Controlling ICU Agitation; Context Determines Strategy Ways to Facilitate Knowledge Transfer
1. Controlling ICU Agitation; Context Determines Strategy Gil Fraser, PharmD, FCCM
Ways to Facilitate Knowledge Transfer Critical Care, MMC
Professor
UVM College of Medicine
fraseg@mmc.org
2. Some Things Are Easy
• Job(s) 1 = Patient comfort, patient and care-giver safety,
maintenance of oxygenation and perfusion
• Assume accumulation of parent drug (lorazepam and
midazolam) and active metabolite (midazolam) with
prolonged use
• Don’t complicate things
– Avoid deliriogenic drugs
– Avoid propofol and dex with high dose vasoactive therapy
• Initiate home medications when appropriate
6. Facilitating Rapid Knowledge
Transfer to the Bedside
• Options
– Use clinical practice guideline as a model
– Create “bundles” for implementing essential
components of practice guidelines
– Develop protocols for managing pain/agitation/delirium
– Offer real time clinical decision support
• ADAPT then ADOPT previously developed tools
8. Clinical Practice Guidelines (CPG)
The Temptation of Simplicity
Appreciating the Thinness of Ice
• Temptation:
– Defer to identified experts for objective evaluation of
issues and controversies
– Use their simplified algorithms for management strategies
• Management decisions should be
– Individualized within the context of the treated patient
• Problem:
– Rush to incorporate vulnerable data into CPGs and quality
improvement efforts
9. What to Do??
No desire to cast aspersions
on CPGs or bundles
Understand their limitations
Do not blindly accept all
recommendations
Base clinical decisions on
individual patient context
Use most recent rigorous
data to assess risk:benefit
10. Your Job for Today
• Value protocolized pain/agitation/delirium
management
• Understand new data that redefine risks and
benefits of drug management strategies
• Evaluate various strategies for beside
implementation of best practice
• Become completely confused about ICU
delirium—defer to Dr. Devlin
11. Importance of Protocolization
• Helps bring “best practice” to the bedside
• Limits practice variation
• Reduces delays in management
– Encourages regular assessment of pain,
agitation, delirium
– Facilitates pharmacologic interventions: drug
choice, dosing, titration
12. Surveys of ICU Sedation Practices
• In the US, 64% use protocol, with 40%
using daily interruption.
• In Canada, 29% use protocol, 40% use daily
interruption.
• Adherence to protocols ~50%
13. Why Are Protocols Not Used?
ICU patients and protocols are too complex
15. Intermittent
Preprocedural Anxiety Delirium
Sustained
SAS 3 or 4 SAS 1 or 2
•Mechanically Ventilated •Frequent Neurologic Evaluation
is Necessary
•High Dose Vasopressors and
Mechanically Ventilated •Frequent Neurologic Evaluation
Not Necessary
•Not Mechanically Ventilated
•High Dose Vasopressors and
Not Mechanically Ventilated •GABA Agonist Withdrawal
•Delirium
•Renal Disease
Over 150
•Liver Disease possible
•Refractory Agitation
clinical scenarios
16. Why Are Protocols Not Used?
• Too complex
• Determination of adequacy of sedation
remains subjective
– How deep is too deep?
– Is deep just right?
17. Deep Sedation
• Greater than 40% patients are more
deeply sedated than desired
• Drug-induced coma present during
32% of patient evaluations
– Yet only 2.6% rated as “oversedated”
Weinert. CCM 2007:35:393
Does This
Payen. Anesthesiology 2007:106:687
Matter?
Martin. ICM 2006; 32:1137
18. Non- Factors Supporting Deep
evidence Sedation = Humane Treatment
based
• Lying in a sleep-like state without motor activity =
comfortable patient
• The ICU experience is inhumane
– The ability to form factual memories is cruel
• Could even lead to PTSD
– Amnesia of the ICU experience is desired
19. Avoiding Coma Impacts Outcomes
What about long-term
outcomes? Fraser and Riker. CCM 2007; 35:635
20. Depth of Sedation?
Periscope depth
“PTSD was highest in
the middle level of
wakefulness and lowest
when least aroused or
the most awake.’
Griffiths. CCM 2008; 36:945
To the ocean floor
22. Pain and/or Discomfort Should ALWAYS
Be Considered a Cause of ICU Agitation
• “Mundane/routine” aspects of ICU care are the most
troublesome for patients
1990
63% remembered moderate to severe pain
Puntillo. Heart Lung 1990; 19:526
2007
50% remembered unmet analgesic needs
Gelinas. Intensive Crit Care Nurs 2007; 23:298
There has been little progress despite 17 years of focused
attention on pain as an important clinical issue
23. New Paradigm: Analgesia-based “Sedation”
Crit Care 2005; 9: R200 , Crit Care 2004; 8:R1, Anesthesiology 2004; 101:640, Br J Anaesth 2007; 98:76,
ICM 2009; 35:291
• Also known as analgosedation or analgesia-
first (A-1) sedation
• Acknowledges that discomfort is a common
cause of agitation
• Continuous infusion remifentanil or
fentanyl
– Rapid onset and offset
• ~ 50% will require additional sedation
24. Redefining the Roles of
Available Sedative Agents
• A very selective review of data
– Dexmedetomidine
– Benzodiazepines
– Propofol
25.
26. Dex Dose, Duration, and Downsides
61% required more than 0.7mcg/kg/h
Duration up to 15 days
Riker. JAMA. 2009; 301:489-99.
27. Time to Successful Extubation ≠
Shorter ICU Stay
Absolute
Time to Dexmedetomidine Midazolam P
Reduction
Extubation (n=244) (n=122) value
(%, days)
Median 3.7 days 5.6 days 32.2%
0.01
(95%CI) (3.1 – 4.0) (4.6-5.9) 1.9 days
Absolute
ICU LOS Dexmedetomidine Midazolam P
Reduction
days (N=244) (N=122) value
(%), days
Median 5.9 days 7.6 days 22.3%
0.24
(95%CI) (5.7 - 7.0) (6.7 – 8.6) 1.7 d
Riker. JAMA. 2009; 301:489-99.
28. Pearls For The Use of Dex
• Do not use loading dose
• Expand dosing range to 0.1-1.4mcg/kg/hr
• Expand permissible treatment duration
>24h
• Anticipate dex-induced hemodynamic
instability and bradycardia
• Combine with other sedative or analgesic
agents as needed
• Transition to clonidine
30. ICU Costs Comparing
Dexmedetomidine vs Midazolam
It’s a Matter of Time and Ability to Discharge
• % time at target sedation range: midazolam =
dexmedetomidine (JAMA 2009; 30:489)
• Blinded evaluation of costs of care
– ICU length of stay, time on vent, drug costs, and cost
of adverse reactions using cost minimization analysis
• Median savings: dex vs midazolam
– Median drug costs: Dex = $1826, Midazolam = $60
– Primary drivers of cost savings = ICU stay and time on
the ventilator; ~ $6K and $3K respectively
– $9,679 (95% CI = $2,314-17,045, p = .01)
Dasta. CCM 2010 epub ahead of print
32. Sedative Infusions:
Propofol >> Benzodiazepines
Wunsch. CCM 2009 (Project IMPACT)
50% receive continuous Propofol infusion use
infusion sedation; most increasing, not lorazepam
propofol, 30% = benzo
33. Benzodiazepine Concerns: Delirium
Benzodiazepines
• Independent risk
factor for development
of delirium
• Especially if used to
induce even brief
periods of coma
Pandharipande. Anesthesiology 2006; 104:21 and J Trauma 2008; 65:34
Ouimet. ICM 2007; 33:66
34. Lorazepam as a Source of Propylene Glycol (PG)
• PG toxicity
– Metabolic acidosis,
hyperosmolality, acute
kidney injury
– Osmol gap of >10-12
may serve as surrogate
for propylene glycol
accumulation in
patients receiving >
1mg/kg/d lorazepam 80% of a vial of lorazepam is PG
Yahwak. Pharmacotherapy 2008: 28:984
36. Propofol: Concerns
• NO analgesia!
– 25% receive opiate infusion while on propofol vs 66% with benzo
infusions Wunsch 2009 CCM
• Hypotension
• Hypertriglyceridemia; lipid source (1.1 kcal/ml)
– Monitor triglycerides twice weekly
• Respiratory depression
• Propofol Infusion Syndrome (PRIS)--rare, but often fatal
• Asystole/bradycardia, cardiovascular collapse, rhabdomyolysis, and
severe metabolic acidosis
• Caution should be exercised at doses >80mcg/kg/min for more than
48 hours—also seen at lower doses within a few hours of initiation
• Most commonly reported in patients also receiving catecholamines
and/or steroids
• Discontinue propofol in the setting of unexplained bradycardia or
metabolic acidosis
37. PRIS: More Common Than Thought?
Iyer. CCM 2009; 37 epub
• 11 year review of refractory status epilepticus pts
• Outcomes in the propofol treated group (N = 31)
– PRIS features occurred in 39%
• 20% of this cohort (N= 3) developed life-threatening cardiac
arrest ----2 died.
– Peak propofol dose in these patients = 141 vs 60mcg/kg/min in
noncardiac arrest PRIS patients.
• None of the PRIS features occurred in patients
who did not receive propofol
38. ICU Agitation Management
• Homemade or canned?
– Doesn’t matter as long as the essential ingredients are
included
• Management strategies are context/patient specific
– Probable reason for agitation
• Pain
• Withdrawal
• Anxiety
• Delirium
– Other modifiers
• Intubated vs not
• Short vs long-term sedation
• Organ dysfunction: heart, brain, liver, and kidney
• Deep vs light
39. Tools to Facilitate Bedside
Application
• Order sets based on agreed-upon institution
specific protocols
• Real-time clinical decision support
• Bundles imbedded with data feedback
40. Real-Time Clinical Decision
Support Tools
Once modifiers are selected, all orders appropriate for this
patient become available
41. Sedation, Analgesia, Delirium (SAD) Bundle
Make your own “bundle” with elements and metrics
1. Screen for the presence of pain, agitation, and delirium and
accurately document on a consistent basis
• How often is this documented each day?
2. Insure that measures to prevent and treat pain, agitation, and
delirium are a part of routine ICU care
• Adhere to institution-specific protocols
• Provide analgesia prior to procedure associated with pain
• Provide management < 0.5 h of discomfort or agitation
• Achieve sedation goal without coma or dangerous agitation
• Document strategies to prevent delirium each day
3. Monitor the effectiveness of these strategies
• % time spent in drug induced coma (SAS 1-2)
• % patients reporting moderate to severe pain
• % SBT stalled due to under and over-sedation
• ICU ventilator time (or ventilator-free time)
• % patients developing delirium during the ICU stay
Adapted from VISICU
42. Managing ICU Agitation
• Complexity is daunting
• Tempting to use guidelines/bundles blindly
– Adapt before you adopt
• Caregiver responsibilities
– Understand that short AND long-term ICU patient
outcomes are affected by therapeutic choice and
method of administration
• Institution responsibilities
– Provide adequate resources to implement systems that
guide “best practice” and allow for feedback to
caregivers
44. They Do Things Differently Down Under
Protocolization of ICU Sedation
• NA and European trials = outcomes
improve with protocolized sedation
• But NOT in Australia!
– Why? Is the strategy not beneficial?
– Do unique aspects of care impact results?
• 1:1 RN to patient ratio Bucknall. Crit Care Med 2008; 36:1444
Elliott. Intensive Care Med 2006; 32:1506
• RNs manage ventilator Fraser. Crit Care Med 2007; 35:635
• ICUs are “closed”
• Twice daily multidisciplinary rounding
• ANZ care model may impact outcomes
more than sedation protocolization
45. How Are Clinical Practice
Guidelines Used?
Purpose: GUIDE management of
complex clinical issues
Reality: PRESCRIBE management of
complex clinical issues
And what’s wrong with that?
46. Intellectual Whiplash
Intensive
Glucose Control Drotrecogin for
Sepsis
Factor VIIa for ACTH stim
ICH testing
Benzo Infusions
Steroids for For Long-term
Septic Shock Sedation
PPI Use for
SUP
Developing “Fad-Free” Guidelines
47. They Do Things Differently Down Under
Protocolization of ICU Sedation
• NA and European trials = improved
outcomes with protocolized sedation
• But NOT in Australia!
– Why? Is the strategy not beneficial?
– Do unique aspects of care impact results?
• 1:1 RN to patient ratio Bucknall. Crit Care Med 2008; 36:1444
Elliott. Intensive Care Med 2006; 32:1506
• RNs manage ventilator Fraser. Crit Care Med 2007; 35:635
• ICUs are “closed”
• Twice daily multidisciplinary rounding
• ANZ care model may impact outcomes
more than sedation protocolization
48. Often Boils Down to Competing Concerns
• Breathing vs comfort
• Hemodynamic stability vs comfort
• Amnesia vs memory formation
• Short-term control vs long-term sequelae
• Coma vs interactive and comfortable
• Side effect profiles: can we accept the risks
– Unusual, but deadly (propofol, remi) vs
common and manageable (dex) vs easily
monitored for and identifiable (opiates)
49. Unique Aspects of ICU Pain
• Pain relief usually involves some evasive action
– Avoidance response not possible in the ICU
• Incredibly common: 71% frequency
• Physiologic consequences
– Initiates stress response, hemodynamic derangement,
hyperglycemia, altered immune function and increases
oxygen consumption
• Psychological consequences
– Anxiety
– Delirium
– PTSD
50. Discomfort from Typical ICU Procedures
Mean Pain Intensity (0-10)
N = 6000 Adults Puntillo. Am J Crit Care. 2001;10:238
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Drain Wound Central Femoral
Turning Trach sx
removal care line sheath
Mean intensity 4.93 4.67 4.42 3.94 2.72 2.65
Less than 25% receive procedural pain
management
Puntillo. Am J Crit Care 2002;11:415, Payen. Anesthesiology 2007;
106:687
51. Screening Double-Blind Follow-Up
up to 96 h Treatment (X - 30 d) 48 h
DEX (Optional load; 0.2-1.4 g/kg/h)
Randomized
2:1 DEX:MDZ Daily Arousal & CAM-ICU
Day 0 Q 4 hr RASS -2 to +1
Nurse Assessment Q Shift
ETT MDZ (Optional load; 0.02-0.1 mg/kg/h)
Riker. JAMA. 2009; 301:489-99.
52. Dexmedetomidine: Indications and
Pharmacology
• Alpha-2-adrenergic agonist
– Has sedating, anxiolytic, and opiate sparing properties
– Permits patient awareness and responsiveness upon
stimulation
– Not indicated when deep sedation or amnesia is required
• Benefits
– Does not cause respiratory depression
– Decreases sympathetic activity
– Reduces shivering
– Shorter time on the ventilator and in the ICU with a lower
incidence of delirium when compared to benzodiazepine-
based sedation Pandharipande. JAMA. 2007;298:2644,
Riker. JAMA 2009; 301:489
53. Dexmedetomidine: Concerns
• Hypotension and bradycardia
– Avoid in patients dependent on sympathetic
tone for hemodynamic stability
• Excessive sedation
• Withdrawal tachycardia/hypertension
(theoretical risk)
54. Disadvantages of Benzodiazepines
• Oversedation and prolonged duration of
mechanical ventilation
– Titrate carefully and use daily wake ups
55. Propofol: Indications and
Pharmacodynamics
• Pharmacology: GABA agonist
• Pharmacokinetics/dynamics: onset 1-2 min,
duration 10 min
• Benefits
– Rapid onset & offset
• Allows easy dose titration to goal and facilitates daily sedation
evaluation
• When compared to benzodiazepines, results in shorter time on
mechanical ventilation and in the ICU Carson. CCM 2006;
34:1326
– Hypnotic and antiemetic
– Can be used for intractable seizures and elevated
intracranial pressures
56. Use of Sedative Infusions
Project IMPACT database
Wunsch. CCM 2009
• 174 U.S. ICUs during 2001-2007
• 50% of >100K mechanically ventilated
adult patients received sedative infusions
– Most patients received propofol
– Pure analgosedation = 10%
• A1 still has a long way to go for acceptance
– Benzodiazepine infusions still widely used
57. Bundles, Guidelines, and Marginal Data
• Sepsis bundle based on “Surviving Sepsis Campaign”
(the CPG with the strongest recommendations =
abandon futile therapy)
– Single center trials
• Early goal directed therapy and intensive glucose control
– Trials with limited scope
• Drotrecogin
– Trials that lacked meaningful endpoints
• Corticosteroids
Not endorsed by IDSA, ATS, ANZICS in part because of the
fear that components of the CPG will morph into performance
or quality measures. Hicks. Crit Care Resuscitation 2008; 10: 6
58. Dexmedetomidine: ICU Roles
• Consider using
– When respiratory function is tenuous
– When tachycardia and hypertension are present
– In conjunction with benzodiazepines for ethanol
withdrawal
• When is dex probably not indicated
– Severe vasodilatory or cardiac shock
– If you wouldn’t use beta blockade, you shouldn’t use
dex
