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Management of Sedation

and Delirium in VentilatedICU Patients

Gabriel TsaoStanford University

School of Medicine

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Introduction

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

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Presentation Outline

Sedation in the ICU

Drug overview

Sedation assessment

Drug selection

Delirium in the ICU

Incidence and mortality

Delirium assessment

Management of delirium

(Serotonin Syndrome on Friday? Sorry, Dr. Spain)

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Sedation in Ventilated Patients

Mechanical ventilation is uncomfortable and

anxiety provoking

Sedation is often necessary for comfort andairway, 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

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Commonly Used Sedatives

Standard sedation

Benzodiazepines - midazolam, lorazepam, diazepam

Anesthetics - propofol

Special circumstance sedation

Central alpha-agonists - clonidine, dexmedetomidine

High-dose opioids

Haloperidol

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Benzodiazepines Sedative-hypnotic agents

Sedative (anxiolytic): blocks acquisition and processing ofnew information

Hypnotic: produces drowsiness and encourages onset and

maintenance of sleep. Lacks analgesia effects

Issues: CNS depression (additive)

Hypotension Respiratory depression

Tolerance

Withdrawal

Midazolam

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Benzodiazepines

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.

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Propofol

IV general anesthetic agent Sedative/hypnotic properties at lower doses

Rapid onset and rapid recovery (ambulate sooner)

Milk of amnesia Similar degree of amnesia as BZDs

No analgesic properties

Requires dedicated line for infusion

Stored in lipid emulsion --> hypertriglyceridemia 1.1 kcal/ml from fat, adjust tube feeds Pancreatitis, particularly in prolonged or high-dose

Check triglyceride levels after 2 days

Adverse Effects Marked hypotension during induction, respiratory depression

(apnea), bradycardia, arrhythmias, propofol infusion syndrome

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Central alpha-agonists

Unlike other sedatives, 2-agonists do not causerespiratory depression or hemodynamic instability Facilitate extubation or withdrawal of mechanical ventilation

Clonidine:

2 >

1 -agonist 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 thanclonidine Stronger sedative and analgesic properties

Requires attending approval for >24 hr use

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Dexmedetomidine

Helpful in extubating patients who failed previous

weaning attempts following prolonged mechanical

ventilation, especially if there exists component of

agitation or delirium.

Method:

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.

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Dexmedetomidine

Retrospective study of 40 ICU patients whoreceived dexmedetomidine from 2000-2003. 22 out of 40 were successfully extubated within 24 hrs

Conclusions Dexmedetomidine reduces sedative requirements

Does no talter analgesic requirements

Transitioning to dexmedetomidine alone from other

sedatives and analgesics may not provide optimalsedation and analgesia

Further studies needed to evaluate dexmedetomidineas 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.

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Fentanyl

High dose opioids have sedative properties

Acute agitation can arise for a variety of etiologies,

including pain.

Short-acting opioid analgesics may provideimmediate patient comfort thus reducing agitation

associated with pain

May decrease sedation requirement

Respiratory depression is additive

Fentanyl family includes: Alfentanil, remifentanil,

sufentanil

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Haloperidol

Still used in some ICUs as a primary sedative

No analgesic or amnesic properties

Drug of choice for delirium

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Assessing Sedation

Modified Ramsey Sedation Scale

Titrate sedation to >2 and

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Assessing Sedation

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Selection of sedative agent

Duration of therapy

Very short term (acutely agitated)

Fentanyl if patient is in pain

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 Med2002; 30(1): 119-142.

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Short Term Sedation (

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Intermediate Sedation (1-3d)

Three way comparison of midazolam, lorazepam

and propofol (mean sedation = 3 days)

30 ventilated surgery trauma patients

Midazolam produced adequate sedation a greaterproportion 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 traumaPatient: A prospective, randomized comparison. Crit Care Med1999; 27:2454-2458.

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Long-term Sedation (>3 days)

Nine open label, randomized trials comparinglong term sedation:

Most compared propofol with midazolam

Propofol consistently provided faster awakening [andextubation] than midazolam with statistical andprobable clinical significance.

Midazolam vs. lorazepam

Double-blind study of long-term sedation No statistical difference in awakening time however,

awakening time with lorazepam was more predictableand cost-effective.


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Sedation Use

Recommendations

Midazolam or diazepam should be used for rapid sedation ofacutely 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 itproduces unpredictable awakening and time to extubationwhen infusions continue longer than 72 hrs. (Grade=A)

Lorazepam is recommended for sedation of most patients viaintermittant IV or continuous infusion (Grade=B)

Triglyceride levels should be monitored after two days ofpropofol infusion (Grade=B)

Use of sedation guidelines, an algorithm or a protocol isrecommended. (Grade=B)


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Sedation Interruption

Daily interruption of sedation in ventilated patients decreased

duration of mechanical ventilation and length of hospital stay.

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.

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Sedative Dependence

Patients exposed to more than one week of highdose opioid or sedative may develop toleranceand/or dependence.

Opioid withdrawal: Pupillary dilation, sweating, lacrimation, rhinorrhea,

yawning, tachycardia, irritability, anxiety

Benzodiazepine withdrawal: Dysphoria, tremor, headache, nausea, sweating, agitation,

anxiety, sleep disturbances, myoclonus, delirium, seizures

Propofol withdrawal not well-described but reportedto resemble BZD withdrawal

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Presentation Outline

Sedation in the ICU Drug overview

Sedation assessment

Drug selection Delirium in the ICU

Incidence and mortality

Delirium assessment Management of delirium

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Delirium highly prevalent in ICU

Increased incidence in ventilated patients

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

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 Med2001; 27: 1892-1900- Inouye SK et al. Nurses recognition of delirium and its symptoms. Arch Intern Med. 2001; 161: 2467-2473.

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Delirium in ventilated patients

Eli EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the ICU. JAMA 2004; 291: 1753-62Milbrandt EB et al. Costs Associated with Delirium in Mechanically Ventilated Patients. Crit Care Med 2004; 32: 955-962, 2004

Independent predictor ofmortality (3-fold increase)

and increased length of stay in ventilated pts.

After adjusting for confounders, delirium was also

associated with a 39% increase in ICU costs.

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Overview of Delirium

Term ICU psychosisis old-fashioned, inaccurate andnot appropriate

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Subtypes of Delirium

Hyperactive - paranoid, agitated

Readily recognized, best prognosis

Purely hyperactive: 1.6% of delirium episodes

Hypoactive - withdrawn, quiet, paranoid

Quiet delirium

Often not well recognized, misdiagnosed

Purely hypoactive episodes 43.5%

Mixed- combination

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 Soc54: 479-484, 2006.

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Assessing Delirium

Richmond Agitation Sedation Scale (RASS)

Evidence of acute change from baseline?

Fluctuating RASS, GCS or other assessment?

Attention Screening Exam: Auditory or Visual

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?

Confusion Assessment Method for ICU (CAM)

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Assessing Delirium

Richmond Agitation Sedation Scale (RASS)

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Pathophysiology Poorly

Understood

Neurobiology of attention

Cortical vs subcortical mechanisms

Neurotransmitter mechanisms Acetylcholine plays a key role in pathogenesis

Anticholinergic drugs caused delirium in healthy

volunteers, reserved by cholinesterase inhibitors

Serum anticholinergic activity correlated with severityof 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.

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Treatment of Hyperactive and

Mixed Delirium

Haloperidol is agent of choice*

Best antipsychotic, few anticholinergic side-effects

Unlikely to cause sedation and hypotension

Typical starting dose: 1-2 mg IV every 2-4 hours

Adjust for elderly and degree of agitation

Can double dose every 20-30 minutes if uncontrolled

--> continuous drip 5-10 mg/hr

QT prolongation

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.

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Other Treatments for

Hyperactive/Mixed Delirium

Role for benzodiazepines

Specifically indicated for EtOH or BZD withdrawal

delirium

If possible, avoid use

Contribute to development of delirium

Ineffective in treating delirium

In ventilated patients, sedation withbenzodiazepines is often necessary

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Treatment of Hypoactive

Delirium

No published data in critical care literature

Antipsychotics may still play a role

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.

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Acknowledgements and

Thanks

Dr. Maldonado

Dr. Purtill

Ngoc Nguyen, Pharm. D.

SICU Team Amy

Sarah

Geoff

Geoff Ben

Thank you for listening!

Documents

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