NEW RESEARCH DIRECTIONS IN DELIRIUM

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NEW RESEARCH DIRECTIONS IN DELIRIUM

• Sharon K. Inouye, M.D., M.P.H.
• Professor of Medicine
• Beth Israel Deaconess Medical Center
• Harvard Medical School
• Milton and Shirley F. Levy Family Chair
• Director, Aging Brain Center
• Hebrew SeniorLife

Talks/U Penn IOA talk 2006_delirium research.ppt
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WHAT IS DELIRIUM?(Acute Confusional State)

• Definition
• acute decline in attention and cognition
• Characteristics
• common problem
• serious complications
• often unrecognized
• may be preventable

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WHAT WE WILL COVER

• Overview of delirium
• Where we have come so far
• Where we are going
• What we still have to do

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WHAT WE KNOW ABOUT DELIRIUM

• Common problem
• Often unrecognized
• Typically of multifactorial etiology
• Serious complications
• Often preventable (40-50 cases)
• --------------------------------------------------
  ----
• We will review each of these areas

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• DELIRIUM IS COMMON

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EPIDEMIOLOGY OF DELIRIUM

• Delirium Rates
• Hospital
• Prevalence (on admission) 10-40
• Incidence (in hospital) 15-60
• Postoperative 15-53
• Intensive care unit 70-87
• Nursing home/post-acute care 20-60
• Mortality
• Hospital mortality 22-76
• One-year mortality 35-40

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CURRENT IMPACT OF DELIRIUM

• 35 of the U.S. population aged 65 years is
  hospitalized each year, accounting for gt 40 of
  all inpatient days
• Assuming a delirium rate of 20
• 7 of all persons 65 years will develop
• delirium annually
• Delirium will complicate hospital stay for gt 2.2
  million persons/year, involving gt 17.5 million
• in-patient days/year
• Estimated costs gt 8 billion/year

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IMPACT OF DELIRIUM

• Beyond hospital costs
• Post-hospital costs (gt100 billion in 1 year)
• Institutionalization
• Rehabilitation
• Home care
• Caregiver burden
• Aging of U.S. population
• Ref Leslie DL et al. Gerontologist 2005 45
  (Spec Iss II) 299.

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DELIRIUM IS OFTEN UNRECOGNIZED
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RECOGNITION OF DELIRIUM

• Previous studies 32-66 cases unrecognized by
  physicians
• Yale-New Haven Hospital study (1988-1989)
• 65 (15/23) unrecognized by physicians
• 43 (10/23) unrecognized by nurses

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NURSES RECOGNITION OF DELIRIUM

• Compared nurse recognition of delirium with
  interviewer ratings (N797)
• Nurses recognized delirium in only 31 of
  patients and 19 of observations
• Nearly all disagreements in ratings were due to
  under-recognition by nurses
• Risk factors for under-recognition hypoactive
  delirium advanced age, vision impairment,
  dementia
• Ref Inouye SK, Arch Intern Med.
  20011612467-2473

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DEVELOPMENT OF THE CONFUSION ASSESSMENT METHOD
(CAM)

• Ref Inouye SK, et. al. Ann Intern Med.
  1990, 113 941-8.

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SIMPLIFIED DIAGNOSTIC CRITERIA

• -- Uses 4 criteria assessed by CAM
• (1) acute onset and fluctuating course
• (2) inattention
• (3) disorganized thinking
• (4) altered level of consciousness
• -- The diagnosis of delirium requires the
  presence of criteria
• (1), (2) and (3) or (4)

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VALIDATION OF CAM

• Site I Site II
• (n30) (n26)
• Sensitivity 10/10 (100) 15/16 (94)
• Specificity 19/20 (95) 9/10 (90)
• Positive predictive
• accuracy 10/11 (91) 15/16 (94)
• Negative predictive
• accuracy 19/19 (100) 9/10 (90)
• Likelihood ratio
• (positive test) 20.0 9.4

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CAM SIGNIFICANCE

• Helped to improve recognition of delirium
• Widely used standard tool for clinical and
  research purposes nationally and internationally
• Translated into at least 8 languages
• Used in over 200 original published studies to
  date

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• Ive seen a dying eye
• Run round and round a room
• In search of something, as it seemed,
• Then cloudier become
• And then, obscure with fog,
• And then be soldered down,
• Without disclosing what it be,
• Twere blessed to have seen.
• Emily Dickinson

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DELIRIUM IS MULTIFACTORIAL
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MULTIFACTORIAL MODEL OF DELIRIUM IN OLDER PERSONS
Ref Inouye SK et al. JAMA 1996 275852-857
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RISK FACTORS FROM PREVIOUS STUDIES

• Reviewed medical literature for original articles
  which examined independent risk factors for
  delirium
• Found 36 studies examining risk factors for
  delirium, summarized on next 2 slides

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PREDISPOSING OR VULNERABILITY FACTORS
Demographics Older age Male gender Cognitive status Dementia Cognitive impairment History of delirium Depression Functional status Functional dependence Immobility Poor activity level History of falls Sensory impairment Vision impairment Hearing impairment Decreased Intake Dehydration Malnutrition Drugs Multiple psychoactive drugs High number of drugs Alcohol abuse Medical Comorbidity High severity of illness High level of comorbidity Chronic renal or hepatic disease Previous stroke Neurologic disease Metabolic derangements Fracture or trauma Terminal illness HIV infection
Inouye SK. NEJM 20063541157-65
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PRECIPITATING FACTORS OR INSULTS
Drugs Sedative hypnotics Narcotics Anticholinergic drugs Polypharmacy Alcohol or drug withdrawal Primary neurological diseases Stroke, particularly nondominant hemispheric Intracranial bleed Meningitis/encephalitis Environmental Intensive care unit admission Physical restraint use Bladder catheter use High number of procedures Pain Emotional stress Prolonged sleep deprivation Intercurrent illnesses Infections Iatrogenic complications Severe acute illness Hypoxia Shock Fever/hypothermia Anemia Dehydration Poor nutritional status Low serum albumin Metabolic derangements (e.g., electrolytes, glucose, acid-base) Surgery Orthopedic surgery Cardiac surgery Duration of cardiopulmonary bypass Non-cardiac surgery
Inouye SK. NEJM 20063541157-65
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DELIRIUM HAS SERIOUS COMPLICATIONS
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DELIRIUM OUTCOMES FROM PREVIOUS STUDIES

• Reviewed medical literature for original articles
  which examined delirium-related outcomes
• Found 34 studies, documenting that delirium is
  associated with poor outcomes (50 control for
  confounders)
• Prolonged LOS
• Nursing home placement
• Death
• Functional and/or cognitive decline

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DELIRIUM IS PREVENTABLE
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THE YALE DELIRIUM PREVENTION TRIAL

• Inouye SK. N Engl J Med 1999340669-76.

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YALE DELIRIUM PREVENTION PROGRAM

• Designed to counteract iatrogenic influences
  leading to delirium in the hospital
• Multicomponent intervention strategy targeted at
  6 delirium risk factors
• Risk Factor Intervention
• Cognitive Impairment.Reality
  orientation
• Therapeutic activities protocol
• Sleep Deprivation..
  Nonpharmacological sleep protocol
• Sleep enhancement protocol
• Immobilization Early mobilization
  protocol
• Minimizing immobilizing equipment
• Vision Impairment.. Vision aids
• Adaptive equipment
• Hearing Impairment.. Amplifying
  devices
• Adaptive equipment and techniques
• Dehydration Early recognition
  and volume repletion

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YALE DELIRIUM PREVENTION TRIAL RESULTS
Outcome Intervention Group (N426) Usual Care Group (N426) Matched OR (CI) or p-value
Incident delirium, n () 42 (9.9) 64 (15.0 ) .60 (.39-.92) p .02
Total delirium days No. delirium episodes 105 62 161 90 p.02 p.03
Delirium severity score 3.9 3.5 p.25
Recurrence rate 13 (31.0) 17 (26.6) p.62
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DELIRIUM PREVENTION TRIALSIGNIFICANCE

• First demonstration of delirium as a preventable
  medical condition
• Targeted multicomponent strategy works
• Significant reduction in risk of delirium and
  total delirium days, without significant effect
  on delirium severity or recurrence
• Primary prevention of delirium likely to be most
  effective treatment strategy
• Effectiveness and cost-effectiveness of the
  program has been demonstrated in multiple
  studies.

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THE HOSPITAL ELDER LIFE PROGRAM(HELP)

• A model of care to prevent delirium and
  functional decline in hospitalized older patients
• Inouye SK, et al. J Am Geriatr Soc.
  2000481697-1706
• Website www.hospitalelderlifeprogram.org

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HELP SITES ACROSS THE USA
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HELP WEBSITEhttp//hospitalelderlifeprogram.org

• Educational materials on acute hospital care and
  delirium in older persons for consumers,
  families, caregivers
• Reference list brief list by topic
  comprehensive searchable bibliography
• Weblinks links to useful websites
• HELP general background information and study
  results

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OTHER DELIRIUM INTERVENTION TRIALS

• Proactive geriatric consultation post hip
  fracture (Marcantonio, JAGS 2001) significant
  36 risk reduction for delirium
• Nursing education and consultation post hip
  fracture (Milisen, JAGS 2001) significant
  reduction in delirium duration and severity
• Multifactorial interventions in medical patients
  (1-Lundstrom, JAGS 2005 2-Naughton, JAGS 2005)
  1-significant reduction in delirium duration and
  LOS 2-significant reduction in delirium rate and
  hospital costs
• Educational intervention for medical staff
  (Tabet, Age Aging 2005) significant reduction
  in delirium prevalence
• Haloperidol prophylaxis (Kalisvaart, JAGS 2005)
  significant decreased severity and duration of
  postoperative delirium

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WHERE WE ARE GOING
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PATHOPHYSIOLOGY OF DELIRIUM

• Poorly understood
• Functional rather than structural lesion
• Characteristic EEG findings (generalized slowing)
• Final common pathway of many pathogenic
  mechanismsresulting in a failure of cholinergic
  transmission

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Flacker JM. J Gerontol Biol Sci 199954B239-46
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AREAS FOR FUTURE RESEARCH

• Is delirium completely reversible? Does it lead
  to permanent neurologic changes or dementia?
• Some patients with delirium never recover
• Increased rates of dementia following delirium
• Neuronal injury from some contributors
• Hypoperfusion by neuroimaging methods
• Does delirium alter the trajectory of dementia?
• Worse outcomes in dementia patients who develop
  delirium

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RELATIONSHIP OF DELIRIUM TO DEMENTIA
Delirium
Dementia A continuum of cognitive
disorders
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DELIRIUM-SPECT STUDY (N22)(Preliminary Study)

• Perfusion results (standard comparisons)
• Frontal lobe hypoperfusion in 5
• Parietal lobe hypoperfusion in 6
• Normal flow in 11
• Paired scans (6) 3 with reversible defects in
  parietal lobes
• Ref Fong T et al. J Geront Med Sci. 2006. In
  Press.

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IMPACT OF DELIRIUM ON AD TRAJECTORY
Slope BC-Slope AB 2.7 points per year
(N34) Zhang Y et al, 2006.
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NEW DIRECTIONS FOR RESEARCH

• Long-term outcome studies of delirium
• Cognitive reserve capacity protective effect of
  education and activities on delirium
• Biomarkers identify disease and severity
  markers (dx and long-term sequelae)
• Neuroimaging identify long-term changes with
  sensitive methods (DTI, perfusion)
• Genetic and molecular mechanisms

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MOLECULAR MECHANISMS LINKING DELIRIUM AND
ALZHEIMERS DISEASE

• In neuronal cell culture, therapeutic levels of
  the inhalational anesthetic isoflurane results in
  A-beta generation and apoptosis
• While anesthesia is identified as an important
  risk factor for postoperative delirium, its
  relationship to AD not well described.
• Isoflurane contributes to mechanisms of AD
  neuropathogensis, and provides a plausible link
  between delirium and AD.

Xie Z. Anesthesiology 2006104988-94 Xie A. J
Gerontol Med Sci 2006. In Press
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FUTURE RESEARCH

• Delirium may provide the unique opportunity for
  early intervention and prevention of cognitive
  damage

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WHAT WE STILL NEED TO DO
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DELIRIUMHEALTH POLICY IMPLICATIONS

• Delirium serves as a marker for quality of
  hospital care for the elderly
• Often iatrogenic
• Linked to processes of care
• Common, bad outcomes
• Delirium serves as a window for identifying
  quality improving changes.
• Inouye SK. Am J Med. 1999106 565-73

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ESTIMATING THE IMPACT OF DELIRIUM

• Fraction of a year of life lost (Leslie, AIM
  2005)
• gt100 billion in direct medical costs per year
  (Leslie, Gerontologist 2005)
• National costs from preventable adverse events
  estimated at 17-29 billion per year
• Delirium likely accounts for at least 1/4 to 1/3
  of these costs, rivaling the amount spent on
  caring for people with HIV/AIDS.
• Further studies to estimate the national impact
  of delirium will be key.

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HEALTH POLICY INITIATIVES

• CAM In AHRQs National Quality Measures
  Clearinghouse (www.qualitymeasures.ahrq.gov)
• Proposal for delirium as measure of hospital
  quality of care hospital and quality
  organizations
• Advocacy for delirium and delirium prevention
  programs (e.g., HELP) work with consumer and
  watchdog groups

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• Add life to years,
• not years to life.

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• Knowing is not enough
• we must apply.
• Willing is not enough
• we must do.
• - Goethe