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Controlling ICU Agitation; Context Determines Strategy   Gil Fraser, PharmD, FCCM

Ways to Facilitate Knowledge Transfer  ...
Some Things Are Easy
• Job(s) 1 = Patient comfort, patient and care-giver safety,
  maintenance of oxygenation and perfusi...
It’s Gotten a Bit Complicated
ICU Sedation
Literature Citations vs Time
             2000
                                                              ...
Managing ICU Agitation Is NOT Easy




                  Maldonado. Crit Care Clin 2008;24:789
Facilitating Rapid Knowledge
       Transfer to the Bedside
• Options
  – Use clinical practice guideline as a model
  – C...
New Sedation Guidelines!

Will be published in
2010
Recommendations
per GRADE
methodology
Clinical Practice Guidelines (CPG)
    The Temptation of Simplicity
          Appreciating the Thinness of Ice
• Temptatio...
What to Do??
       No desire to cast aspersions
       on CPGs or bundles

       Understand their limitations

       Do...
Your Job for Today
• Value protocolized pain/agitation/delirium
  management
• Understand new data that redefine risks and...
Importance of Protocolization
• Helps bring “best practice” to the bedside
• Limits practice variation
• Reduces delays in...
Surveys of ICU Sedation Practices

• In the US, 64% use protocol, with 40%
  using daily interruption.
• In Canada, 29% us...
Why Are Protocols Not Used?

ICU patients and protocols are too complex
Sedation/Analgesia Algorithm for Ventilated Patients
Intermittent


        Preprocedural               Anxiety                    Delirium



                                ...
Why Are Protocols Not Used?

• Too complex
• Determination of adequacy of sedation
  remains subjective
  – How deep is to...
Deep Sedation
• Greater than 40% patients are more
  deeply sedated than desired
• Drug-induced coma present during
  32% ...
Non-          Factors Supporting Deep
evidence Sedation = Humane Treatment
 based
   • Lying in a sleep-like state without...
Avoiding Coma Impacts Outcomes




What about long-term
outcomes?              Fraser and Riker. CCM 2007; 35:635
Depth of Sedation?
                                         Periscope depth




“PTSD was highest in
  the middle level of...
ICU Pain and Discomfort
Pain and/or Discomfort Should ALWAYS
  Be Considered a Cause of ICU Agitation
 • “Mundane/routine” aspects of ICU care are...
New Paradigm: Analgesia-based “Sedation”
Crit Care 2005; 9: R200 , Crit Care 2004; 8:R1, Anesthesiology 2004; 101:640, Br ...
Redefining the Roles of
    Available Sedative Agents

• A very selective review of data
  – Dexmedetomidine
  – Benzodiaz...
Dex Dose, Duration, and Downsides
61% required more than 0.7mcg/kg/h
Duration up to 15 days




              Riker. JAMA....
Time to Successful Extubation ≠
             Shorter ICU Stay
                                                   Absolute
...
Pearls For The Use of Dex
• Do not use loading dose
• Expand dosing range to 0.1-1.4mcg/kg/hr
• Expand permissible treatme...
30 Minute Dexmedetomidine Dose
                      Adjustments Reduce Hypotension
Gerlach. J Crit Care 2009; 24:568
ICU Costs Comparing
    Dexmedetomidine vs Midazolam
It’s a Matter of Time and Ability to Discharge
• % time at target sed...
Benzodiazepines
Sedative Infusions:
     Propofol >> Benzodiazepines
               Wunsch. CCM 2009 (Project IMPACT)




50% receive cont...
Benzodiazepine Concerns: Delirium

Benzodiazepines
• Independent risk
  factor for development
  of delirium
• Especially ...
Lorazepam as a Source of Propylene Glycol (PG)


• PG toxicity
   – Metabolic acidosis,
     hyperosmolality, acute
     k...
Propofol
Propofol: Concerns
• NO analgesia!
   – 25% receive opiate infusion while on propofol vs 66% with benzo
     infusions Wun...
PRIS: More Common Than Thought?
                         Iyer. CCM 2009; 37 epub


• 11 year review of refractory status e...
ICU Agitation Management
• Homemade or canned?
   – Doesn’t matter as long as the essential ingredients are
     included
...
Tools to Facilitate Bedside
             Application

• Order sets based on agreed-upon institution
  specific protocols
•...
Real-Time Clinical Decision
                  Support Tools

Once modifiers are selected, all orders appropriate for this
...
Sedation, Analgesia, Delirium (SAD) Bundle

Make your own “bundle” with elements and metrics
   1.   Screen for the presen...
Managing ICU Agitation
• Complexity is daunting
• Tempting to use guidelines/bundles blindly
   – Adapt before you adopt
•...
Time to leave….. thanks for your attention




   fraseg@mmc.org
They Do Things Differently Down Under
          Protocolization of ICU Sedation
• NA and European trials = outcomes
  impr...
How Are Clinical Practice
        Guidelines Used?


Purpose: GUIDE management of
complex clinical issues
Reality: PRESCRI...
Intellectual Whiplash
                     Intensive
                  Glucose Control        Drotrecogin for
            ...
They Do Things Differently Down Under
          Protocolization of ICU Sedation
• NA and European trials = improved
  outc...
Often Boils Down to Competing Concerns

•   Breathing vs comfort
•   Hemodynamic stability vs comfort
•   Amnesia vs memor...
Unique Aspects of ICU Pain
• Pain relief usually involves some evasive action
   – Avoidance response not possible in the ...
Discomfort from Typical ICU Procedures
  Mean Pain Intensity (0-10)
  N = 6000 Adults Puntillo. Am J Crit Care. 2001;10:23...
Screening                Double-Blind                Follow-Up
   up to 96 h            Treatment (X - 30 d)             4...
Dexmedetomidine: Indications and
          Pharmacology
• Alpha-2-adrenergic agonist
   – Has sedating, anxiolytic, and op...
Dexmedetomidine: Concerns
• Hypotension and bradycardia
  – Avoid in patients dependent on sympathetic
    tone for hemody...
Disadvantages of Benzodiazepines

• Oversedation and prolonged duration of
  mechanical ventilation
  – Titrate carefully ...
Propofol: Indications and
           Pharmacodynamics
• Pharmacology: GABA agonist
• Pharmacokinetics/dynamics: onset 1-2 ...
Use of Sedative Infusions
               Project IMPACT database
                      Wunsch. CCM 2009

• 174 U.S. ICUs d...
Bundles, Guidelines, and Marginal Data

 • Sepsis bundle based on “Surviving Sepsis Campaign”
   (the CPG with the stronge...
Dexmedetomidine: ICU Roles
• Consider using
   – When respiratory function is tenuous
   – When tachycardia and hypertensi...
Controlling ICU Agitation; Context Determines Strategy Ways to Facilitate Knowledge Transfer
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Controlling ICU Agitation; Context Determines Strategy Ways to Facilitate Knowledge Transfer

  1. 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. 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
  3. 3. It’s Gotten a Bit Complicated
  4. 4. ICU Sedation Literature Citations vs Time 2000 1838 1800 1576 1600 1400 1200 Citations 991 1000 800 613 600 400 197 200 80 85 8 0 1960-9 1970-9 1980-4 1985-9 1990-4 1995-9 2000-4 2005-9
  5. 5. Managing ICU Agitation Is NOT Easy Maldonado. Crit Care Clin 2008;24:789
  6. 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
  7. 7. New Sedation Guidelines! Will be published in 2010 Recommendations per GRADE methodology
  8. 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. 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. 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. 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. 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. 13. Why Are Protocols Not Used? ICU patients and protocols are too complex
  14. 14. Sedation/Analgesia Algorithm for Ventilated Patients
  15. 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. 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. 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. 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. 19. Avoiding Coma Impacts Outcomes What about long-term outcomes? Fraser and Riker. CCM 2007; 35:635
  20. 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
  21. 21. ICU Pain and Discomfort
  22. 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. 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. 24. Redefining the Roles of Available Sedative Agents • A very selective review of data – Dexmedetomidine – Benzodiazepines – Propofol
  25. 25. Dex Dose, Duration, and Downsides 61% required more than 0.7mcg/kg/h Duration up to 15 days Riker. JAMA. 2009; 301:489-99.
  26. 26. 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.
  27. 27. 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
  28. 28. 30 Minute Dexmedetomidine Dose Adjustments Reduce Hypotension Gerlach. J Crit Care 2009; 24:568
  29. 29. 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
  30. 30. Benzodiazepines
  31. 31. Sedative Infusions: Propofol >> Benzodiazepines Wunsch. CCM 2009 (Project IMPACT) 50% receive continuous Propofol infusion use infusion sedation; most increasing, not lorazepam propofol, 30% = benzo
  32. 32. 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
  33. 33. 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
  34. 34. Propofol
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. Tools to Facilitate Bedside Application • Order sets based on agreed-upon institution specific protocols • Real-time clinical decision support • Bundles imbedded with data feedback
  39. 39. Real-Time Clinical Decision Support Tools Once modifiers are selected, all orders appropriate for this patient become available
  40. 40. 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
  41. 41. 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
  42. 42. Time to leave….. thanks for your attention fraseg@mmc.org
  43. 43. 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
  44. 44. 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?
  45. 45. 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
  46. 46. 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
  47. 47. 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)
  48. 48. 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
  49. 49. 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
  50. 50. 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.
  51. 51. 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
  52. 52. Dexmedetomidine: Concerns • Hypotension and bradycardia – Avoid in patients dependent on sympathetic tone for hemodynamic stability • Excessive sedation • Withdrawal tachycardia/hypertension (theoretical risk)
  53. 53. Disadvantages of Benzodiazepines • Oversedation and prolonged duration of mechanical ventilation – Titrate carefully and use daily wake ups
  54. 54. 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
  55. 55. 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
  56. 56. 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
  57. 57. 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

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