1. Management of Sedation and Delirium in Ventilated ICU Patients Gabriel Tsao Stanford University School of Medicine

2. 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

3. 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)

4. Sedation in Ventilated Patients 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

5. Commonly Used Sedatives “Standard” sedation Benzodiazepines - midazolam, lorazepam, diazepam Anesthetics - propofol Special circumstance sedation Central alpha-agonists - clonidine, dexmedetomidine High-dose opioids Haloperidol

6. Benzodiazepines Sedative-hypnotic agents Sedative (anxiolytic): blocks acquisition and processing of new information Hypnotic: produces drowsiness and encourages onset and maintenance of sleep. Lacks analgesia effects Issues: CNS depression (additive) Hypotension Respiratory depression Tolerance Withdrawal Midazolam

7. 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.

8. 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

9. Central alpha-agonists Unlike other sedatives,  2 -agonists do not cause respiratory 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 than clonidine Stronger sedative and analgesic properties Requires attending approval for >24 hr use

10. 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.

11. Dexmedetomidine Retrospective study of 40 ICU patients who received dexmedetomidine from 2000-2003. 22 out of 40 were successfully extubated within 24 hrs Conclusions 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.

12. Fentanyl 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 May decrease sedation requirement Respiratory depression is additive Fentanyl family includes: Alfentanil, remifentanil, sufentanil

13. Haloperidol Still used in some ICUs as a primary sedative No analgesic or amnesic properties Drug of choice for delirium

14. Assessing Sedation Modified Ramsey Sedation Scale Titrate sedation to >2 and <5

15. Assessing Sedation

16. 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 Med 2002; 30(1): 119-142.

17. Short Term Sedation (<24 hrs) Randomized open-label trials compared propofol and midazolam most often (eight out of nine trials) Similar clinical outcomes following <24 hr infusion. 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.

18. 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 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.

19. Long-term Sedation (>3 days) Nine open label, randomized trials comparing long term sedation: Most compared propofol with midazolam “Propofol consistently provided faster awakening [and extubation] than midazolam with statistical and probable 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 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.

20. Sedation Use Recommendations 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.

21. 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.

22. Sedative Dependence Patients exposed to more than one week of high dose opioid or sedative may develop tolerance and/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 reported to resemble BZD withdrawal

23. Presentation Outline Sedation in the ICU Drug overview Sedation assessment Drug selection Delirium in the ICU Incidence and mortality Delirium assessment Management of delirium

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

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

26. Overview of Delirium Term ICU psychosis is “old-fashioned, inaccurate and not appropriate”

27. 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 Soc 54: 479-484, 2006.

28. 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)

29. Assessing Delirium Richmond Agitation Sedation Scale (RASS)

30. 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 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.

31. 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.

32. 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 with benzodiazepines is often necessary

33. 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.

35. Acknowledgements and Thanks Dr. Maldonado Dr. Purtill Ngoc Nguyen, Pharm. D. SICU Team Amy Sarah Geoff Ben Thank you for listening!