A New Frontier In Critical Care: Saving the Brain of Injured Elderly E. Wesley Ely, MD, MPH Professor of Medicine Pulmonary, Critical Care & Health Services Research Associate Director of Aging Research – VA GRECC Vanderbilt University, Nashville, TN

“Do you see what I see? The epistemology of interdisciplinary inquiry” H. G. Petrie. The Journal of Aesthetic Education 1976;10:29-43

PAINT A PICTURE

Wall Street Journal THE INFORMED PATIENT By LAURA LANDRO Hospitals Combat an Insidious Complication Delirium in ICU Patients, October 17, 2007; Page D1 “Gravely ill with pneumonia and sepsis, SBM was heavily sedated on a ventilator for 10 days in She suffered several complications in the ICU -- including delirium, a state of temporary confusion and disorientation that frequently occurs in critically ill patients. But after she returned to work, Ms. Miller, now 54 years old, was unable to concentrate or organize her thoughts. She had to retire early...”

Anecdote: Sepsis Patient 64 y/o female executive: Previously healthy Community-acquired pneumonia, sepsis ARDS and on vent for 10 days Had ICU delirium Lungs, heart, kidneys recovered without complications Head CT and MRI normal, neuro exam non-focal Debilitating “executive dysfunction” syndrome

Anecdote: Sepsis Patient 1 year follow-up letter Dear Doctor, you remember my sister, who is a 64 year old CEO with many employees. After she developed delirium, we couldn’t seem to get her mental clouding cleared for quite some time. She has tried to go back to work, and driving, and functioning although she can not seem to fully bounce back. I saw her for the first time about a month ago, when she came out for my daughter's Bat Mitzvah. She seems to have lost her "spark". She was such a personality pre-illness, so gregarious and really the life of the party. She is very flat now, and has memory problems. She doesn't remember anything about her illness or her hospitalization. Some long term, but mostly short term memory problems. She looks much older, and is walking very slowly, always holding onto railings, etc. She looks like a very elderly woman now. The illness really changed her. ref: Tremendous deterioration in cognitive and functional capacity (Kiely & Marcantonio, J Gerontol 2006;61:204-08)

DEMOGRAPHICS DRIVE US

Severe Sepsis Incidence by Age 0 20,000 40,000 60,000 80, , ,000 < Age/Years Number of cases Incidence rate Cases Incidence/1,000 Population Angus, Crit Care Med 2001; 29:

Aging and Mechanical Ventilation Incidence of acute respiratory failure requiring mechanical ventilation rises 10-fold from age 55 to 85 Behrendt, Chest 2000;118: Greater numbers of older patients are being treated in our ICUs than ever before Jakob, Crit Care Med 1997;23: ~60% of all ICU days are incurred by patients >65 years old Angus et al., JAMA 2000;284: These facts have altered the ICU landscape

“DIG THE BREAK”

BRAIN DYSFUCTION - a new frontier -

MeSH and Text for “Delirium in ICU”

MeSH and Text for “Delirium in ICU” Since Year 2000

Delirium Monitoring in ICU

Definition of Delirium Delirium is (1) fluctuation/change in mental status (2) inattention either/or (3) disorganized thinking (4) altered level of consciousness DSM IV and CAM-ICU

Patient Comfort PainSedationDelirium 0-10 Scale VAS Scale Subjective/ Physiologic indicators Sedation Assessment Scale (e.g. RASS, SAS, MAAS) CAM-ICU IC-DSC Jacobi J et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30: Assessment of ICU Patients

Educational Delirium Website

DELIRIUM and SEDATION: Outcomes Tools to Use Vanderbilt RCTs

Delirium and Outcomes - - Increased ICU Length of Stay (8 vs 5 days) - - Increased Hosp Length of Stay (21 vs. 11days) - - Increased time on the Ventilator (9 vs 4 days) - - Higher costs ($22,000 vs $13, 000 in ICU costs) - - Estimated $4 to $16 billion associated U.S. costs fold increased risk of death - - Every delirium day increased by 35% ‘ICU accelerated dementia’ Ely EW, ICM2001; 27, Thomason J, Crit Care 2005;9: Lin SM, CCM 2004; 32: Ely EW, JAMA 2004; 291: Milbrandt E,CCM 2004; 32: Jackson J, Neuropsych Rev 2004; 14: Ouimet S, ICM 2007;33:66-73 Pisani M, Crit Care 2006;10:R121

Saving Lives Through New Treatment Approaches

The Awakening and Breathing Controlled (ABC) Trial To determine the efficacy and safety of a protocol combining daily (A) spontaneous Awakening trials and (B) spontaneous Breathing trials Multicenter Investigation –Vanderbilt Hospital (Girard, Thomason, Ely) –University of Chicago Hospitals (Kress & Hall) –Saint Thomas Hospital, Nashville (Canonico) –Hospital of the Univ. of Pennsylvania (Fuchs) –Penn Presbyterian Medical Center (Taichman)

1 day 2 days Fulminant Dz (33%) “Weaning” period (66%) Esteban A, et al. JAMA 2002;287: Total time on ventilator – 2 to 7 days

The ABC Trial Control Intervention Girard T et al, Lancet 2008 in press

ABC Trial: Baseline Characteristics Characteristic* SBT (n=168) SAT+SBT (n=167) Age, mean years±SD61±1658±17 Female, n (%)83 (49.4)77 (46.1) APACHE II score26.5 [21-31]26 [21-33] ICU admission diagnosis, n (%) Sepsis and/or ARDS89 (53)79 (49) MI/CHF29 (17)22 (13) COPD/Asthma12 (7)17 (10) Other38 (23)45 (27) RASS on first study day-4 [-5 to -2] *Median [interquartile range] except as noted

ABC Trial: Main Outcomes Outcome*SBTSAT+SBTp value † Ventilator-free days Time to Event, days Successful extubation ICU discharge Hospital discharge Death at 28 days, n (%) 58 (34.5)47 (28)0.21 Days of brain dysfunction Coma Delirium *Median [interquartile range] except as noted Girard T et al, Lancet 2008 in press

Improved one-year survival in ABC Trial Patients Alive (%) Days SBT (n=168) SAT+SBT (n=167) p=0.01 Girard T et al, Lancet 2008 in press

The MENDS Trial Vanderbilt University, Nashville TN Washington Hospital Center, Washington DC Maximizing Efficacy of targeted sedation and reducing Neurological Dysfunction

MENDS Study Pandharipande P et al, JAMA 2007;298:

MENDS Trial: Baseline Characteristics DemographicLorazepam (n=51) Dexmedetomidine (n=52) P value Age59 (45, 67)60 (49,65)0.96 Males45%56%0.42 APACHE II27 (23,32)28.5 (23, 32)0.95 SOFA score9 (7,11)10 (8,12)0.23 Sepsis diagnosis39%38%0.95 Pandharipande P et al, JAMA 2007;298:

Days Lorazepam Dexmedetomidine JAMA 2007;298:

MIND Study (Modifying the INcidence of Delirium) 6 sites: Vanderbilt TN, UNC-CH, U of Iowa, Baylor TX, St. Thomas TN, Moses Cone NC

RELATED DEMENTORS

Case History 54 year old executive develops CAP/ARDS/Sepsis Mechanical ventilation, MODS, delirium Survived but “brain swimming in mollasses” 2 years later not working but happy and active “Doc, others don’t know” Anecdote: Young Sepsis Patient

Data on link between delirium and long-term CI growing; no proven link to sedation. This person retained a functional life, and though lost her profession, has stabilized.

The BRAIN ICU Project - Overview -

Wes Ely, MD, MPH Critical Care and Aging Research Robert Dittus, MD, MPH Division Chief GIM, GRECC Director Gordon Bernard, MD Asst. Vice Chancellor for Research Lorraine Ware, MD Biomarkers in Critical Care Pratik Pandharipande, MD, MSCI Anesthesiology & Critical Care Paula Watson, MD Sleep Medicine, Critical Care Tim Girard, MD, MSCI Aging Critical Care Russ Miller, MD, MPH & Rich Tyson, MD Pulm/Critical Care Fellows Bryan Cotton, MD; Bill Obremskey MD Trauma and Orthopedic Surgery Herbert Meltzer, MD; Stephan Heckars, MD Psychiatry Sharon Gordon, PhD; Jim Jackson, PhD Geriatric Neuropsychology Venice Anderson, MS Psychological Testing Expertise Howard Kirshner, MD Behavioral Neurology Mike Stein, PhD & Usha Nair PhD Clinical Pharmacology Ayumi Shintani PhD, MPH, Frank Harrell, PhD Biostatisticians Ted Speroff, PhD Psychometrics, Safety Jennifer Thompson, BS, MA Database, Biostatistics Renee Stiles, PhD; Steve Deppen, MS Resource Use / Cost Brenda Pun, RN, MSN, ACNP Project and Nurse Coordinator Joyce Okahashi and Kate VDH, RN, MSN Research Nurses (BRAIN) Cayce Strength, BSN Research Nurse (SOMNUS) Meredith Gambrell, BS Grants & Program Coordinator Hope Campbell, PharmD and others Investigational Pharmacy Vivek Agarwal, Rina Patel, Natalie Jacobowski, Eli Zimmerman Medical Students Our Research Engine: Over 30 Specialist Team Members

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