Management of Sedation
and Delirium in Ventilated
ICU Patients
Gabriel Tsao
Stanford University
School of Medicine
Introduction
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In the United States, 55,000 patients are cared
for daily in 6000 ICUs.
The most common reason for admission is
respiratory failure and the need for mechanical
ventilator.
The vast majority of patients on ventilators
require sedation
60-80% of ventilated patients develop delirium at
some point during their hospital course
Ely EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the ICU. JAMA 2004; 291: 1753-62
Presentation Outline
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Sedation in the ICU
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Delirium in the ICU
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Drug overview
Sedation assessment
Drug selection
Incidence and mortality
Delirium assessment
Management of delirium
(Serotonin Syndrome on Friday? Sorry, Dr. Spain)
Sedation in Ventilated Patients
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Mechanical ventilation is uncomfortable and
anxiety provoking
Sedation is often necessary for comfort and
airway, line, foley, nursing protection
>85% of ventilated patients receive sedation
Weinert CR, et al. Epidemiology of sedation and sedation adequacy for mechanically ventilated patients in a medical and surgical
intensive care unit. Crit Care Med 2007. 35(2): 393-401
Commonly Used Sedatives
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“Standard” sedation
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Benzodiazepines - midazolam, lorazepam, diazepam
Anesthetics - propofol
Special circumstance sedation
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Central alpha-agonists - clonidine, dexmedetomidine
High-dose opioids
Haloperidol
Benzodiazepines
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Sedative-hypnotic agents
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Sedative (anxiolytic): blocks acquisition and processing of
new information
Hypnotic: produces drowsiness and encourages onset and
maintenance of sleep.
Lacks analgesia effects
Issues:
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CNS depression (additive)
 Hypotension
 Respiratory depression
Tolerance
Withdrawal
Midazolam
Benzodiazepines
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Diazepam not used extensively in ICU, metabolites and renal excretion
Use of BZD in liver dz: LOT - Lorazepam Oxazepam Temazepam
Flumazenil reversal for BZD overdose
 Competitive antagonist
 Short half-life, heavy sedation may resume
 Concern for withdrawal especially after prolonged BZD use
 Use low dose (0.15 mg dose x1), second dose if some response
observed.
Propofol
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IV general anesthetic agent
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“Milk of amnesia”
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Similar degree of amnesia as BZDs
No analgesic properties
Requires dedicated line for infusion
Stored in lipid emulsion --> hypertriglyceridemia
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Sedative/hypnotic properties at lower doses
Rapid onset and rapid recovery (ambulate sooner)
1.1 kcal/ml from fat, adjust tube feeds
Pancreatitis, particularly in prolonged or high-dose
Check triglyceride levels after 2 days
Adverse Effects
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Marked hypotension during induction, respiratory depression
(apnea), bradycardia, arrhythmias, propofol infusion syndrome
Central alpha-agonists
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Unlike other sedatives, 2-agonists do not cause
respiratory depression or hemodynamic instability
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Clonidine: 2 > 1 -agonist
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Facilitate extubation or withdrawal of mechanical ventilation
Initial pressor due to direct 1 stimulation of arterioles
Central 2 stimulation in CNS inhibits sympathetic activity,
reduces plasma epinephrine and norepinephrine levels.
Dexmedetomidine: a more selective 2-agonist than
clonidine
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Stronger sedative and analgesic properties
Requires attending approval for >24 hr use
Dexmedetomidine
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Helpful in extubating patients who failed previous
weaning attempts following prolonged mechanical
ventilation, especially if there exists component of
agitation or delirium.
Method:
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Start infusion rate of 0.5-0.7 ug/kg/hr
Background sedation and analgesia titrated down or discontinued
if possible
Dexmedetomidine titrated to blood pressure and heart-rate
Brought to PS 10, PEEP 5 and checked ABGs
All five patients were extubated within three hours starting
dexmedetomidine, one reintubated.
Siobal MS, et al. Use of Dexmedetomidine to Faciliate Extubation in Surgical ICU Patients who Failed Previous Weaning Attempts
Following Prolonged Mechanical Ventilation: A Pilot Study. Respire Care 2006; 51(5): 492-496.
Dexmedetomidine
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Retrospective study of 40 ICU patients who
received dexmedetomidine from 2000-2003.
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22 out of 40 were successfully extubated within 24 hrs
Conclusions
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Dexmedetomidine reduces sedative requirements
Does not alter analgesic requirements
Transitioning to dexmedetomidine alone from other
sedatives and analgesics may not provide optimal
sedation and analgesia
Further studies needed to evaluate dexmedetomidine
as a bridge to extubation
MacLaren R, et al. Adjunctive Dexmedetomidine Therapy in the ICU: A Retrospective Assessment of Impact on Sedative and
Analgesic Requirements. Pharmacotherapy. March 2007: 351-359.
Fentanyl
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High dose opioids have sedative properties
Acute agitation can arise for a variety of etiologies,
including pain.
Short-acting opioid analgesics may provide
immediate patient comfort thus reducing agitation
associated with pain
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May decrease sedation requirement
Respiratory depression is additive
Fentanyl family includes: Alfentanil, remifentanil,
sufentanil
Haloperidol
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Still used in some ICUs as a primary sedative
No analgesic or amnesic properties
Drug of choice for delirium
Assessing Sedation
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Modified Ramsey Sedation Scale
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Titrate sedation to >2 and <5
Assessing Sedation
Selection of sedative agent
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Duration of therapy
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Very short term (acutely agitated)
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Fentanyl if patient is in pain
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Fentanyl has not been compared with other sedatives
in controlled trials
Midazolam and diazepam both have rapid onset
Propofol not indicated because of adverse bolus
effects
Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med
2002; 30(1): 119-142.
Short Term Sedation (<24 hrs)
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Randomized open-label trials compared propofol
and midazolam most often (eight out of nine trials)
Similar clinical outcomes following <24 hr
infusion.
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Propofol may have slight advantage with more rapid
extubation.
Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med
2002; 30(1): 119-142.
Intermediate Sedation (1-3d)
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Three way comparison of midazolam, lorazepam
and propofol (mean sedation = 3 days)
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30 ventilated surgery trauma patients
Midazolam produced adequate sedation a greater
proportion of time. Propofol and lorazepam
associated with undersedation and oversedation
respectively.
Morphine was provided on an as needed basis
McCollam JS, et al. Continuous infusions of lorazepam, midazolam and propofol for sedation of the critically-ill surgery trauma
Patient: A prospective, randomized comparison. Crit Care Med 1999; 27:2454-2458.
Long-term Sedation (>3 days)
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Nine open label, randomized trials comparing
long term sedation:
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Most compared propofol with midazolam
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“Propofol consistently provided faster awakening [and
extubation] than midazolam with statistical and
probable clinical significance.”
Midazolam vs. lorazepam
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Double-blind study of long-term sedation
No statistical difference in awakening time however,
awakening time with lorazepam was more predictable
and cost-effective.
Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med
2002; 30(1): 119-142.
Sedation Use
Recommendations
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Midazolam or diazepam should be used for rapid sedation of
acutely agitated patients. (Grade=C)
Propofol is preferred sedative when rapid awakening (e.g.
neurologic assessment or extubation) is important (Grade=B)
Midazolam is recommended for short-term use only, as it
produces unpredictable awakening and time to extubation
when infusions continue longer than 72 hrs. (Grade=A)
Lorazepam is recommended for sedation of most patients via
intermittant IV or continuous infusion (Grade=B)
Triglyceride levels should be monitored after two days of
propofol infusion (Grade=B)
Use of sedation guidelines, an algorithm or a protocol is
recommended. (Grade=B)
Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med
2002; 30(1): 119-142.
Sedation Interruption
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Daily interruption of sedation in ventilated patients decreased
duration of mechanical ventilation and length of hospital stay.
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Randomized, controlled study of 128 pts
Daily, stopped sedation until patient was awake or
uncomfortable/agitated
Mean duration of mechanical ventilation 4.9 days compared to
7.3 days control group (p=0.004)
More complications (pulling out EG tube) occurred in control
compared to intervention group (7% to 3%)
Benefit confirmed by subsequent studies
Kress JP, et al. Daily Interruption of Sedative Infusions in Critically Ill Patients Undergoing Mechanical Ventilation. NEJM 2000;
342:1471-1477.
Schweickert WD, et al. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients.
Crit Care Med 2004; 32(6):1272-1276.
Sedative Dependence
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Patients exposed to more than one week of high
dose opioid or sedative may develop tolerance
and/or dependence.
Opioid withdrawal:
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Benzodiazepine withdrawal:
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Pupillary dilation, sweating, lacrimation, rhinorrhea,
yawning, tachycardia, irritability, anxiety
Dysphoria, tremor, headache, nausea, sweating, agitation,
anxiety, sleep disturbances, myoclonus, delirium, seizures
Propofol withdrawal not well-described but reported
to resemble BZD withdrawal
Presentation Outline

Sedation in the ICU




Drug overview
Sedation assessment
Drug selection
Delirium in the ICU
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Incidence and mortality
Delirium assessment
Management of delirium
Delirium highly prevalent in ICU
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Increased incidence in ventilated patients
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Incidence in critically ill patients range from 35-60%.
Up to 81.7% of mechanically ventilated pts developed
delirium at some point during Vanderbilt study.
Underdiagnosed condition
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Delirium goes undiagnosed in >66% of patients
- Ely EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the ICU. JAMA 2004; 291: 1753-62
- Ely EW et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001; 27: 1892-1900
- Inouye SK et al. Nurses’ recognition of delirium and its symptoms. Arch Intern Med. 2001; 161: 2467-2473.
Delirium in ventilated patients
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Independent predictor of mortality (3-fold increase)
and increased length of stay in ventilated pts.
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After adjusting for confounders, delirium was also
associated with a 39% increase in ICU costs.
Eli EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the ICU. JAMA 2004; 291: 1753-62
Milbrandt EB et al. Costs Associated with Delirium in Mechanically Ventilated Patients. Crit Care Med 2004; 32: 955-962, 2004
Overview of Delirium
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Term ICU psychosis is “old-fashioned, inaccurate and
not appropriate”
Subtypes of Delirium
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Hyperactive - paranoid, agitated
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Hypoactive - withdrawn, quiet, paranoid
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Readily recognized, best prognosis
Purely hyperactive: 1.6% of delirium episodes
“Quiet delirium”
Often not well recognized, misdiagnosed
Purely hypoactive episodes 43.5%
Mixed - combination
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Most common in ICU patients 54.9%
Worst prognosis
Peterson JF, et al. Delirium and Its Motoric Subtypes: A Study of 614 Critically Ill Patients. J Am Geriatr Soc 54: 479-484, 2006.
Assessing Delirium
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Confusion Assessment Method for ICU (CAM)
Evidence of acute change from baseline?
Fluctuating RASS, GCS or other assessment?
Attention Screening Exam: Auditory or Visual
Richmond Agitation Sedation Scale (RASS)
Questions:
Will a stone float on water?
Are there fish in the sea?
Does one pound weight more than two pounds?
Can you use a hammer to pound on a nail?
Assessing Delirium
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Richmond Agitation Sedation Scale (RASS)
Pathophysiology Poorly
Understood
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Neurobiology of attention
Cortical vs subcortical mechanisms
Neurotransmitter mechanisms
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Acetylcholine plays a key role in pathogenesis
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Anticholinergic drugs caused delirium in healthy
volunteers, reserved by cholinesterase inhibitors
Serum anticholinergic activity correlated with severity
of delirium
Mach, JR, Dysken, MW, Kuskowski, M, et al. Serum anticholinergic activity in hospitalized older persons with delirium:
A preliminary study. J Am Geriatr Soc 1995; 43:491.
Treatment of Hyperactive and
Mixed Delirium
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Haloperidol is agent of choice*
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Best antipsychotic, few anticholinergic side-effects
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Typical starting dose: 1-2 mg IV every 2-4 hours
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Unlikely to cause sedation and hypotension
Adjust for elderly and degree of agitation
Can double dose every 20-30 minutes if uncontrolled
--> continuous drip 5-10 mg/hr
QT prolongation
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Cardiac monitoring at higher doses, measure K+ and Mg2+
Discontinue if QTc>450ms or extrapyramidal symptoms
develop
American Psychiatric Association. Practice Guidelines for Treatment of Patients with Delirium. 1999.
UK Clinical Pharmacy Association. Detection, Prevention and Treatment of Delirium in Critically Ill Patients. June 2006.
Other Treatments for
Hyperactive/Mixed Delirium
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Role for benzodiazepines
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Specifically indicated for EtOH or BZD withdrawal
delirium
If possible, avoid use
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Contribute to development of delirium
Ineffective in treating delirium
In ventilated patients, sedation with
benzodiazepines is often necessary
Treatment of Hypoactive
Delirium
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No published data in critical care literature
Antipsychotics may still play a role
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Treat like hyperactive delirium
Stimulants such as methylphenidate may be
used
American Psychiatric Association. Practice Guidelines for Treatment of Patients with Delirium. 1999.
UK Clinical Pharmacy Association. Detection, Prevention and Treatment of Delirium in Critically Ill Patients. June 2006.
Acknowledgements and
Thanks
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Dr. Maldonado
Dr. Purtill
Ngoc Nguyen, Pharm. D.
SICU Team
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Amy
Sarah
Geoff
Geoff
Ben
Thank you for listening!