Controlling ICU Agitation; Context Determines Strategy

Ways to Facilitate Knowledge Transfer

Gil Fraser, PharmD, FCCM

Critical Care, MMC

Professor

UVM College of Medicine

fraseg@mmc.org

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• Don’t complicate things– Avoid deliriogenic drugs

– Avoid propofol and dex with high dose vasoactive therapy

• Initiate home medications when appropriate

It’s Gotten a Bit Complicated

ICU Sedation

Literature Citations vs Time

1576

1838

1400

1600

1800

2000

880 85

197

613

991

0

200

400

600

800

1000

1200

1400

1960-9 1970-9 1980-4 1985-9 1990-4 1995-9 2000-4 2005-9

Cit

ati

on

s

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

– Create “bundles” for implementing essential

components of practice guidelines

– Develop protocols for managing pain/agitation/delirium– Develop protocols for managing pain/agitation/delirium

– Offer real time clinical decision support

• ADAPT then ADOPT previously developed tools

New Sedation Guidelines!

Will be published in

2010

Recommendations Recommendations

per GRADE

methodology

Clinical Practice Guidelines (CPG)

The Temptation of SimplicityAppreciating 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• Management decisions should be– Individualized within the context of the treated patient

• Problem:– Rush to incorporate vulnerable data into CPGs and quality

improvement efforts

What to Do??No desire to cast aspersions on CPGs or bundles

Understand their limitations

Do not blindly accept all recommendationsDo not blindly accept all recommendations

Base clinical decisions on individual patient context

Use most recent rigorous data to assess risk:benefit

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 • Evaluate various strategies for beside implementation of best practice

• Become completely confused about ICU delirium—defer to Dr. Devlin

Importance of Protocolization

• Helps bring “best practice” to the bedside

• Limits practice variation

• Reduces delays in management

– Encourages regular assessment of pain, – Encourages regular assessment of pain,

agitation, delirium

– Facilitates pharmacologic interventions: drug

choice, dosing, titration

Surveys of ICU Sedation Practices

• In the US, 64% use protocol, with 40%

using daily interruption.

• In Canada, 29% use protocol, 40% use daily • In Canada, 29% use protocol, 40% use daily

interruption.

• Adherence to protocols ~50%

Why Are Protocols Not Used?

ICU patients and protocols are too complex

Sedation/Analgesia Algorithm for Ventilated Patients

Intermittent

Sustained

Preprocedural Anxiety Delirium

SAS 3 or 4 SAS 1 or 2

•Mechanically Ventilated •Frequent Neurologic Evaluation•Mechanically Ventilated

•High Dose Vasopressors and Mechanically Ventilated

•Not Mechanically Ventilated

•High Dose Vasopressors andNot Mechanically Ventilated

•Frequent Neurologic Evaluationis Necessary

•Frequent Neurologic EvaluationNot Necessary

•GABA Agonist Withdrawal•Delirium•Renal Disease•Liver Disease•Refractory Agitation

Over 150

possible

clinical scenarios

Why Are Protocols Not Used?

• Too complex

• Determination of adequacy of sedation

remains subjectiveremains subjective

– How deep is too deep?

– Is deep just right?

• Greater than 40% patients are more deeply sedated than desired

• Drug-induced coma present during 32% of patient evaluations

Deep Sedation

32% of patient evaluations– Yet only 2.6% rated as “oversedated”

Weinert. CCM 2007:35:393

Payen. Anesthesiology 2007:106:687

Martin. ICM 2006; 32:1137

Does This

Matter?

Factors Supporting Deep

Sedation = Humane Treatment

• 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

Non-

evidence

based

• Could even lead to PTSD

– Amnesia of the ICU experience is desired

Avoiding Coma Impacts Outcomes

Fraser and Riker. CCM 2007; 35:635

What about long-term

outcomes?

Periscope depth

Depth of Sedation?

“PTSD was highest in

the middle level of

To the ocean floor

the middle level of

wakefulness and lowest

when least aroused or

the most awake.’

Griffiths. CCM 2008; 36:945

ICU Pain and Discomfort

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 painPuntillo. Heart Lung 1990; 19:526Puntillo. Heart Lung 1990; 19:526

2007

50% remembered unmet analgesic needsGelinas. 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

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 agitationcause of agitation

• Continuous infusion remifentanil or

fentanyl

– Rapid onset and offset

• ~ 50% will require additional sedation

Redefining the Roles of

Available Sedative Agents

• A very selective review of data

– Dexmedetomidine

– Benzodiazepines– Benzodiazepines

– Propofol

Dex Dose, Duration, and Downsides

61% required more than 0.7mcg/kg/h

Duration up to 15 days

Riker. JAMA. 2009; 301:489-99.

Time to Successful Extubation ≠

Shorter ICU Stay

Time to

Extubation

Dexmedetomidine

(n=244)

Midazolam

(n=122)

Absolute

Reduction

(%, days)

P

value

Median

(95%CI)

3.7 days

(3.1 – 4.0)

5.6 days

(4.6-5.9)

32.2%

1.9 days0.01

Riker. JAMA. 2009; 301:489-99.

ICU LOS

daysDexmedetomidine

(N=244)

Midazolam(N=122)

Absolute

Reduction

(%), days

P

value

Median

(95%CI)

5.9 days

(5.7 - 7.0)

7.6 days

(6.7 – 8.6)

22.3%

1.7 d0.24

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>24h

• Anticipate dex-induced hemodynamic instability and bradycardia

• Combine with other sedative or analgesic agents as needed

• Transition to clonidine

30 Minute Dexmedetomidine Dose

Adjustments Reduce HypotensionGerlach. 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 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 – 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

Benzodiazepines

Sedative Infusions:

Propofol >> BenzodiazepinesWunsch. CCM 2009 (Project IMPACT)

50% receive continuous

infusion sedation; most

propofol, 30% = benzo

Propofol infusion use

increasing, not lorazepam

Benzodiazepine Concerns: Delirium

Benzodiazepines• Independent risk

factor for development

of delirium

• Especially if used to • 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

Lorazepam as a Source of Propylene Glycol (PG)

• PG toxicity

– Metabolic acidosis,

hyperosmolality, acute

kidney injury

– Osmol gap of >10-12 – 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

Propofol

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– 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

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. 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

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• Pain

• Withdrawal

• Anxiety

• Delirium

– Other modifiers • Intubated vs not

• Short vs long-term sedation

• Organ dysfunction: heart, brain, liver, and kidney

• Deep vs light

Tools to Facilitate Bedside

Application

• Order sets based on agreed-upon institution

specific protocols

• Real-time clinical decision support • Real-time clinical decision support

• Bundles imbedded with data feedback

Real-Time Clinical Decision

Support Tools

Once modifiers are selected, all orders appropriate for this

patient become available

Sedation, Analgesia, Delirium (SAD) Bundle

Make your own “bundle” with elements and metrics1. 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 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

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 – 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

Time to leave….. thanks for your attention

fraseg@mmc.org

They Do Things Differently Down UnderProtocolization of ICU Sedation

• NA and European trials = outcomes

improve with protocolized sedation

• But NOT in Australia!

– Why? Is the strategy not beneficial?– Why? Is the strategy not beneficial?

– Do unique aspects of care impact results?

• 1:1 RN to patient ratio

• RNs manage ventilator

• ICUs are “closed”

• Twice daily multidisciplinary rounding

• ANZ care model may impact outcomes

more than sedation protocolization

Bucknall. Crit Care Med 2008; 36:1444

Elliott. Intensive Care Med 2006; 32:1506

Fraser. Crit Care Med 2007; 35:635

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?

Intellectual Whiplash

Intensive

Glucose Control

Factor VIIa for

ICH

Drotrecogin for

Sepsis

ACTH stim

testing

Developing “Fad-Free” Guidelines

Steroids for

Septic Shock

Benzo InfusionsFor Long-term

Sedation

PPI Use for

SUP

They Do Things Differently Down UnderProtocolization of ICU Sedation

• NA and European trials = improved

outcomes with protocolized sedation

• But NOT in Australia!

– Why? Is the strategy not beneficial?– Why? Is the strategy not beneficial?

– Do unique aspects of care impact results?

• 1:1 RN to patient ratio

• RNs manage ventilator

• ICUs are “closed”

• Twice daily multidisciplinary rounding

• ANZ care model may impact outcomes

more than sedation protocolization

Bucknall. Crit Care Med 2008; 36:1444

Elliott. Intensive Care Med 2006; 32:1506

Fraser. Crit Care Med 2007; 35:635

Often Boils Down to Competing Concerns

• Breathing vs comfort

• Hemodynamic stability vs comfort

• Amnesia vs memory formation

• Short-term control vs long-term sequelae• 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)

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

Discomfort from Typical ICU Procedures

Mean Pain Intensity (0-10)

N = 6000 Adults

22.5

33.5

44.5

5

Puntillo. Am J Crit Care. 2001;10:238

00.5

11.5

2

Mean intensity 4.93 4.67 4.42 3.94 2.72 2.65

TurningDrain

removal

Wound

careTrach sx

Central

line

Femoral

sheath

Less than 25% receive procedural pain

management

Puntillo. Am J Crit Care 2002;11:415, Payen. Anesthesiology 2007;

106:687

Screeningup to 96 h

Double-Blind Treatment (X - 30 d)

Follow-Up

48 h

DEX (Optional load; 0.2-1.4 µg/kg/h)

Randomized 2:1 DEX:MDZ

ETT

Day 0

DEX (Optional load; 0.2-1.4 µg/kg/h)

MDZ (Optional load; 0.02-0.1 mg/kg/h)

Daily Arousal & CAM-ICUQ 4 hr RASS -2 to +1

Nurse Assessment Q Shift

Riker. JAMA. 2009; 301:489-99.

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– 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

Dexmedetomidine: Concerns

• Hypotension and bradycardia

– Avoid in patients dependent on sympathetic

tone for hemodynamic stability

• Excessive sedation

• Withdrawal tachycardia/hypertension

(theoretical risk)

Disadvantages of Benzodiazepines

• Oversedation and prolonged duration of

mechanical ventilation

– Titrate carefully and use daily wake ups

Propofol: Indications and

Pharmacodynamics

• Pharmacology: GABA agonist

• Pharmacokinetics/dynamics: onset 1-2 min, duration 10 min

• Benefits– Rapid onset & offset– 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

Use of Sedative InfusionsProject 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

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

Dexmedetomidine: ICU Roles

• Consider using– When respiratory function is tenuous

– When tachycardia and hypertension are present

– In conjunction with benzodiazepines for ethanol withdrawalwithdrawal

• When is dex probably not indicated– Severe vasodilatory or cardiac shock

– If you wouldn’t use beta blockade, you shouldn’t use dex