-ˈlir-ē-əm\ plural deliriums or deliria 1 : a diagnosable disorder per DSM or ICD 2 : an identifiable clinical syndrome (e.g., per CAM) 3 a : frenzied excitement; AGITATION (e.g., DTs) b : what we “treat” with neuroleptics

Related terms: delirious, deliriogen(ic), deliriofascient, deliriant Why delirium is important

Delirium as a disorder

Managing delirium disorder Why delirium is important

1-year hospital-wide delirium prevalence Common in Swiss adults aged 65+ (n = 10,261) • 32% annual prevalence • Lowest 7-9%: rheum, ophtho, endocrine • Highest 83%: ICU (pooled) • Delirium associated with • Twice length of stay: 14.3d v 7.7d • Pre-existing dementia: OR 12.0 How many is a bunch? • In-hospital mortality: OR 24.2 Vladimer Shioshvili (Creative Commons)

Fuchs GHP 2020 Why delirium is important Costly More than 2M older adults a year An additional 17M+ hospital days Attributable cost of $40B – $150B Includes in-hospital costs, complications, re- admissions, institutionalization, falls, etc.

Park Place Expensive Real Estate Monopoly Philip Taylor (Creative Commons)

Leslie Arch Intern Med 2008 4Ms: Age Friendly Health Systems

Matters Medications

Delirium

Mentation Mobility Matters: ominous

Hospital outcomes Mortality Longer stay Delayed extubation Nosocomial complications

Long-term outcomes Functional decline Placement Dementia Mortality

the omen Thein BMC Ger 2020 Mario Antonio Pena Zapataría (Creative Commons) Goldberg JAMA Neuro 2020 Matters: dangerous

Risk of harm to self/others • Fall risk • Poor PO intake • Impulsive decisions • Care non-adherence • Combative behaviors • Extubation/line removal

Beware of red men dive bombing off cliffs Ruth Hartnup (Creative Commons) Mentation: distressing

The (other) great psychiatric imitator • Illusions/hallucinations • Personality change • Despondency • Fear/anxiety • Irritability • Paranoia • Apathy • Panic

Woman and Grief X1klima (Creative Commons) Mentation: frightening

Often like a waking nightmare

Misinterpret care as danger

Dissociative experiences

Many develop PTSD

fear and panic Dieterich01 (Pixabay, CC) Pills (white rabbit)

Erich Ferdinand (CC by 2.0)

Medications…

Too many to list Mobility

Life interrupted

(or fitfully activated) Why delirium is important Overlooked Internists miss up to 2/3 Intensivists miss up to 2/3 ED physicians miss up to 2/3 Nurses miss up to 2/3

Siddiqi Age Ageing 2006; van Eijk Crit Care Med 2009; Elie CMAJ 2000; Inouye Arch Intern Med 2001 Why delirium is important

Delirium as a disorder

Managing delirium disorder What is delirium? A disorder of brain wave slowing?

1944–1945 A disorder of imbalance, threshold, or reserve?

Cognitive reserve Baseline neural integrity Physiological insults Resting brain perfusion Inflammation Nutritional status Oxidative stress Hydration status Neuroendocrine disruption Sleep/circadian rhythm integrity Circadian arrhythmia Sensory stimulation Brain aging Physical activity level Neurotransmitter dysfunction Cognitive activation Network dysconnectivity Seesaw Degree of socialization Antony_Mayfield (CC)

Classically: Inouye Dem Ger Cog Disorers 1999 A disorder of acetylcholine deficiency?

Theorized by Blass 1981 A disorder of aberrant stress response? A disorder of glucose metabolism? A neuroinflammatory state? A disorder of wake or circadian integrity?

Early: Lipowski 1980 A disorder of network disintegration?

(in relation to the default mode network) Is this delirium?

Maldonado IJGP 2018 Limitations of our current model

• “All delirium is created equal” • Calls for a one-size-fits-all approach • Fails to make allowance for an epiphenomenal phenotype • Limited guidance on behavioral & psychological symptoms • No clinical guidance when precipitants are: • Ambiguous • Never identified • Not readily reversible • In the past (e.g., surgery, TBI) • Already resolved

Oldham & Holloway Neurology 2020 Delirium disorder: An integrated model

Delirium Acute Encephalopathy Delirium Disorder

Phenotype Delirium Δ Mentation Delirium

Pathophysiology Neuropathophysiology Neuropathophysiology

Precipitant(s) Underlying cause(s) Underlying cause Underlying causes

Slooter Updated nomenclature ICM 2020 Delirium (DSM-5) Acute encephalopathy Delirium disorder Oldham & Holloway Neurology 2020 The model of delirium disorder

*There are graded thresholds for sub-syndromal delirium, delirium, and coma

Cunningham & Oldham. Neuroscience of delirium. In Cambridge Textbook of Neuroscience for Psychiatrists. In press. The model of delirium disorder

Value-added model 1. Differentiates the phenotype of delirium from the broader disorder 2. Suggests a plurality of physiological types (i.e., deliria) 3. Encourages characterization of pathophysiology even in the absence of treatable precipitants 4. Acknowledges that the delirium phenotype may be epiphenomenal 5. Offers a broader palette of treatment targets

Oldham & Holloway Neurology 2020 Why delirium is important

Delirium as a disorder

Managing delirium disorder What can we do about it?

Pro-cognitive Delirium The “other BPSD” factors Perfusion Nutrition Hydration Pathophysiology Sleep/wake Activity Senses Stimulation Socialization Precipitant(s)

Delirium disorder

Oldham AJGP 2018 Pro-cognitive Delirium The “other BPSD” 1. Predict factors and Perfusion Nutrition prevent Hydration Pathophysiology Sleep/wake delirium Activity disorder Senses Stimulation Socialization Precipitant(s)

Delirium disorder Cunningham & Oldham. Neuroscience of delirium. In Cambridge Textbook of Neuroscience for Psychiatrists. In press. 1. Predict and prevent delirium disorder

Universal risk factors Patient-specific risk factors Advanced age Women: heart surgery Cognitive impairment Men: hip surgery Functional impairment Multimorbidity Prediction models Acuity of illness Polypharmacy Generalizability is key Frailty

Jansen PLOS ONE 2014 1. Predict and prevent delirium disorder

Hospital Elder Life Program (HELP) model

• HELP effectiveness (14 studies) • Lower delirium incidence (OR 0.47, 0.37–0.59) • Lower risk of falls (OR 0.58, 0.35–0.95) • Trend toward reduced length of stay • Trend toward preventing institutionalization

• HELP cost savings (9 studies, 2018 U.S. dollars) • $1600–$3800 per patient in hospital costs • $16,000+ per person-year in long-term care costs the year after delirium

Inouye JAGS 2000; Hshieh AJGP 2018 1. Predict and prevent delirium disorder

• “A-to-F” bundle (i.e., ABCDEF) for the ICU • Multicomponent, non-pharmacological interventions • Consensus: they prevent a 30–40% of delirium • Unclear whether they “treat” incident delirium • Pharmacological approaches (León-Salas 2020) • Dexmedetomidine efficacious • Postop acetaminophen (but not gabapentin) • Antipsychotics equivocal • Melatonergics inefficacious • Sleep aids inconclusive Holly Curr Trans Ger Exp Geront Rep 2013 Zegers BMJ Open 2016 Oh Ann Int Med 2019, Neufeld JAGS 2016, Fok IJGP 2015 Delirium The “other BPSD”

Pro- cognitive Pathophysiology factors 2. Identify and treat Precipitant(s) delirium precipitants Delirium disorder 2. Identify and treat delirium precipitants

Lines • Delirium is multi-determined Intake • Delirium work-up Vitals • Often an acute precipitant Evidence • Look for other contributors of cause Behaviors • LIVEBAR nursing initiative Ambulation Retention Delirium precipitants: I WATCH DEATH

Inflammation Infection (UTI or PNA), post-infectious, autoimmune Withdrawal Alcohol or sedative/hypnotics Acute metabolic disturbances Organ failure (liver, kidney), lytes, errors of metabolism Toxins Rx (toxicity or side effect), drugs, OTC, floral, heavy metals, poisons, et al. CNS pathology Seizure, space-occupying/NPH, neurodegeneration, demyelination, et al. Hypoxia Anemia, CO/CN poisoning, respiratory failure, et al. Deficiencies B1, B3, B6, sleep, ambulation Endocrine Glucose, thyroid, adrenals Acute vascular/MI Perfusion-related, hemorrhage-related, HTN/PRES Trauma Postoperative, blunt-force, electrocution, thermal/pyrexia Hematologic TTP, DIC, HUS, hyperviscosity, et al. 3. Manage Delirium The “other BPSD” the syndrome Pro- cognitive Pathophysiology factors

Precipitant(s)

Delirium disorder 3. Manage the syndrome (i.e., BPSD) First-line: non-pharm approach

1. Keep doing all the 1° prevention interventions as 2° and 3° prevention 2. The T-A-DA-A approach • Tolerate • Anticipate • Don’t agitate • Ambulate 3. The Delirium Toolbox 4. Simulated family presence Flaherty JAGS 2011; Rudolph JAMDA 2014; Waszynski Int J Nurs Stud 2018 3. Manage the syndrome (i.e., BPSD) First-line: address polypharmacy

• De-prescribing: clean up the med list • Anticholinergics • Sedatives • Other offending agents (e.g., ciprofloxacin) • Beers criteria • Check blood levels where relevant

Khan JAGS 2019 Campbell JAGS 2019 3. Manage the syndrome (i.e., BPSD) Pharm approaches: antipsychotics

• Not FDA-approved for delirium or its symptoms • Antipsychotics are not “anti-deliri-otics” • Black-box for increased mortality in elderly patients with dementia- related psychosis • Antipsychotics should be restricted to treating agitation or psychosis that is severe, dangerous, or significantly distressing

Oldham J Neuropsych Clin Neurosci 2018 Nikooie Ann Int Med 2019 PBO-controlled RCTs for delirium tx – antipsychotics

• Mixed delirium cohort – positive (reduction in DRS) (Tahir 2010) • Quetiapine 25 mg, titrated to 175 mg/d in divided doses vs placebo (n = 42)

• ICU delirium, 3 academic sites – positive (time to 1st resolution) (Devlin 2010) • Quetiapine 50 mg BID, titrated to 400 mg/d in divided doses (n = 36)

• ICU delirium, ventilated – negative (days w/o delirium/coma) (Page 2013) • Haloperidol 2.5 mg q8h IV vs placebo (n = 142)

• Palliative care delirium, 11 Australian sites – negative (delirium symptoms) (Agar 2017) • Haloperidol or risperidone PO up to 4 mg/d in divided doses (n = 247)

• ICU delirium, ventilated, 6 sites – negative (days w/o delirium/coma) (Girard 2010) Apple-Orange Hybrid Richie Girardin (CC BY-SA 2.0) • Up to haloperidol 10 mg or ziprasidone 20 mg q12h IV vs placebo (n = 101)

• ICU delirium, 16 US sites – negative (time to 1st resolution) (Girard 2018) • Up to haloperidol 10 mg or ziprasidone 20 mg q12h IV vs placebo (n = 1183) PBO-controlled RCTs for delirium tx – other agents

• Agitated ICU delirium, ventilated, 15 sites – positive (ventilator-free time) (Reade 2016) • Dexmedetomidine 0.5 mcg/kg/h, up to 1.5 mcg/kg/h vs placebo (n = 74)

• Agitated delirium despite ~10 mg haloperidol, oncology – positive-ish (RASS) (Hui 2017) • Adjunctive lorazepam 3 mg IV x1 vs placebo, added to haloperidol 2 mg (n = 90)

• Geriatric delirium, Oslo, 1 site – under-recruitment (MDAS score) (Hov 2019) • PO clonidine load then 75 mcg BID, vs placebo (n = 20)

• ICU delirium, 6 Dutch sites – very negative (delirium duration) (van Eijk 2010) • Adjunctive rivastigmine 1.5 mg BID, up titrated to 6 mg BID, added to haloperidol (n = 104) 3. Manage the syndrome (i.e., BPSD) Pharm approaches: practical options

Agitation/activation Restlessness/akathisia • Dex/guanfacine • Gabapentinoids • Trazodone (caution w/ opioids) • Mirtazapine • Valproic acid Catatonic features • Lorazepam Inanition/abulia • Stimulants Insomnia • Sedating antidepressants • Modafinil • • Bright light therapy (?) Sedating neuroleptics • Melatonin (chronobiotic) 4. Define and target pathophysiology

Delirium The “other BPSD” 4. Define Pro- patho- cognitive Pathophysiology physiology factors

Precipitant(s)

Delirium disorder Major mechanisms of delirium

Wilson Nat Rev: Dis Prim 2020 Discrete neurotransmitters Arousal, sleep/wake Neuroinflammation Microglial activation Acetylcholine Histamine Astrocytic chemokines Pons/basal forebrain Tuberomammillary nucleus Cytokine, NO, ROS

Dopamine Norepinephrine Metabolic insufficiency Mesolimbic pathway Locus coeruleus Vascular/astrocytic dysfunction Brain hypoperfusion/hypoxia Glutamate/GABA Melatonin Neurovascular impairment Diffusely distributed Pineal gland Brain glucose uptake

Network Dysfunction

Cunningham & Oldham. Neuroscience of delirium. In Cambridge Textbook of Delirium Neuroscience for Psychiatrists. In press. 4. Define and target pathophysiology

Delirium neurophysiology Prototype Theorized translational intervention Neuroinflammation Autoimmune encephalitis Immunomodulation, antioxidants, hypothermia Metabolic insufficiency Cardiac arrest Intranasal insulin, vitamin supplementation Sleep/circadian rhythms Sleep restriction/deprivation Light therapy, melatonin, hypnotics, et al. Neurotransmitter dysfunction  Cholinergic deficiency Anticholinergic toxidrome Cholinesterase inhibitors, physostigmine  Dopamine excess Stimulant intoxication Dopamine receptor modulators, benzodiazepines  Glutamate excess Anti-NMDAR Ab encephalitis NMDA antag., gabapentinoids, Ca channel modulat.  GABA-ergic excess Benzodiazepine intoxication Benzodiazepine receptor modulators  Noradrenergic excess Alcohol withdrawal delirium α1-antagonist, α2-agonist, β-blocker  Serotonergic excess Serotonin syndrome Cyproheptadine, mirtazapine, pimavanserin Network vulnerability Underlying dementia Pro-cognitive factors for multi-system benefit

Adapted from: Oldham, Flaherty, Maldonado AJGP 2018 Why delirium is important

Delirium as a disorder

Managing delirium disorder Delirium Harmonization Efforts at URMC

Optimizing Guidelines Nurses Providers Epic • Delirium group on • Adult non-ICU • LIVEBAR initiative • Delirium order set Story tab inpatient delirium (currently piloting) (under construction) • Delirium report guideline • Care plans (under • Dot phrase for construction) delirium/acute • Delirium columns • Recommended approach to using encephalopathy • Unit-based (pending LIVEBAR) monthly delirium potentially reports (under delirium-inducing construction) medications Delirium group on Story view Delirium accordion report Delirium columns Delirium Harmonization Efforts at URMC

Delirium Disorder and the Great Unlearning