Learning Objectives
• Manage adult patients who need sedation and
analgesia while receiving ventilator support according
to current standards and guidelines
• Use validated scales for sedation, pain, agitation and
delirium in the management of these critically ill
patients
• Assess recent clinical findings in pain, agitation, and
delirium management and incorporate them into the
management of ICU patients
Reflect On Your Current Practice
•
•
•
•
Are you familiar with the new PAD guidelines?
Have you incorporated them into your practice?
Are you targeting a light level of sedation?
Do you use the ABCDE bundle or a similar
structure at your institution?
• What are the barriers to changing your practice?
• What are the barriers to changing your system?
Need for Sedation and Analgesia
•
•
•
•
•
Prevent pain and anxiety
Decrease oxygen consumption
Decrease the stress response
Patient-ventilator synchrony
Avoid adverse neurocognitive sequelae
–
–
–
–
Depression
PTSD
Delirium
Anxiety
• Avoid post-intensive care syndrome
Rotondi AJ, et al. Crit Care Med. 2002;30:746-752.
Weinert C. Curr Opin in Crit Care. 2005;11:376-380.
Kress JP, et al. Am J Respir Crit Care Med. 1996;153:1012-1018.
A Word About the 2013 PAD Guidelines
• Supporting organizations
– American College of Critical Care Medicine (ACCM)
– Society of Critical Care Medicine (SCCM)
– American Society of Health-System Pharmacists (ASHP)
• Some of this presentation is based on the guidelines
• Guideline recommendations are evidence-based
and will not apply to all patients
• Intended as a roadmap for developing integrated,
evidence-based, and patient-centered protocols
Barr J, et al. Crit Care Med. 2013;41:263-306.
What’s Different about this Version of the
PAD Guidelines? Methods
• GRADE measures quality and strength
• Quality of Evidence:
– Evaluation of the available data
– High or low quality?
– A (high), B (moderate), C (low)
• Strength of Recommendation:
– Confidence that following the recommendation will cause
more good than harm (1 or 2)
– Strong “We Recommend”
– Weak
“We Suggest”
Grading of Recommendations Assessment, Development and Evaluation method
http://www.gradeworkinggroup.org. Accessed March 2013.
What’s Different About this Version of
the PAD Guidelines? Results
• Psychometric assessments comparing pain, sedation and
delirium monitoring tools
• More patient-centered, integrated and interdisciplinary
approach to managing pain, agitation, and delirium
– Far less emphasis on specific across-the-board pharmacologic
recommendations
• Greater emphasis on the pathophysiology, risks and
management of delirium
Barr J, et al. Crit Care Med. 2013;41:263-306.
What’s Different About this Version of
the PAD Guidelines? Scope
• Far larger than the 2002 guidelines!
– 2002
– 2008
– 2013
28 recommendations
36 recommendations (Surviving Sepsis Guidelines)
53 recommendations and statements
• Not meant to be comprehensive
–
–
–
–
Expect Variability
Less Prescriptive
More Proscriptive
Strategies rather than agents
• Result = a lot of flexibility
– Pros
– Cons
• Expect variation (that is still compliant)
Barr J, et al. Crit Care Med. 2013;41:263-306.
What’s Different About this Version of
the PAD Guidelines? Scope
• Far larger than the 2002 guidelines!
– 53 recommendations and statements
 vs 28 recommendations in 2002
 vs 36 recommendations in the 2008 Surviving Sepsis Guidelines
• Not meant to be comprehensive:
– Addresses only questions of greatest importance to ICU clinicians
– Some questions have no recommendations due to lack of
research
– Identifies areas for future research
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Statements vs Recommendations
Position
Statements
N
22
Type
Descriptive
Scored
For
Quality
Quality
Recommendations
32
A. High
B. Moderate
C. Low/very
low
Strength
Example
Delirium is associated
with prolonged ICU
and hospital LOS in
adult ICU patients (A)
A, B, C
+ For
- Against
Actionable
Barr J, et al. Crit Care Med. 2013;41:263-306.
Levels
1. Strong
2. Weak
We recommend
routine monitoring of
delirium in adult ICU
patients (+1B)
Pain, Agitation, and Delirium
Are Interrelated
Delirium
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Care Bundle
TREAT
ASSESS
A
PAIN
AGITATION
DELIRIUM
Assess pain ≥ 4x/shift & prn
Preferred pain assessment tools:
• Patient able to self-report → NRS (0-10)
• Unable to self-report → BPS (3-12) or
CPOT (0-8)
Patient is in significant pain if NRS ≥ 4, BPS > 5,
or CPOT ≥ 3
Assess agitation, sedation ≥4x/shift & prn
Preferred sedation assessment tools:
• RASS (-5 to +4) or SAS (1 to 7)
• NMD→ suggest using brain function monitoring
Assess delirium Q shift & prn
Preferred delirium assessment tools:
• CAM-ICU (+ or -)
• ICDSC (0 to 8)
Depth of agitation, sedation defined as:
• Agitated if RASS = +1 or +4, or SAS + 5 to 7
• Awake and calm if RASS = 0, or SAS = 4
• Lightly sedated if RASS = -1 to -2, or SAS = 3
• Deeply sedated if RASS = -3 to -5, or SAS = 1
to 2
Delirium present if:
• CAM-ICU is positive
• ICDSC ≥ 4
Treat pain within 30’ then reassess:
• Non-pharmacologic treatment-relaxation
therapy
• Pharmacologic treatment:
–Non-neuropathic pain → IV opioids +/- nonopioid analgesics
–Neuropathic pain → gabapentin or
carbamazepine, + IV opioids
–S/p AAA repair, rib fractures → thoracic
epidural
Targeted sedation or DSI (Goal: patient purposely
follows commands without agitation):
RASS = -2-0, SAS = 3-4
• If under sedated (RASS > 0, SAS >4)
assess/treat pain → treat w/sedatives prn
• (non-benzodiazepine withdrawal is suspected)
• If over sedated (RASS < -2, SAS < 3) hold
sedatives until at target, then restart at 50% of
previous dose
•
•
•
•
•
PREVENT
•
Administer pre-procedural analgesia and/or
non-pharmacologic interventions (e.g.,
relaxation therapy)
Treat pain first, then sedate
Barr J, et al. Crit Care Med. 2013;41:263-306.
•
Consider daily SBT, early mobility and exercise
when patients are at goal sedation level, unless
contraindicated
EEG monitoring if:
– At risk for seizures
– Burst suppression therapy is indicated for ↑
ICP
•
•
•
•
•
Treat pain as needed
Reorient patients; familiarize
surroundings; use patient’s eyeglasses,
hearing aids if needed
Pharmacologic treatment of delirium:
– Avoid benzodiazepines unless
ETOH or benzodiazepine withdrawal
is suspected
– Avoid rivastigmine
– Avoid antipsychotics if ↑ risk of
Torsades de pointes
Identify delirium risk factors: dementia,
HTN, ETOH abuse, high severity of
illness, coma, benzodiazepine
administration
Avoid benzodiazepine use in those at ↑
risk for delirium
Mobilize and exercise patients early
Promote sleep (control light, noise;
cluster patient care activities; decrease
nocturnal stimuli)
Restart baseline psychiatric meds, if
indicated
Pain, Agitation, and Delirium
Are Interrelated
Delirium
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Pain Assessment
Recommendations
• We recommend that pain be routinely monitored in all
adult ICU patients (+1B)
• The BPS and the CPOT are the most valid and
reliable behavioral pain scales for monitoring pain in
adult ICU patients who are unable to self-report and
in whom motor function is intact and behaviors are
observable (B)
• We do not suggest that vital signs be used alone for
pain assessment in adult ICU patients (–2C)
• We suggest that vital signs may be used as a cue to
begin further assessment of pain (+2C)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Assessing Pain
• For patients able to self-report
– Numeric Rating Scale
– “On a scale of 0 to 10, how do you rate your
current level of pain?”
• For patients unable to self-report
− Behavioral Pain Scale (BPS)
− Critical Care Pain Observation Tool (CPOT)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Payen JF, et al. Crit Care Med. 2001;29(12):2258-2263.
Gélinas C, et al. Am J Crit Care. 2006;15:420-427.
Behavioral Pain Scale (BPS) 3-12
Item
Facial
expression
Upper limbs
Compliance
with ventilation
Description
Score
Relaxed
1
Partially tightened (eg, brow lowering)
2
Fully tightened (eg, eyelid closing)
3
Grimacing
4
No movement
1
Partially bent
2
Fully bent with finger flexion
3
Permanently retracted
4
Tolerating movement
1
Coughing but tolerating ventilation for
most of the time
2
Fighting ventilator
3
Unable to control ventilation
4
Payen JF, et al. Crit Care Med. 2001;29:2258-2263.
Critical Care Pain Observation Tool
Gélinas C, et al. Am J Crit Care. 2006;15:420-427.
Assessing Pain Reduces
Sedative/Hypnotic Use
What proportion of MV ICU patients received
sedative or hypnotic medication?
Day 2 Pain Assessment?
P value
No (n = 631)
Yes (n = 513)
Any sedative
86 %
75 %
< 0.01
Midazolam
65 %
57 %
< 0.01
Propofol
21 %
17 %
0.06
Other
6%
4%
0.03
Payen JF, et al. Anesthesiology. 2009;111:1308-1316.
Assessing Pain Associated
With Improved Outcomes
Outcome
Day 2 Pain
Assessment?
Unadjusted
OR
P
Adjusted
OR
P
No
Yes
ICU Mortality
22%
19%
0.91
0.69
1.06
0.71
ICU LOS
18 d
13 d
1.70
< 0.01
1.43
0.04
MV duration
11 d
8d
1.87
< 0.01
1.40
0.05
Ventilator
Acquired
Pneumonia
24%
16%
0.61
< 0.01
0.75
0.21
Payen JF, et al. Anesthesiology. 2009;111:1308-1316.
PAD Pain Management
Recommendations
• Preemptively treat chest tube removal with either analgesics and/or
nonpharmacologic therapy (1C)
• Suggest preemptively treating other types of procedural pain with
analgesic and/or nonpharmacologic therapy (2C)
• Use opioids as first-line therapy for treatment of non-neuropathic pain
(1C)
• Suggest using non-opioid analgesics in conjunction with opioids to reduce
opioid requirements and opioid related side effects (2C)
• Use gabapentin or carbamazepine, in addition to intravenous opioids, for
treatment of neuropathic pain (1A)
• Use thoracic epidural for postoperative analgesia in abdominal surgery
patients (1B)
• Suggest thoracic epidural analgesia be used for patients with traumatic rib
fractures (2B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Pain, Agitation, and Delirium
Are Interrelated
Delirium
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Agitation/Sedation Assessment
Recommendations
• Depth and quality of sedation should be routinely assessed
in all ICU patients (1B)
• The RASS and SASS are the most valid and reliable
scales for assessing quality and depth of sedation in ICU
patients (B)
• Suggest using objective measures of brain function to
adjunctively monitor sedation in patients receiving
neuromuscular blocking agents (2B)
• Use EEG monitoring either to monitor non-convulsive
seizure activity in ICU patients at risk for seizures, or to
titrate electrosuppressive medication to achieve burst
suppression in ICU patients with elevated intracranial
pressure (1A)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Sedation-Agitation Scale (SAS)
Score
State
Behaviors
7
Dangerous
Agitation
6
Very Agitated
5
Agitated
4
Calm and
Cooperative
3
Sedated
Difficult to arouse, awakens to verbal stimuli or gentle
shaking but drifts off
2
Very Sedated
Arouses to physical stimuli but does not communicate
or follow commands
1
Unarousable
Minimal or no response to noxious stimuli, does not
communicate or follow commands
Pulling at ET tube, climbing over bedrail, striking at
staff, thrashing side-to-side
Does not calm despite frequent verbal reminding,
requires physical restraints
Anxious or mildly agitated, attempting to sit up, calms
down to verbal instructions
Calm, awakens easily, follows commands
Riker RR, et al. Crit Care Med. 1999;27:1325-1329.
Brandl K, et al. Pharmacotherapy. 2001;21:431-436.
Richmond Agitation
Sedation Scale (RASS)
Sessler CN, et al. Am J Respir Crit Care Med. 2002;166(10):1338-1344.
PAD Depth of Sedation Statements
• Maintaining light levels of sedation in adult ICU patients is
associated with improved clinical outcomes (eg, shorter
duration of mechanical ventilation and a shorter ICU
length of stay [LOS]) (B)
• Maintaining light levels of sedation increases the
physiologic stress response, but is not associated with an
increased incidence of myocardial ischemia (B)
• The association between depth of sedation and
psychological stress in these patients remains unclear (C)
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Depth of Sedation Recommendations
• We recommend that sedative medications be
titrated to maintain a light rather than a deep
level of sedation in adult ICU patients, unless
clinically contraindicated (+1B)
• We recommend either daily sedation interruption
or a light target level of sedation be routinely
used in mechanically ventilated adult ICU
patients (+1B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Early Deep Sedation
Survival
Fraction Intubated
Longer MV and Reduced 6 Month-Survival
Shehabi Y, et al. Am J Respir Crit Care Med. 2012;186(8):724-731.
Mental Health After Light or Deep Sedation
• Patients: adults requiring mechanical ventilation
• Sedation with midazolam
– Light: Ramsay 1-2, intermittent injection
– Deep: Ramsay 3-4, continuous infusion
• Results
– Primary endpoints (4 weeks after ICU discharge)
 Trend towards more PTSD symptoms with deep sedation
 No difference in anxiety or depression scores
– Other endpoints: light sedation patients averaged
 1 day shorter on MV (P = 0.03)
 1.5 days shorter LOS (P = 0.03)
Treggiari MM, et al. Crit Care Med. 2009;37(9):2527-2534.
Daily Sedation Interruption Decreases
Duration of Mechanical Ventilation
• Hold sedation infusion until
patient awake and then
restart at 50% of the prior
dose
• “Awake” defined as any 3 of
the following:
– Open eyes in response to
voice
– Use eyes to follow
investigator on request
– Squeeze hand on request
– Stick out tongue on request
• Fewer diagnostic tests to assess changes in mental status
• No increase in rate of agitated-related complications or
episodes of patient-initiated device removal
• No increase in PTSD or cardiac ischemia
Kress JP, et al. N Engl J Med. 2000;342:1471-1477.
Needham DM, et al. Crit Care Med. 2012;40(2):502-509
ABC Trial
To determine the efficacy and safety of a protocol
linking:
spontaneous awakening trials (SATs) &
spontaneous breathing trials (SBTs)
Girard TD, et al. Lancet. 2008;371:126-134.
ABC Trial: Main Outcomes
Outcome*
SBT
SAT+SBT
P-value
12
15
0.02
Successful extubation, days
7.0
5
0.05
ICU discharge, days
13
9
0.02
Hospital discharge, days
19
15
0.04
97 (58%)
74 (44%)
0.01
Coma
3.0
2.0
0.002
Delirium
2.0
2.0
0.50
Ventilator-free days
Time-to-Event, days
Death at 1 year, n (%)
Days of brain dysfunction
*Median, except as noted
Girard TD, et al. Lancet. 2008;371:126-134.
ABC Trial: 1 Year Mortality
Girard TD, et al. Lancet. 2008;371:126-134.
SAT Protocol
SBT Protocol
Protocol + SAT/SBT versus
Protocol + SBT Alone
Mehta S, et al. JAMA. 2012;308(19):1985-1992.
Nursing-Implemented Sedation Protocol:
Barnes Jewish Pilot United States
25
P < 0.001
Protocol n = 162
Routine n = 159
Significant patient characteristics/metrics/outcomes
Protocol
Routine
P value
CIVS†
66 (40)
66 (42)
0.9
Duration CIVS, hrs*
3.5 ± 4
5.6 ± 6.4
0.003
Bolus†
118 (72)
127 (80)
0.14
Reintubated†
14 (8.6)
21 (13)
0.2
Trached†
10 (6.2)
21 (13.2)
0.04
20
Median Time (days)
20
14
15
P = 0.13
10
P = 0.003
4.8
5
7.5
5.7
*Data presented in median; †Data presented as n (%)
CIVS: continuous intravenous infusion sedation
2.3
0
Duration of MV
ICU LOS
Hospital LOS
Single center, prospective, trial of 332 consecutive ICU patients requiring mechanical ventilation randomized
to protocolized sedation (n = 162) or routine care (n = 159) at Barnes Jewish Hospital from 8/97 to 7/98.
Protocol used goal orientated sedation to target Ramsey with bolus requirements before initiation of
continuous infusion and uptitration of opioids and benzodiazepines.
Brook AD, et al. Crit Care Med. 1999;27(12):2609-2615.
Nursing-Implemented Sedation Protocol:
Bocage University Hospital France
25
Significant patient characteristics/metrics/outcomes
Protocol n = 197
P = 0.003
21
Control n = 226
Protocol
Control
P value
Daily midazolam,
mg*
44 ± 31
92 ± 59
0.001
Duration
midazolam, hrs**
3
5
0.18
Reintubated†
11 (6)
29 (13)
0.01
VAP diagnosis†
12 (6)
34 (15)
0.005
Median Time (days)
20
17
P = 0.004
15
11
P = 0.001
10
5
8
4.2
*Data presented in mean; ** Data presented in median
†Data presented as n (%)
5
0
Duration of MV
ICU LOS
Hospital LOS
Single center, prospective, before-after trial of 423 ICU patients requiring mechanical ventilation for > 48
hours before (n = 226) and after (n = 197) implementation of sedation protocol at Bocage University Hospital
from 5/99 to 12/03. Protocol used goal orientated sedation to target Q3hr Cambridge scale with bolus
requirements before initiation of continuous infusion and uptitration of midazolam
Quenot JP, et al. Crit Care Med. 2007;35(9):2031-2036.
Pharmacist Enforced Adherence to an ICU
Sedation Guideline: Boston Medical Center MICU
25
RPh intervention n = 78
P = 0.001
Significant patient characteristics/metrics/outcomes
Control n = 78
19.8
Median Time (days)
20
RPh
Control
P value
15 (19.2)
6 (7.7)
0.03
Lorazepam
equivalents/vent
day, mg*
65.2 ±
114.1
74.8 ±
76.1
0.54
Fentanyl
equivalents/vent
day, mcg*
102.5 ±
328
400 ±
1026
0.02
Alcohol/drug
overdose†
P = 0.002
15
P = 0.0004
11.8
10.6
8.9
10
7
5.3
*Data presented in mean ; †Data presented as n (%)
5
0
Duration of MV
ICU LOS
Hospital LOS
Single center trial of 156 adult MICU patients requiring mechanical ventilation before (n = 78)
and after (n = 78) implementation of RPh enforced guideline sedation management at Boston
Medical Center. Guideline addressed use of agent selection, goal oriented therapy, and dose
limitation strategies.
Marshall J, et al. Crit Care Med. 2008;36(2):427-433.
PAD Choice of Sedative
Recommendations
• We suggest that analgesia-first sedation be used in mechanically
ventilated adult ICU patients (+2B)
• We suggest that sedation strategies using nonbenzodiazepine
sedatives (either propofol or dexmedetomidine) may be preferred
over sedation with benzodiazepines (either midazolam or
lorazepam) to improve clinical outcomes in mechanically ventilated
adult ICU patients (+2B)
• We suggest that in adult ICU patients with delirium unrelated to
alcohol or benzodiazepine withdrawal, continuous IV infusions of
dexmedetomidine rather than benzodiazepine infusions be
administered for sedation to reduce the duration of delirium in these
patients (+2B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Analgosedation
• Analgesic first (A-1), supplement with sedative
• Acknowledges that discomfort may cause agitation
• Remifentanil-based regimen
– Reduces propofol use
– Reduces median MV time
– Improves sedation-agitation scores
• Not appropriate for drug or alcohol withdrawal
Park G, et al. Br J Anaesth. 2007;98:76-82.
Rozendaal FW, et al. Intensive Care Med. 2009;35:291-298.
Analgosedation
• 140 critically ill adult patients undergoing mechanical
ventilation in single center
• Randomized, open-label trial
– Both groups received bolus morphine (2.5 or 5 mg)
– Group 1: No sedation (n = 70 patients) - morphine prn
– Group 2: Sedation (20 mg/mL propofol for 48 h, 1 mg/mL
midazolam thereafter) with daily interruption until awake (n = 70,
control group)
• Endpoints
– Primary
 Number of days without mechanical ventilation in a 28-day period
– Other
 Length of stay in ICU (admission to 28 days)
 Length of stay in hospital (admission to 90 days)
Strøm T, et al. Lancet. 2010;375:475-480.
Analgosedation
Results
• Patients receiving no sedation had
–
–
–
–
More days without ventilation (13.8 vs 9.6 days, P = 0.02)
Shorter stay in ICU (HR 1.86, P = 0.03)
Shorter stay in hospital (HR 3.57, P = 0.004)
More agitated delirium (N = 11, 20% vs N = 4, 7%, P = 0.04)
• No differences found in
– Accidental extubations
– Need for CT or MRI
– Ventilator-associated
pneumonia
Strøm T, et al. Lancet. 2010;375:475-480.
Benzodiazepines vs Propofol
Better Outcomes With Propofol
Study/Year
Grounds et al 1987
Population
Cardiac surgery
Outcome Improved
Faster awakening
Aitkenhead et al 1989
General ICU
More consistent awakening, faster weaning
McMurray et al 1990
Cardiac surgery
Carrasco et al 1993
General ICU
Faster awakening
More accurate sedation, faster awakening,
lower costs
Roekaerts et al 1993
Cardiac surgery
Faster awakening, earlier extubation
Ronan et al 1995
Surgical ICU
Faster awakening
Sherry et al 1996
Cardiac surgery
Lower costs
Chamorro et al 1996
General ICU
Better ventilator synchrony, faster awakening
Barrientos-Vega et al 1997
General ICU
Earlier extubation
Weinbroum et al 1997
Sanchez-Izquierdo-Riera et al
1998
McCollam et al 1999
General ICU
Faster awakening
Trauma ICU
Faster awakening
Trauma ICU
Less oversedation
Mixed ICU
More accurate sedation, earlier extubation
Medical ICU
Fewer ventilator days
Hall et al 2001
Carson et al 2006
Ely EW, et al. Chest. 2012;142(2);287-289.
Benzodiazepines vs Propofol
Study/Year
Population
Outcome Improved
Searle et al/1997
Cardiac surgery
None
Kress et al/2000
Medical ICU
None
Cardiac surgery
None
…
…
Trials finding no differences in outcomes
Huey-Ling et al/2008
Trials finding better outcomes with BZD
None
Ely EW, et al. Chest. 2012;142(2);287-289.
Benzodiazepines vs Dexmedetomidine
Study/Year
Population
Outcome Improved
Trials finding better outcomes with dex
Pandharipande et al/2007
Mixed ICU
Riker et al/2009
Mixed ICU
Ruokonen et al/2009
Mixed ICU
Maldonado et al/2009
Cardiac surgery
Esmaoglu et al/2009
Eclampsia
Dasta et al/2010
Mixed ICU
Jakob et al/2012
General ICU
More accurate sedation,
more delirium/coma-free
days
Lower prevalence of
delirium, earlier extubation
Shorter duration of
mechanical ventilation
Lower incidence and
duration of delirium
Shorter ICU length of stay
Lower ICU costs
Lighter sedation, fewer
ventilation days
Trials finding no differences in outcomes
None
…
…
…
…
Trials finding better outcomes with the BZD
None
Ely EW, et al. Chest. 2012;142(2);287-289.
MENDS: Dexmedetomidine vs Lorazepam
• Double-blind RCT of dex (0.15–1.5 mcg/kg/hr) vs lorazepam (1–10 mg/hr)
• Titrated to sedation goal (using RASS) established by ICU team
• Dexmedetomidine resulted in more time spent within sedation goals than
lorazepam (P = 0.04). Differences in 28-day mortality and delirium-free days were
not significant
• While incidence of HR ≤ 60 was greater with Dex (17 vs 4%, P = 0.03, the
incidence of HR ≤ 40 was not different (2 vs 2%)
Pandharipande PP, et al. JAMA. 2007;298(22) 2644-2653.
SEDCOM: Dexmedetomidine vs Midazolam
• Double-blind, randomized, multicenter trial comparing long-term (> 24 hr)
dexmedetomidine (n = 244) with midazolam (n = 122)
• Sedatives (DEX 0.2-1.4 μg/kg/hr or MDZ 0.02-0.1 mg/kg/hr) titrated for light
sedation (RASS -2 to +1), administered up to 30 days
• All patients underwent daily arousal assessments and drug titration Q 4 hours
Midazolam
(N = 122)
DEX
(N = 244)
PValue
Time in target sedation range, %
75.1
77.3
0.18
Duration of sedation, days
4.1
3.5
0.01
Time to extubation, days
5.6
3.7
0.01
Patients receiving open-label, %
midazolam
49
63
0.02
18.9
42.2
0.001
0.8
4.9
0.07
Outcome
Bradycardia, %
Bradycardia requiring intervention, %
Riker RR, et al. JAMA. 2009;301(5):489-499.
MIDEX and PRODEX Trials
MIDEX
PRODEX
•
2 phase 3 multicenter RCTs
•
Dexmedetomidine vs midazolam (MDZ) or propofol
•
~ 250 patients per arm, MV > 24 hours
•
Daily interruption of sedation, SBT
Arm
Time at
RASS
Target
Median
MV, h
ICU
LOS, h
Arousability
(total VAS)
Hypo
tension
Brady
cardia
MDZ
56.6%
164
243
30.0
11.6%
5.2
Dex
60.7%
123
211
49.7
20.6%
14.2
P-value
0.15
0.03
< 0.001
0.007
< 0.001
Propofol
64.7%
118
185
40.1
13.4%
10.1%
Dex
64.6%
97
164
51.3
13.0%
13%
0.97
0.24
P-value
Jakob SM, et al. JAMA. 2012;307:1151-1160.
< 0.001
Pain, Agitation, and Delirium
Are Interrelated
Delirium
Barr J, et al. Crit Care Med. 2013;41:263-306.
Cardinal Symptoms of Delirium and Coma
Morandi A, et al. Intensive Care Med. 2008;34:1907-1915.
ICU Delirium
• Develops in ~2/3 of critically ill patients
• Hypoactive or mixed forms most common
• Increased risk
– Benzodiazepines
– Extended ventilation
– Immobility
• Associated with weakness
• Undiagnosed in up to 72%
of cases
Vasilevskis EE, et al. Chest. 2010;138(5):1224-1233.
Sequelae of Delirium
During the
ICU/Hospital Stay
After Hospital
Discharge
• Increased mortality
• Longer intubation time
• Average 10 additional days in hospital
• Higher costs of care
• Increased mortality
• Development of dementia
• Long-term cognitive impairment
• Requirement for care in chronic care facility
• Decreased functional status at 6 months
Bruno JJ, Warren ML. Crit Care Nurs Clin North Am. 2010;22(2):161-178.
Shehabi Y, et al. Crit Care Med. 2010;38(12):2311-2318.
Rockwood K, et al. Age Ageing. 1999;28(6):551-556.
Jackson JC, et al. Neuropsychol Rev. 2004;14:87-98.
Nelson JE, et al. Arch Intern Med. 2006;166:1993-1999.
Delirium Duration and Mortality
Kaplan-Meier Survival Curve
P < 0.001
Each day of delirium in the ICU increases the hazard of mortality by 10%
Pisani MA. Am J Respir Crit Care Med. 2009;180:1092-1097.
Delirium After Stroke
•
•
•
Increased 12-month mortality risk
Stroke patients +/- delirium
Will delirium treatment change outcome?
Shi Q, et al. Stroke. 2012;43(3):645-649.
Worse Long-term
Cognitive Performance
• Duration of delirium was an independent
predictor of cognitive impairment
– An increase from 1 day of delirium to 5 days was
associated with nearly a 5-point decline in cognitive
battery scores
• Patient testimony
“One quite literally loses one’s grip on what is true and
what is false because the true and the false are
mixed together in a mess of experience.”
Girard TD, et al. Crit Care Med. 2010;38:1513-1520.
Misak CJ. Am J Respir Crit Care Med. 2004;170(4):357-359.
PAD Delirium Assessment
Statements
• In adult ICU patients, delirium is associated
with
– Increased mortality (A)
– Prolonged ICU and hospital LOS (A)
– Development of post-ICU cognitive impairment (B)
• Routine monitoring of delirium in adult ICU
patients is feasible in clinical practice (B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Delirium Assessment
Recommendations
• We recommend routine monitoring of delirium
in adult ICU patients (+1B)
• The CAM-ICU and the ICDSC are the most
valid and reliable delirium monitoring tools in
adult ICU patients (A)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Confusion Assessment Method (CAM-ICU)
Ely EW, et al. Crit Care Med. 2001;29:1370-1379.
Ely EW, et al. JAMA. 2001;286:2703-2710.
http://www.mc.vanderbilt.edu/icudelirium/assessment.html. Accessed January 2013.
Intensive Care Delirium
Screening Checklist
1. Altered level of consciousness
2. Inattention
3. Disorientation
4. Hallucinations
5. Psychomotor agitation or retardation
6. Inappropriate speech
7. Sleep/wake cycle disturbances
8. Symptom fluctuation
Score 1 point for each component present during shift
• Score of 1-3 = Subsyndromal Delirium
• Score of ≥ 4 = Delirium
Bergeron N, et al. Intensive Care Med. 2001;27:859-864.
Ouimet S, et al. Intensive Care Med. 2007;33:1007-1013.
Pediatric CAM-ICU
146 paired assessments
Mean age = 12.2 years
2 critical care clinicians vs. pediatric
psychiatrist
Sensitivity = 83% (95% CI, 66-93%)
Specificity = 99% (95% CI, 95-100%)
Inter-rater reliability κ = 0.96
Smith HA, et al. Crit Care Med. 2011;39(1):150-157.
PAD Treatment of Delirium
Recommendations
• There is no published evidence that treatment
with haloperidol reduces the duration of
delirium in adult ICU patients (No evidence)
• Atypical antipsychotics may reduce the
duration of delirium in adult ICU patients (C)
• We do not recommend administering
rivastigmine to reduce the duration of delirium
in ICU patients (–1B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Quetiapine vs. Placebo
Delirium +
Haloperidol PRN
Quetiapine (n = 18)
•
•
•
•
•
•
Placebo (n = 18)
Randomized, double-blind, placebo-controlled
Multisite (3 centers)
36 ICU patients
PO delivery of study drug
Quetiapine dose: 50-200 mg q12h
Primary outcome: time to first resolution of delirium
(ie, first 12-hour period when ICDSC ≤ 3)
Devlin JW, et al. Crit Care Med. 2010;38(2):419-427.
Proportion of Patients with Delirium
Patients with First Resolution of Delirium
Log-Rank
P = 0.001
Placebo
Quetiapine
Day During Study Drug Administration
Quetiapine added to as-needed haloperidol results in faster delirium resolution,
less agitation, and a greater rate of transfer to home or rehabilitation.
Devlin JW, et al. Crit Care Med. 2010;38:419-427.
The MIND Study
Haloperidol
Ziprasidone
n = 35
•
•
•
•
•
•
Placebo
n = 32
Modifying the INcidence of Delirium (MIND)
Randomized and double-blind
Multisite (6 centers)
103 MV patients
PO/IM delivery of study drug
Doses
– Haloperidol
– Ziprasidone
5-20 mg
40-160 mg
Girard TD, et al. Crit Care Med. 2010;38(2):428-437.
n = 36
MIND Study Results
Haloperidol
(n = 35)
Ziprasidone
(n = 32)
Placebo
(n = 36)
P
Delirium/coma-free days
14 [6-18]
15 [9-18]
12.5 [2-17]
0.66
Ventilator-free days
8 [0-15]
12 [0-19]
12 [0-23]
0.25
12 [5-16]
10 [4-14]
7 [5-12]
0.70
14 [9-NA†]
14 [9-NA†]
15 [9-NA†]
0.68
11
13
17
0.81
0 [0-0.2]
0 [0-0]
0 [0-0]
0.56
27 [25-31]
28 [24-35]
33 [23-36]
0.50
Outcome*
Length of stay
ICU
Hospital
Mortality, %
Extrapyramidal side effects
Daily EPS score
Cognition at discharge
Mean T-score
*Median [interquartile range] except as noted
Girard TD, et al. Crit Care Med. 2010;38(2):428-437.
Haloperidol Prophylaxis
• Patients
– Predicted risk for delirium of ≥ 50%
– History of alcohol abuse or dementia
• Treatment
– Haloperidol 1 mg/8 hrs
– Historical and parallel controls
• Endpoints
– Delirium incidence
– Delirium free days without coma
– 28-day mortality
van den Boogaard M, et al. Crit Care. 2013;17(1):R9.
n = 177
n = 299
Haloperidol Prophylaxis
van den Boogaard M, et al. Crit Care. 2013;17(1):R9.
Haloperidol Prophylaxis: Survival
van den Boogaard M, et al. Crit Care. 2013;17(1):R9.
Haloperidol Prophylaxis Decreases Delirium
All
Daily Prevalence of Delirium, (%)
Haloperidol
Cumulative %
Incidence of Delirium, (%)
Type of Surgery
IntraOthers
Abdominal
Placebo
Log-rank P = 0.021
Time to Onset of Delirium, days
Haloperidol
Placebo
Age
APACHE-2
Intubated (%)
Days After Surgery
Wang W, et al. Crit Care Med. 2012;40:812-820.
Haloperidol
(n = 229)
Placebo
(n = 228)
Pvalue
74.0 ± 5.8
74.4 ± 7.0
0.50
8.7± 3.0
8.6 ± 2.8
0.58
78.6
77.6
0.80
Rivastigmine for Delirium?
Survival (%)
• FDA approved for dementia of Alzheimer’s or
Parkinson’s
• Cholinesterase inhibitor
• Result
− Mortality (vs placebo): 22% vs 8%, P = 0.07
− Delirium (vs placebo): 5 vs 3 days, P = 0.06
• Conclusion:
Time (days after inclusion)
− Need RCTs for delirium as endpoint
− Don’t use rivastigmine for ICU delirium
http://www.accessdata.fda.gov. Accessed March 2013.
Van Eijk MM, et al. Lancet. 2010;376(9755):1829-1837.
PAD Management of Delirium
Recommendation
• We recommend performing early mobilization of
adult ICU patients whenever feasible to reduce
the incidence and duration of delirium (+1B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
Early Mobilization
Trial Design
• 104 sedated patients with daily interruption
–
Early exercise and mobilization (PT & OT; intervention; n = 49)
–
PT & OT as ordered by the primary care team (control; n = 55)
• Primary endpoint: number of patients returning to independent
functional status at hospital discharge
–
Ability to perform 6 activities of daily living
–
Ability to walk independently
• Assessors blinded to treatment assignment
• Secondary endpoints
–
Number of hospital days with delirium
–
Ventilator-free days during the first 28 days of hospital stay
–
Length of stay in the ICU and in hospital
Schweickert WD, et al. Lancet. 2009;373:1874-1882.
Perform Safety Screen First
•
•
•
•
•
•
Patient responds to verbal stimulation (ie, RASS ≥ -3)*
FIO2 ≤ 0.6
PEEP ≤ 10 cmH2O
No  dose of any vasopressor infusion for at least 2 hours
No evidence of active myocardial ischemia (24 hrs)
No arrhythmia requiring the administration of new antiarrhythmic
agent (24 hrs)
Pass
Exercise/Mobility
Therapy
Schweickert WD, et al. Lancet. 2009;373:1874-1882.
Fail
Too Ill for
Exercise/Mobility
*Range of motion may be
started in comatose patients,
but not considered Early
Exercise/Mobility
Early Mobilization Protocol: Result
• Return to independent functional status at discharge
– 59% in intervention group
– 35% in control group (P = 0.02)
Schweickert WD, et al. Lancet. 2009;373:1874-1882.
Early PT and OT in
Mechanically Ventilated ICU Patients
All Patients
16
14
Median Time (days)
P = 0.93
PT/OT with DSI n = 49
DSI alone n = 55
13.5
12
P = 0.08
10
8
P = 0.02
7.9
P = 0.02
6.1
6
4
4
2
12.9
5.9
3.4
2
0
Duration of ICU
Delirium
Mechanical
Ventilation
Schweickert WD, et al. Lancet. 2009;373(9678):1874-1882.
ICU LOS
Hospital LOS
Protocol for Early Mobility Therapy
Acute Respiratory Failure Patients
Morris PE, et al. Crit Care Med. 2008;36(8):2238-2243.
Early Mobility Therapy Results
Primary Endpoint: more protocol patients received PT
than did usual care (80% vs. 47%, P ≤ 0.001)
Usual Care*
(n = 135)
Protocol*
(n = 145)
P-Value
Days to first out of bed
11.3
5.0
0.001
Ventilator days
10.2
8.8
0.163
ICU LOS days
6.9
5.5
0.025
Hospital LOS days
14.5
11.2
0.006
*Values adjusted for BMI, Acute Physiology and Chronic
Health Evaluation II, and vasopressors
Morris PE, et al. Crit Care Med. 2008;36(8):2238-2243.
Helpful Approach to
Delirium Management
1. Stop
2. THINK
3. Lastly medicate
Stop and THINK
Do any meds need to be
stopped or lowered?
• Especially consider
sedatives
Toxic Situations
• Is patient on minimal
amount necessary?
Hypoxemia
Infection/sepsis (nosocomial)
Immobilization
Nonpharm interventions
– Daily sedation cessation
– Targeted sedation plan
• Do sedatives need to be
changed?
• CHF, shock, dehydration
• Deliriogenic meds (tight titration)
• New organ failure (liver/kidney)
• Hearing aids, glasses, reorient,
sleep protocols, music, noise
control, ambulation
K+ or electrolyte problems
PAD Team Recommendation
• We recommend using an interdisciplinary ICU
team approach that includes provider education,
pre-printed and/or computerized protocols and
order forms, and quality ICU rounds checklists to
facilitate the use of pain, agitation, and delirium
management guidelines or protocols in adult
ICUs (+1B)
Barr J, et al. Crit Care Med. 2013;41:263-306.
PAD Interdisciplinary Team
Pharmacy
Champion
Physical
Therapy
Champion
RT
Champion
Hospital
Administrators
RN
Champion
MD
Champion
Courtesy J Barr, MD
Family
Integrated
Approach to
PAD
Patient
Introducing ABCDE in the ICU:
Practical Advice for
Implementing Protocols
ABCDE Bundle
Morandi A, et al. Curr Opin Crit Care. 2011;17:43-49.
What Is the ABCDE Bundle?
We Need Coordinated Care
• Many tasks and demands on critical care staff
• Great need to align and support the people,
processes, and technology already in ICUs
• ABCDE bundle is multicomponent,
interdependent, and designed to:
– Improve clinical team collaboration
– Standardize care processes
– Break the cycle of oversedation and prolonged
ventilation
Vasilevskis EE, et al. Chest. 2010;138(5):1224-1233.
Awake and Breathing Coordination
↓ Duration of mechanical ventilation
↓ Duration of coma
↓ Mortality
Choose light sedation & avoid benzos
↓ Duration of mechanical ventilation
↓ Mortality
↓ Delirium
Delirium screening
↓ Delirium detection
Early Mobility & Environment
↓ Duration of delirium
↓ Disability
↓ ICU Length of Stay
↓ Rehospitalization/Mortality
Morandi A, et al. Curr Opin Crit Care. 2011;17(1):43-49.
Vasilevskis EE, et al. Crit Care Med. 2010;38(10 Suppl):S683-691.
Vasilevskis EE, et al. Chest. 2010;138(5):1224-1233.
The PAD Road Map
A Script for Reporting Pain, Agitation and
Delirium in Multidisciplinary Rounds
Investigate
Where is the patient
going?
Where is the patient
now?
How did we get there?
Discussion Points
Report
Target scores:
• Agitation/Sedation
• Pain Level (some chronic pain patients may never be pain free)
Current assessment scores:
• Pain: NRS/CPOT/BPS
• Agitation/Sedation: RASS/SAS
• Delirium: CAM-ICU/ICDSC
List medications patient is currently receiving or has received in the
past shift for pain, agitation and delirium.
•
•
•
Do the goals need to be adjusted?
Do these assessments represent any change in the patient’s
underlying pathology/illness?
Do any medications need discontinued or reduced?
Do any medications need to be started?
Balas MC, et al. Crit Care Nurse. 2012;32:35-47.
General Barriers to
Changing the ICU Culture
• Tendency to maintain the status quo
• Resistance of independent groups to alter their
behaviors and relinquish some autonomy
• Perceived disproportionality of outcomes from the
proposed change to the efforts required for change
• Lack of significant prioritization
• Insufficient personal accountability for completing
change
• Inadequate knowledge about clinical outcomes
Hatler CW, et al. Am J Crit Care. 2006;15:549-555.
Quality Improvement Project:
Implementing ABCDE
• Multidisciplinary team focused on reducing heavy
sedation, using SAT-SBT protocol and increasing
MICU staffing to include full-time physical and
occupational therapists with new consultation
guidelines
• Results:
–
–
–
–
–
Delirium decreased
Sedation use decreased
Physical mobility improvement
Decrease hospital length of stay
Increased MICU admissions
Needham DM, et al. Arch Phys Med Rehabil. 2010;91(4):536-542.
Needham DM, et al. Top Stroke Rehabil. 2010;17(4):271-281.
QI Program for Changing the ICU Culture
Summarize the Evidence
Identify Local Barriers to
Implementation
Measure Performance
Ensure All Patients
Receive the Interventions
Needham DM, et al. Top Stroke Rehabil. 2010;17(4):271-281.
Key Steps for Effective Change
• Linking effective care processes with hospital and
long-term patient outcomes
• Creating a strategy to improve teamwork and
collaboration
• Creating a process for early mobilization
• Recognizing that current practice patterns may
interfere with mobility
• Agreeing on a need to change
• Identification of a local champion
Wheelan SA, et al. Am J Crit Care. 2003;12:527-534.
Durbin CG. Crit Care Med. 2006;34(3 Suppl):S12-S17.
Closing the Gap Between the PAD
Guidelines and ICU Practice
• Multifaceted, interdisciplinary approach
• Adapt to local practice patterns and resource
availability
– Institution-specific protocols and order sets
•
•
•
•
•
•
•
Education
Engagement of local thought leaders
Point-of-use reminders
Decision-support tools
Caregiver-specific practice feedback
Continuous protocol evaluation and modification
Integration into electronic information systems
Barr J, et al. Crit Care Med. 2013;41:263-306.
Conclusions
• PAD guidelines provide evidence-based statements
and recommendations
• Use validated scales to assess pain, agitation, and
delirium in the ICU
• Analgosedation has been shown to improve outcomes;
consider sedation only if necessary
Conclusions
• Target a light level of sedation
• Titrate all sedative medications using a validated
assessment tool to keep patients comfortable and
arousable if possible
• Use of benzodiazepines should be minimized
• Consider nonpharmacological management of
delirium and reduce exposure to risk factors
• Early mobility in ICU patients decreases delirium and
improves functional outcomes at discharge
• The ABCDE bundle is a model for using the PAD
recommendations
Optional Slides
ICU Sedation: The Balancing Act
Patient Comfort
and Ventilatory Optimization
Oversedation
Undersedation
• Patient recall
• Device removal
• Ineffectual mechanical ventilation
• Initiation of neuromuscular blockade
• Myocardial or cerebral ischemia
• Decreased family satisfaction w/ care
Jacobi J, et al. Crit Care Med. 2002;30:119-141.
G
O
A
L
• Prolonged mechanical ventilation
• Increase length of stay
• Increased risk of complications
- Ventilator-associated pneumonia
• Increased diagnostic testing
• Inability to evaluate for delirium
Improper Sedation
30.6%
•
Continuous sedation carries the risks
associated with oversedation and may
increase the duration of mechanical
ventilation (MV)1
•
MV patients accrue significantly more
cost during their ICU stay than non-MV
patients2
15.4%
– $31,574 versus $12,931, P < 0.001
54.0%
•
Sedation should be titrated to achieve a
cooperative patient and daily wake-up,
a JC requirement1,2
Undersedated3
Oversedated
On Target
1. Kress JP, et al. N Engl J Med. 2000;342:1471-1477.
2. Dasta JF, et al. Crit Care Med. 2005;33:1266-1271.
3. Kaplan LJ, Bailey H. Crit Care. 2000;4(suppl 1):P190.
Oversedation in the ICU is Common
60
50
40
30
Sedation Assessment
Completed
20
Deep Sedation
SAS </=2)
(e.g.
10
0
Day 2
(n = 1,360)
Day 4
(n = 1,256)
• N = 274 MICU patients
• 32% unarousable
• 21% no spontaneous motor
activity
Payen JF et al. Anesthesiology. 2007;106:687-695.
Weinert CR, et al. Crit Care Med. 2007;35:393-401.
• Little variation over 24 hours
in LOC, motor activity, or
drug dose given
• Only 2.6% of RNs thought
“oversedated”
.
Characteristics of an Ideal Sedative
• Rapid onset of action allows rapid recovery after
discontinuation
• Effective at providing adequate sedation with
predictable dose response
• Easy to administer
• Lack of drug accumulation
• Few adverse effects
• Minimal adverse interactions with other drugs
• Cost-effective
• Promotes natural sleep
Ostermann ME, et al. JAMA. 2000;283:1451-1459.
Jacobi J, et al. Crit Care Med. 2002;30:119-141.
Dasta JF, et al. Pharmacother. 2006;26:798-805.
Nelson LE, et al. Anesthesiol. 2003;98:428-436.
Consider Patient Comorbidities When
Choosing a Sedation Regimen
•
•
•
•
•
•
•
Chronic pain
Organ dysfunction
CV instability
Substance withdrawal
Respiratory insufficiency
Obesity
Obstructive sleep apnea
Delirium
Nonpharmacologic Interventions
•
•
•
•
•
1.
Early mobility1
Environmental changes (eg, noise reduction)
Sensory aids (eg, hearing aids, glasses)
Reorientation and stimulation
Sleep preservation and enhancement
Schweickert WD, et al. Lancet. 2009;373:1874-1882.
Sleep Abnormalities in the ICU
• More time in light sleep
• Less time in deep sleep
• More sleep fragmentation
There is little evidence that
sedatives in the ICU restore
normal sleep
Friese R. Crit Care Med. 2008;36:697-705.
Weinhouse GL, Watson PL. Crit Care Clin. 2009;25:539-549.
Processes:
What Does Your Team Have in Place?
•
•
•
•
What do you do well? (ABCDEs)
Where do you need help?
What is in motion?
What has not started?
Developing Support for Change
Research Results
Education of All Providers
Personal Experience
Patient Feedback
Support for Change
Early Mobility Therapy Results
Usual Care
(n = 135)
Protocol
(n = 145)
P-Value
Days to first out of bed
11.3
5.0
0.001
Ventilator days
10.2
8.8
0.163
ICU LOS days
6.9
5.5
0.025
Hospital LOS days
14.5
11.2
0.006
Morris PE, et al. Crit Care Med. 2008;36(8):2238-2243.