agitation/sedation and delirium in critically ill patients

1. Agitation/Sedation and
Delirium in Critically Ill Patients
Allison N. Boyd, PharmD, BCCCP
Clinical Pharmacist Specialist – Trauma/Burn
Cell: 401.500.9663 | Office: 401.444.3295
aboyd1@lifespan.org

2. Pain, Agitation, and Delirium
Agitation
Delirium
Pain

3. Richmond Agitation and Sedation Scale
Score Term Description
+4 Combative Overtly combative, violent, immediate danger to self
+3 Very agitated Pulls or removes tube(s) or catheter(s); aggressive
+2 Agitated Frequent non-purposeful movement, fights ventilator
+1 Restless Anxious but movements not aggressive or vigorous
0 Alert and Calm
-1 Drowsy Not fully alert, but has sustained awakening (eye-
opening/eye contact) to voice (≥ 10 seconds)
-2 Light sedation Briefly awakens with eye contact to voice (< 10 seconds)
-3 Moderate sedation Movement or eye opening to voice (but no eye contact)
-4 Deep sedation No response to voice, but movement or eye opening to
physical stimulation
-5 Unarousable No response to voice or physical stimulation
Devlin J, et al. Crit Care Med 2018.
What tool is used to assess for sedation
in the ICU?

4. Target Level of Sedation
• Light sedation preferred to deep sedation in critically ill,
mechanically ventilated adults
• The 2013 PAD guidelines defined ‘light sedation’ as RASS scale
score > -2 and eye opening of at least 10 seconds
• 2018 PADIS update: this level of sedation is probably deeper than required
for management of mechanically ventilated adults in an ICU
• Common Exceptions:
• ARDS/invasive ventilation mode
• Chemically paralyzed patients (goal RASS -5)
• Elevated ICP
• Open abdomen
Devlin J, et al. Crit Care Med 2018.

5. Wake Up and Breathe
• Spontaneous Awakening/Spontaneous Breathing Trial
• Should occur every morning if no exclusion criteria met
• Spontaneous Awakening Trial Protocol (SAT)
• Sedative is held if RASS score is -5 to -2 while analgesic is
continued
• If RASS -5 to -2 despite stopping sedative, opioid infusion rate
is decreased by 50% (if applicable)
• Sedation should continue to be held if patient remains in RASS
goal
• If patient becomes agitated (RASS score above goal), sedation
is restarted at 50% previous rate

6. Choice of Sedative Agent
• Propofol and dexmedetomidine are preferred over benzodiazepines due to
improved outcomes such as ICU LOS, duration of mechanical ventilation, and
decreased rates of delirium
• Risks and benefits of intermittent benzodiazepines is unclear, general practice
at this time is to avoid if possible due to risks known to be associated with
continuous infusions
• When utilizing a neuromuscular blocking agent: dexmedetomidine not
appropriate as a sedative agent
• Bispectral index (BIS) monitoring is utilized at some institutions
• At RIH, it is imperative to initiate sedative agents prior to neuromuscular blocking agent to
ensure adequate sedation (RASS -5) prior to paralyzing the patient
• RASS cannot be utilized to assess sedation once patient is paralyzed
Devlin J, et al. Crit Care Med 2018.

7. Commonly Used Sedative Agents
Generic (Trade) Dose Onset Duration
Hemodynamic
Effect
Clinical Pearls
Propofol
(Diprivan®)†
CI: 5-80 mcg/kg/min 30 sec 3-10 min
Bradycardia
Hypotension
Provides 1.1 kcal/mL
Doses > 80 mcg/kg/min associated
with PRIS
Dexmedetomidine
(Precedex®)†
CI: 0.3-1.5 mcg/kg/hr 5-10 min 60-120 min
Bradycardia
Hypotension
Rebound HTN
Lighter level of sedation
Opioid-sparing
Expensive (10x cost of propofol)
No respiratory depression
Lorazepam
(Ativan®)
PO: 2-4 mg Q4-6 hrs
IV: 2-4 mg Q2-6 hrs
PO: 30-60 min
IV: 5-20 min
6-8 hrs
Some
hypotension
No active metabolite
Midazolam
(Versed®)
IV: 2-5 mg Q1-2 hrs
CI: 2-10 mg/hr
3-5 min 1.5-3 hrs
Some
hypotension
Active metabolite
Highly lipophilic – PK/PD become
unpredictable after 48-72 hours
†Preferred sedatives

8. ICU Delirium
• Common complication in 20-80% of ICU patients
• Associated with increased morbidity and mortality
• Higher rates of self-extubation and catheter removal
• Prolonged duration of mechanical ventilation
• Increased ICU and hospital length of stay
• Long-term cognitive impairment
• Increased likelihood of discharge to a long-term care facility
• Increased risk of death
• 26-34% mortality rate
• Each additional day with delirium associated with an increased risk of
death

9. Confusion Assessment Method for the
ICU (CAM-ICU)
What Tool Is Used to Assess for Delirium
in the ICU?

10. Delirium Subtypes
Hyperactive (< 2%)
• Agitation
• Restlessness
• Combative
• Attempts to
remove
tubes/lines
Hypoactive (44%)
• Quiet
• Withdrawn
• Flat affect
• Lethargy
• Decreased
responsiveness
• Difficult to assess
Mixed (54%)
• Combination of
hyper and
hypoactive

11. Stepwise Approach to Delirium
Step 1: Identify and eliminate potentially contributing factors
Step 2: Implement and/or optimize non-pharmacologic therapy
Step 3: Pharmacologic management

12. Step 1: Identify and Eliminate Potential
Contributing Factors
• Sepsis
• Shock states (including blood transfusions)
• Glycemic dysregulation
• Electrolyte abnormalities
• Hypoxia
• Dehydration
• Inadequate pain control
• Drug withdrawal
• Lack of continuation of home antipsychotics
• Environmental (sleep deprivation, immobilization, restraints)
Devlin J, et al. Crit Care Med 2018.
Pandharipande P, et al. Anesthesiology 2006;104:21-6.

13. Step 2: Implement/Optimize
Non-pharmacologic Therapy
• Frequent verbal reorientation
• Access to eyeglasses and hearing aids
• Head of bed elevation
• Early mobility, PT/OT when able
• Minimize restraint and foley catheter use
• Maintenance of sleep-wake cycle
• Minimize environmental and procedural disturbances at night
• Spontaneous awakening trial (SAT) at least daily
• Spontaneous breathing trial (SBT) at least daily
Devlin J, et al. Crit Care Med 2018.
Pandharipande P, et al. Anesthesiology 2006;104:21-6.

14. Step 3: Pharmacologic Management
• Dependent on patient-specific risk factors and etiology
• Ensure appropriate pain management
• Discontinue deliriogenic medications
• Resume home psychiatric medications (if applicable)
• Treat withdrawal (if applicable)
• Consider antipsychotics
• Not recommended for the prevention of delirium
• Not recommended for routine treatment of delirium
• Patients who experience significant distress secondary to symptoms of delirium
such as anxiety, fearfulness, hallucinations, delusions, or who are agitated and
may be physically harmful to themselves or others may benefit
Devlin J, et al. Crit Care Med 2018.

15. Choice of Antipsychotic
Medication
EPS/Tardive
dyskinesia
QTc prolongation Sedation Hypotension
Anticholinergic side
effects
Haloperidol +++ ++ ++ 0 0
Olanzapine 0 + + + ++
Quetiapine 0 + ++ ++ ++
Ziprasidone 0 ++ 0 + +

16. Antipsychotics in the Literature
Haloperidol vs. Ziprasidone vs. Placebo
• MIND 2010: RCT of 6 tertiary medical centers in the US
• Included 101 mechanically ventilated medical and surgical patients
• Randomly assigned to receive haloperidol, ziprasidone, or placebo for up to 14 days
• Primary endpoint: number of days patients were alive without delirium or coma – no
difference [14 (6-18) vs. 15 (9.1-18) vs. 12.5 (1.2-17.2); p = 0.66]
• No differences in ventilator-free days, hospital length of stay, and mortality
• MIND-USA 2018: RCT of 16 medical centers in the US
• Included 1183 patients with acute respiratory failure or shock and hypoactive or
hyperactive delirium
• Randomly assigned to receive haloperidol, ziprasidone, or placebo for up to 14 days
• Primary endpoint: number of days alive without delirium or coma – no difference [7.9 (4.4-
9.6) vs. 8.7 (5.9-10) vs. 8.5 (5.6-9.9); p = 0.26]
• No differences in extrapyramidal symptoms or excessive sedation
Girard TD, et al. Crit Care Med 2010 Feb;38(2):427-37.
Girard TD, et al. N Engl J Med 2018;379:2506-16.

17. Antipsychotics in the Literature
Haloperidol vs. Olanzapine
• Skrobik YK, et al. 2003: Prospective, randomized study at a single 16-bed mixed ICU
• Included 214 ICU patients diagnosed with delirium
• Randomly assigned to receive either haloperidol or olanzapine
• Primary endpoint: decrease in daily delirium index scores – no difference (p = 0.83)
• No differences in benzodiazepine requirements, rescue haloperidol, opioids, or other
sedatives
Quetiapine vs. Placebo
• Devlin JW, et al. 2010: RCT of 3 academic medical centers
• Included 36 ICU patients diagnosed with delirium, tolerating enteral nutrition, and without
a complicating neurologic condition
• Randomly assigned to receive either quetiapine or placebo
• Primary endpoint: time to first resolution of delirium – shorter with quetiapine [1 (0.5-3) vs.
4.5 (2-7); p = 0.001]
• Quetiapine associated with reduced duration of delirium and less agitation
• No differences in ICU length of stay, mortality, QTc prolongation, or extrapyramidal
symptoms
Skrobik YK, et al. Intensive Care Med 2004 Mar;30(3):444-9.
Devlin JW, et al. Crit Care Med 2010 Feb;38(2):419-27.

18. Commonly Used Antipsychotics
Generic (Trade) Usual Dose Onset Half-Life Clinical Pearls
Haloperidol
(Haldol®)
IM/IV/PO:
2.5-5 mg Q6 hr
PO: 2-5 hrs
IM/IV: 20 min
PO: 14-37 hrs
IM/IV: 20 hrs
Can cause QTc prolongation and extrapyramidal
symptoms
Do NOT administer to patients with a diagnosis
of Parkinson’s Disease
Quetiapine
(Seroquel®)
PO: 25-200 mg
Q8-12 hr
1.5 hrs
6 hrs (parent)
12 hrs
(metabolite)
Can cause QTc prolongation
Max dose studied for delirium is 400 mg/day;
doses up to 800 mg/day are used for other
indications
Becomes more antihistaminergic at higher doses
Olanzapine
(Zyprexa®)
PO/IM/IV:
5-10 mg Q24 hr
IM/IV: 30 min
PO: 6 hrs
PO/IM/IV: 30
hrs
Can cause QTc prolongation
Half-life 1.5 longer in elderly patients
Max dose studied for delirium is 10 mg/day,
doses up to 20 mg/day are used for other
indications
Ziprasidone
(Geodon®)
PO: 20-40 mg
Q12 hr
IM: 10-20 mg
Q12 hr
PO: 6-8 hrs
IM: < 1 hr
PO: 7 hrs
IM: 2-5 hrs
Can cause QTc prolongation
PO formulation requires taking with a high
calorie meal (>500 cal) for adequate absorption
Maximum IM dose = 40 mg/day

19. Other Medications – Valproic Acid
• Objective: To describe the use of valproate therapy for agitation in critically
ill patients, examine its safety, and describe its relationship with agitation
and delirium
• Methods: Retrospective cohort study of 53 ICU patients over approximately 2
year period in two medical centers
• Results: The incidence of agitation (96% vs. 61%; p < 0.0001) and delirium
(68% vs. 49%; p = 0.012) was significantly decreased by valproate day 3.
Treatment with opioids and dexmedetomidine also decreased.
• Conclusions: Valproate therapy was associated with a reduction in agitation,
delirium, and concomitant psychoactive medication use within 48 hours of
initiation.
Gagnon DJ, et al. J Crit Care 2017 Feb;37:119-25.

20. Other Medications – Valproic Acid
• Discussion – thoughts??
Limitations:
• Retrospective study  association  causality
• Small sample size
• Improvement a result of valproic acid or natural progression of ICU agitation?
• No placebo group makes this impossible to assess
• Agitation and delirium data not reliably recorded
• Non-pharmacologic interventions for delirium were not assessed
• Only 22% trauma patients, 9% TBI, and 2% surgery patients
• Concomitant psychoactive medication use
• No difference in percentage of patients receiving BZD
• Increase in total daily dose of quetiapine despite decrease in percentage of patients
• No difference in percentage of patients receiving haloperidol
• Increase in both percentage and total daily dose of patients receiving phenobarbital
Gagnon DJ, et al. J Crit Care 2017 Feb;37:119-25.

21. Valproic Acid – Key Takeaways
• Valproic acid may be an effective alternative for ICU-related agitation and
delirium
• Valproic acid appears to be safe for use in critically ill patients
• Many questions are left unanswered for the use of this agent, including:
• Ideal timing of initiation, effective dose, and duration of therapy
• Whether therapeutic drug monitoring plays a role in this setting and the ideal reference
range
• Long term effects of valproic acid therapy
Gagnon DJ, et al. J Crit Care 2017 Feb;37:119-25.

22. What About TBI?
• Systematic Review: 2019
• Objective: To assess the efficacy and safety of pharmacological agents in the management of
agitated behaviors following TBI
• Methods: Systematic review including data up until December 2018
• Three categories of studies:
• Agitated behavior was the presenting symptom
• Agitated behavior was not the presenting symptom but was measured as an outcome variable
• Safety of pharmacological interventions administered to control agitated behaviors
• Results:
• 21 studies included
• Propranolol reduced maximum intensities of agitation per week and physical restraint use
• Methylphenidate improved anger measures following 6 weeks of treatment
• Valproic acid reduced weekly agitated behavior scale ratings
• Olanzapine reduced irritability, aggressiveness, and insomnia between weeks 1 and 3 of treatment
• Amantadine showed variable effects and may increase the risk of agitation in the critically ill
• Antipsychotics were associated with an increased duration of post-traumatic amnesia
• Conclusions: Propranolol, methylphenidate, valproic acid, and olanzapine may offer some
benefit. Antipsychotics may increase the length of post-traumatic amnesia. More studies are
needed in this area.
Williamson D, et al. BMJ Open 2019 Jul 9;9(7):e029604.

23. Key Takeaways
• Using the lightest level of sedation possible while still keeping
the patient comfortable has been associated with the best
outcomes
• Benzodiazepines should be avoided if possible but may be
necessary in the hemodynamically unstable patient
• Address contributing factors and implement non-
pharmacologic treatment for ICU delirium prior to initiating
medications
• Antipsychotics may be used for the agitated patient who is
experiencing delirium

24. Agitation/Sedation and
Delirium in Critically Ill Patients
Allison N. Boyd, PharmD, BCCCP
Clinical Pharmacist Specialist – Trauma/Burn
Cell: 401.500.9663 | Office: 401.444.3295
aboyd1@lifespan.org