Liberation from Mechanical Ventilation E. Wesley Ely, MD, MPH

Wake Up and Breathe:
Liberation and Animation
E Wesley Ely, MD, MPH
Professor, Department of Medicine
Vanderbilt University School of Medicine
Director of Aging Research, VA Tennessee Valley Geriatric
Research, Education and Clinical Center (GRECC)

Disclosures
E. Wesley Ely, MD, MPH would like to disclose the
following commercial/financial relationships:
Grants, Consulting, or Honoraria:
Pfizer, Hospira, Eli Lilly, Aspect, GSK

Pain
Lack of sleep
Difficulty
breathing
Depression
Anxiety
Delirium
PTSD
Rotondi AJ, et al. Crit Care Med 2002;30:746-52

Risk Factors for PTSD*
Factor †
B (95% CI) p value
Age in years Non-linear effect 0.04
APACHE II 0.02 (-0.32, 0.37) 0.90
Days of delirium 0.91 (-0.82, 2.63) 0.31
Female gender 7.36 (1.62, 13.11) 0.02
Total lorazepam dose 0.39 (0.17, 0.61) 0.001
*PTSD symptoms measured with the Post-Traumatic Stress Syndrome
10-Questions Inventory (PTSS-10)
†Regression coefficient
Girard TD, et al. Crit Care 2007;11:R28

% Neurocognitive Sequelae
No ICU Recall = More Brain Sequelae
25
ICU Recall
No Recall
20
15
10
5
0
Discharge One-Year Two-Years
Larson MJ. JINS. 2007;13:595-605.

Liberation & Animation
Ely EW, et al. N Engl J Med 1996;335:1864-9
Kress JP, et al. N Engl J Med 2000;342:1471-7
Girard TD, et al. Lancet 2008;371:126-34
Pandharipande PP, et al. JAMA 2007;298:2644-53
Riker R. et al, JAMA. 2009;301:489-499
Schweickert et al, Lancet 2009;373:1874-82
SBT
SAT
ABC (SAT+SBT)
Sedation choice
Sedation choice
Early Mobility

Liberation & Animation
Ely EW, et al. N Engl J Med 1996;335:1864-9
Kress JP, et al. N Engl J Med 2000;342:1471-7
Girard TD, et al. Lancet 2008;371:126-34
Pandharipande PP, et al. JAMA 2007;298:2644-53
Riker R. et al, JAMA. 2009;301:489-499
Schweickert et al, Lancet 2009;373:1874-82
SBT
SAT
ABC (SAT+SBT)
Sedation choice
Sedation choice
Early Mobility

Liberation
decrease exposure

Sedation Protocols: The Evidence
Trial RCT Outcome(s) Improved by Protocol
Brook et al.1999 Yes Ventilator days, ICU LOS
Kress et al. 2000 Yes Ventilator days, ICU LOS
Brattebo et al. 2002 No Ventilator days
de Lemos et al. 2005 Yes Ventilator days, ICU LOS
De Jonghe et al. 2005 No Ventilator days, time to awaken
Chanques et al. 2006 No Ventilator days, pain/agitation, infection
Quenot et al. 2007 No Ventilator days, extubation success, VAP
Arias-Rivera et al. 2008 No Extubation success
Bucknall et al. 2008 Yes None
Girard et al. 2008 Yes Ventilator days, hospital LOS, survival
Robinson et al. 2008 No Ventilator days, hospital LOS
Tobar et al. 2008 Yes Oversedation rate

Patients Receiving
Mechanical Ventilation (%)
100
80
Weaning protocol
SBT reduced weaning time
by =
2 days
60
p

Patients Receiving
Mechanical Ventilation (%)
Daily Interruption of Sedatives
100
80
SAT reduced ventilator time
by =
2 days
60
40
Control (n=60)
Adjusted
p

Girard TD, et al. Lancet 2008;371:126-34

ABC Trial – Objectives
• To determine the efficacy and safety of
a protocol combining
spontaneous daily interruption awakenings of sedatives trials and (SATs) and
spontaneous breathing trials (SBTs)
• Ventilator-free days
• ICU and hospital length of stay
• Survival
• Duration of coma and delirium
• Long-term neuropsychological outcomes

Spontaneous Awakening Trial
-BOTH groups getting patient targeted sedation-

Spontaneous Breathing Trial

Daily Dose of Benzodiazepines
Benzodiazepines
0 10 20 30 40 50 60 70
Usual Care+SBT
SBT+SAT
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Study Day

Daily Dose of Opiates
6000
Usual Care+SBT
SBT+SAT
Opiates
4000
2000
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Study Day

Baseline Characteristics
Characteristic*
Control
(n=168)
Intervention
(n=167)
Age, years 64 [51-75] 60 [48-71]
Female, % 49 46
APACHE II score 26.5 [21-31] 26 [21-33]
ICU admission diagnosis, n (%)
Sepsis/ARDS 53 47
MI/CHF 17 13
COPD/Asthma 7 10
Altered mental status 7 11
Other 16 19
Girard TD, et al. Lancet 2008;371:126-34

Patients Discharged from the ICU (%)
ICU Length of Stay
100
reduced ICU stay by =4 days
80
60
SAT+SBT (n=167)
40
SBT (n=168)
20
p=.01
0
0
7
14 21 28
Days
Girard TD, et al. Lancet 2008;371:126-34

Patients Discharged from the Hospital (%)
Hospital Length of Stay
100
80
reduced hospital stay by =
4 days
60
SAT+SBT (n=167)
40
SBT (n=168)
20
p=.04
0
0
7
14 21 28
Days
Girard TD, et al. Lancet 2008;371:126-34

Patients Alive (%)
100
80
One-Year Survival
NNT=7
60
SAT+SBT (n=167)
40
Usual Care+SBT (n=168)
20
p=.01
0
0
60 120 180 240 300 360
Days
Girard TD, et al. Lancet 2008;371:126-34

SATs (Daily Interruption) Used
in Minority Around World
• Canada – 40% get SATs (273 physicians in 2005)
• U.S. – 40% get SATs (2004-05)
• Germany– 34% get SATs (214 ICUs in 2006)
• France – 40-50% deeply sedated with 90% on
continuous infusion (44 ICUs in 2005)
• UK – 28% use sedation breaks, 82% use
midazolam when on > 24 hours
• Brazil – 32% get SATs (1,015 MDs in 2008)
Mehta S, CCM 2006;34:374-80.
Devlin J, CCM 2006;34:556-57.
Payen JF, Anesthes 2007;106:687-95.
Tanios M, Proc Am Thorac Soc 2005;2:A793.
Martin J and Spies C, Crit Care 2007;11:R124
Ramaswamy S, Intens Care Med (ESICM 2009)
Salluh J, J Crit Care 2009;epub ahead of print

Long-Term Cognitive Outcomes
Time of Cognitive Assessment Odds Ratio (95% CI) P-value
Hospital Discharge
1.86 (1.04, 3.34)
0.04
3-Month Follow-Up
2.01 (1.09, 3.71)
0.02
12-Month Follow-Up
2.23 (1.13, 4.41)
0.02
0 1 2 3 4 5
Favors Usual Care+SBT
Favors SAT+SBT
Jackson JC, et al. 2009, in submission

Cognitive Function at 12 months
(predicted mean T-score)
Delirium and Long-Term Cognitive Outcomes
60
50
p=.005
40
30
20
10
0
0 5 10 15 20
Days of ICU Delirium
Girard TD, et al. 2009, unpublished data

Randomized Trial of Light vs.
Deep Sedation
Treggiari MM, Romand JA, Yanez ND, Deem SA,
Goldberg J, Hudson L, Heidegger CP, Weiss NS.
Crit Care Med. 2009;37:2527-34

Study Aim
To test the effect of two different sedation
goals, light and deep sedation, on
short and long-term mental health
Treggiari M, Crit Care Med. 2009;37:2527-34

Outcome
Primary Endpoint
4 weeks after ICU discharge
Ramsay
1-2
Ramsay
3-4
n = 52 n = 50
P
PTSD score 46 29 56 29 .07
Anxiety score 5.3 5.0 5.0 4.2 .64
Depression score 3.4 3.7 3.1 3.7 .72
Treggiari M, Crit Care Med. 2009;37:2527-34

Antiquated
thinking
a concept
whose time
has come
and gone

Animation
early mobilization

Early Mobilization Protocol in
Mechanically Ventilated Patients
Schweickert et al, Lancet 2009;373:1874-82

Schweickert et al, Lancet 2009;373:1874-82

24% improvement (1.7-fold better)
return to independent functional
status at discharge (NNT=4)
Schweickert et al, Lancet 2009;373:1874-82

Animation = Less Delirium
Variable
ICU/Hosp
Delirium Days
Time in ICU
with Delirium
Time in Hosp.
with Delirium
Intervention
(n=49)
Control
(n=55)
P-
value
2 days 4 days 0.03
33% 57% 0.02
28% 41% 0.01
Schweickert et al, Lancet 2009;373:1874-82

Milestones Achieved Safely
~3 days earlier (p

The BRAIN ICU Project
- Overview -
Patient enrollment
INDEPENDENT VARIABLES
Delirium Duration
Time
12-month follow-up
DEPENDENT VARIABLES
Long Term Cognitive
Impairment (LTCI) Battery
Drug Exposure
Health-Related Quality
of Life (HRQL) Battery

Our Research Engine:
Over 40 Specialist Team Members
• 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
• Mike Hooper, MD and Matt King, MD Pulm/Critical Care Fellows
• Bryan Cotton, MD; Bill Obremskey MD Trauma and Orthopedic Surgery
• Herbert Meltzer, MD; Stephan Heckers, MD Psychiatry
• Sharon Gordon, PhD; Jim Jackson, PhD Geriatric Neuropsychology
• Venice Anderson, MS Psychological Testing Expertise
• Adrian Jarquin-Valdivia and Peter Donofrio Neurology and Neuromuscular
• Mike Stein, PhD Clinical Pharmacology
• Ayumi Shintani PhD, MPH, Frank Harrell, PhD Biostatisticians
• Ted Speroff, PhD Psychometrics, Safety
• Jennifer Thompson, BS, MA and Svetlana Eden, MS Biostatistics
• Renee Stiles, PhD; Steve Deppen, MS Resource Use / Cost
• Brenda Pun, RN, MSN, ACNP Project and Nurse Coordinator
• Joyce Okahashi, Cayce Strength, and Leanne Boehm ICU Research Nurses
• Peter Howard, Kim Vigil,and Beth Malo MD Neurology and Sleep
• Meredith Gambrell, BS Grants & Program Coordinator
• Hope Campbell, PharmD and others Investigational Pharmacy
• Jessica Adams Medical Students
• Heidi Smith MD, MSCI, Jenny Boyd, MD MSCI Pediatric ICU
• Cathy Fuchs, MD and Amanda Wilson MD Psychiatry Reference Raters
• Jin Han MD, MSCI Emergency Department