The document summarizes strategies for improving sedation management in the ICU. It discusses the benefits of daily sedation interruption and early mobility to reduce duration of mechanical ventilation. A key study found that combining daily wake-ups and early mobility resulted in fewer ICU delirium days, shorter ICU and hospital stays, and improved functional status at discharge compared to usual care. The document also reviews optimal sedative agents like dexmedetomidine that may reduce delirium risk compared to benzodiazepines.

1. Sedation in the ICU: Liberation strategies for improved outcomes Leanne Boehm, MSN, RN, ACNS-BC Delirium and Cognitive Impairment Study Group Vanderbilt University Medical Center Nashville, TN USA

2. Disclosures Hospira

3. Need for Sedation & Analgesia Prevention of pain and anxiety Decrease oxygen consumption Decrease the stress response Patient-ventilator synchrony Avoid adverse neurocognitive sequelae Depression, PTSD Rotondi AJ, et al. Crit Care Med . 2002;30:746-52A . Weinert C, et al. Curr Opin in Crit Care . 2005;11(4):376-380. Kress JP, et al. J Respir Crit Care Med . 1996;153:1012-1018.

4. Pitfalls of sedatives and analgesics Oversedation: Failure to initiate spontaneous breathing trials (SBT) leads to increased duration of mechanical ventilation Longer duration of ICU stay Impede assessment of neurologic function Increase risk for delirium Numerous agent-specific adverse events Kollef M, et al. Chest . 1998;114:541-548. Pandharipande, et al. Anesthesiology . 2006;124:21-26.

5. Identifying and Treating Pain

6. Behavioral Pain Scale (BPS) 3-12 Payen JF, et al. Crit Care Med. 2001;29(12):2258-2263. Item Description Score Facial expression Relaxed 1 Partially tightened (eg, brow lowering) 2 Fully tightened (eg, eyelid closing) 3 Grimacing 4 Upper limbs No movement 1 Partially bent 2 Fully bent with finger flexion 3 Permanently retracted 4 Compliance with ventilation Tolerating movement 1 Coughing but tolerating ventilation for most of the time 2 Fighting ventilator 3 Unable to control ventilation 4

7. Critical Care Pain Observation Tool 0-8 Gelinas C, et al. Am J Crit Care. 2006;15:420-427.

8. A note on pain control Pain can cause agitation and lead to excessive use of sedatives Adequate pain management often reduces the need for sedation 1 Reports suggest narcotic-based sedation may result in improved patient outcomes 2-3 1 Kress JP et al, AJRCCM 2002; 168(8): 1024-8 2 Breen D et al, Crit Car 2005; 9(3): R200-10 3 Pandharipande P & Ely EW, Crit Car 2005; 9(3): 247-8

9. Analgosedation “ Analgesia-first sedation” & sedative if needed Increasingly used in many countries Acknowledges discomfort as a cause of agitation Usually continuous infusion 30-74% required benzodiazepine/propofol rescue Study of remifentanil vs midazolam sedation Reduction in vent time (2 d) and ICU LOS (1d) Not appropriate for drug or alcohol withdrawal Dahaba AA, et al. Anesthesiology. 2004;101:640-646. Park G, et al. Br J Anaesth. 2007;98:76-82. Rozendall FW, et al. Intensive Care Med. 2009;35:291-298. Strøm T, et al. Lancet . 2010;375(9713):475-480

10. Sedation assessment and maintaining a sedation goal

11. Sedation Scales Pun & Dunn, AJN 2007; 107(7):40-48

12. ICU Sedation: The Balancing Act Patient Comfort and Ventilatory Optimization G O A L Patient recall Device removal Ineffectual mechanical ventilation Initiation of neuromuscular blockade Myocardial or cerebral ischemia Decreased family satisfaction w/ care Severe discomfort Hypertension Tachycardia Increased ICP Increase metabolic demand Delirium Prolonged mechanical ventilation Increase length of stay Increased risk of complications (I.e. VAP) Increased diagnostic testing Inability to evaluate for delirium Cardio/respiratory depression Decreased GI motility Immunosuppression Delirium Jacobi J, et al. CCM. 2002;30:119-141 Carrasco G. Crit Care. 2000;4:217-225 McGaffigan PA. CCN. 2002 ; Fe b(suppl): 29-36 Blanchard AR. Postgrad Med . 2002;111:59-74 ASHP Therapeutic Guidelines. Best Practices for Health-System Pharmacy. 2003-2004;486-512 Oversedation Undersedation

13. Setting Targets Aim for Cooperative: Calm & Easily Arousable State while minimizing pain, anxiety, or agitation unless contraindicated Easy transition from sleep to wakefulness 1 Can participate in weaning and physical therapy 1 Perform therapeutic maneuvers Able to perform a cognitive evaluation Adjust depending on patient need Over the course of Illness/Treatment Initial Intubation vs Stabilization Weaning Phase 1 Bekker AY, et al. Neurosurgery 2005;57(1 Suppl 1):1-10

14. The importance of preventing and identifying delirium

15. What is delirium? Common clinical syndrome that is characterized by: Inattention Acute cognitive dysfunction Thought to be due to disruption of neurotransmission related to: Drug toxicity Inflammation Acute stress responses

16. Delirium Morandi, A et al., ICM 2009;34:1907-15

17. Prevalence of Delirium in the ICU 60–80% MICU/SICU/TICU ventilated patients develop delirium 20–50% of lower severity ICU patients develop delirium Majority goes undiagnosed if routine monitoring is not implemented Hypoactive or mixed forms most common Ouimet S, et al. Intensive Care Med . 2007;33:66-73 Ely EW, et al. JAMA . 2001;286,2703-2710 Pandharipande PP, et al. J Trauma . 2008;65:34-41 Ely EW, et al. Intensive Care Med . 2001;27:1892-1900. Dubois MJ, et al. Intensive Care Med 2001;27:1297-1304

18. Patient Factors Increased age Alcohol use Male gender Living alone Smoking Renal disease Depression Vision/Hearing impaired Environment Admission via ED or through transfer Isolation No clock No daylight No visitors Noise Use of physical restraints Sleep deprivation Predisposing Disease Cardiac disease Cognitive impairment (eg, dementia) Pulmonary disease HIV Acute Illness Length of stay Fever Medicine service Lack of nutrition Hypotension Sepsis Metabolic disorders Tubes/catheters Medications: Anticholinergics Corticosteroids - Benzodiazepines Less Modifiable More Modifiable DELIRIUM Inouye SK, et al. JAMA .1996;275:852. Van Rompaey B, et al. Crit Care 2009;13:R77. Skrobik Y. Crit Care Clin . 2009;25(3):585-591. Devlin J, et al. ICM , 2007; 33:929-940.

19. Sequelae of Delirium After Hospital Discharge During the ICU/Hospital Stay - Increased mortality - 3x greater re-intubation rate - Average 10 additional days in hospital - Higher costs of care - Increased mortality - Long-term cognitive impairment - D/c requirement for chronic care facility - Decreased functional status at 6 months Milbrandt EB, et al. Crit Care Med. 2004;32:955-962. Nelson JE, et al. Arch Intern Med. 2006;166:1993-1999. Ely EW, et al. JAMA. 2004;291:1753-1762. Jackson JC, et al. Neuropsychol Rev. 2004;14(2):87-98.

20. Confusion Assessment Method (CAM-ICU) or 3. Altered level of consciousness 4. Disorganized thinking = Delirium Ely EW, et al. Crit Care Med . 2001;29:1370-1379. Ely EW, et al. JAMA . 2001;286:2703-2710. 1. Acute onset of mental status changes or a fluctuating course 2. Inattention and and

21. Intensive Care Delirium Screening Checklist 1. Altered level of consciousness 2. Inattention 3. Disorientation 4. Hallucinations 5. Psychomotor agitation or retardation 6. Inappropriate speech 7. Sleep/wake cycle disturbances 8. Symptom fluctuation Bergeron N, et al. Intensive Care Med . 2001;27:859-864. Ouimet S, et al. Intensive Care Med. 2007;33:1007-1013. Score 1 point for each component present during shift Score of 1-3 = Subsyndromal Delirium Score of ≥ 4 = Delirium

22. If sedation is required, what is the optimal sedative choice?

23. Characteristics of an Ideal Sedative Rapid onset of action allows rapid recovery after d/c 1 Effective at providing adequate sedation with predictable dose response 1,2 Easy to administer 1,3 Lack of drug accumulation 1 Few adverse effects 1-3 Minimal adverse interactions with other drugs 1-3 Cost-effective 3 Promotes natural sleep 4 1. Ostermann ME, et al. JAMA. 2000;283:1451-1459. 2. Jacobi J, et al. Crit Care Med . 2002;30(1):119-141. 3. Dasta JF, et al. Pharmacother. 2006;26:798-805. 4. Nelson LE, et al. Anesthesiol . 2003;98:428-436.

24. Choice of Sedatives Benzodiazepines GABA A receptor modulation in CNS Facilitates binding of GABA Hyperpolarize cells, making them more resistant to excitation Propofol Not well understood GABA receptor modulation is likely Dexmedetomidine α 2 -adrenergic agonist (inhibits NE release in CNS & PNS) CNS : sedation/hypnosis, anxiolysis, and analgesia PNS : decreases BP and HR; activates endogenous sleep-promoting pathway No respiratory suppression Enables cognitive evaluation & patient communication

25. Consider Comorbidities When Choosing a Sedation Regimen Chronic pain Organ dysfunction CV instability Substance withdrawal Respiratory insufficiency Obesity Obstructive sleep apnea

26. Risk of delirium with benzodiazepines Pandharipande P, et al. J Trauma. 2008; 65:34-41. Pandharipande P, et al. Anesthesiol. 2006:104:21-26.

27. Propofol vs benzodiazepines Outcomes improved by propofol : sedation quality, ventilator synchrony, time to awakening, variability of awakening, time to extubation from discontinuation of sedation, overall time to extubation, ventilator days, ICU LOS among survivors, costs of sedation

28. MENDS MICU/SICU Patients Ventilated & Sedated N=103 Control Lorazepam (GABA) ± Fentanyl Intervention Dexmedetomidine ( α 2) ± Fentanyl Pandharipande PP, et al. JAMA 2007;298:2644-53 Double-blind RCT of dexmedetomidine vs lorazepam infusion Intervention: Dexmedetomidine 0.15–1.5 mcg/kg/hr Lorazepam infusion 1–10mg/hr No daily interruption, patient targeted sedation

29. MENDS: dexmedetomidine vs lorazepam Pandharipande P et al – JAMA, 2007; 298:2644-2653 Dexmedetomidine resulted in : More days alive without delirium or coma (p=.01) Lower prevalence of coma (p=.001) More time spent within sedation goals (p=.04) Differences in 28-day mortality and delirium-free days were not significant

30. SEDCOM MICU Patients Ventilated & Sedated n=366 Control Midazolam (GABA) ± Fentanyl Intervention Dexmedetomidine ( α 2) ± Fentanyl Riker, R., et al. JAMA 2009; 301(5): 489-499 Double-blind, RCT comparing long-term dexmedetomidine vs midazolam Sedatives (dex 0.2-1.4 μ g/kg/hr or midaz 0.02-0.1 mg/kg/hr) titrated for light sedation, administered up to 30 days Daily arousal assessments and drug titration Q4h

31. SEDCOM: dexmedetomidine vs midazolam Dexmedetomidine resulted in : less time on the ventilator (p=.01) less delirium (p<.001) less tachycardia (p<.001) less hypertension (p=.02) Most notable adverse effect of dexmedetomidine was bradycardia (p<.001)

32. Strategies to Reduce the Duration of Mechanical Ventilation in Patients Receiving Continuous Sedation

33. Daily sedation interruption decreases days of MV Hold infusion until patient awake, then restart at 50% of prior dose “ Awake” defined as 3 of the following 4: Open eyes in response to voice Use eyes to follow investigator on request Squeeze hand on request Stick out tongue on request Kress JP, et al. N Engl J Med. 2000;342:1471-1477. Fewer diagnostic tests to assess changes in mental status No increase in rate of agitated-related complications or episodes of patient-initiated device removal No increase in PTSD or cardiac ischemia

34. The ABC Trial (both groups get patient targeted sedation) Control Intervention Girard TD, et al. Lancet. 2008;371:126-134.

35. The ABC Trial SBT+usual care vs SAT+SBT Patients in the intervention group: Less time in coma (p=.002) 2 days less on the ventilator (p=.02) 4 days less in the ICU (p=.02) 4 days less in the hospital (p=.04) Less exposure to benzodiazepines Were more likely to be alive in 1 year (p=.01) More self extubations, but not more reintubations Girard TD, et al. Lancet. 2008;371:126-134.

36. Early Mobilization Schweickert et al, Lancet 2009;373:1874-82

37. Mobility A fundamental nursing activity Enhances gas exchange Reduces VAP rates Shortened duration of MV Enhances long-term functional ability

38. Schweickert WD, et al. Lancet. 2009;373:1874-1882. 24% improvement (1.7-fold better) return to independent functional status at discharge (NNT=4)

39. Daily Wake-Up + Early Mobility Schweickert WD, et al. Lancet . 2009;373:1874-1882. Outcome Intervention (n=49) Control (n=50) P Functionally independent at discharge 29 (59%) 19 (35%) .02 ICU delirium (days) 2.0 (0.0-6.0) 4.0 (2.0-7.0) .03 Time in ICU with delirium (%) 33% (0-58) 57% (33-69) .02 Hospital delirium (days) 2.0 (0.0-6.0) 4.0 (2.0-8.0) .02 Hospital days with delirium (%) 28% (26) 41% (27) .01 Barthel Index score at discharge 75 (7.5-95) 55 (0-85) .05 ICU-acquired paresis at discharge 15 (31%) 27 (49%) .09 Ventilator-free days 23.5 (7.4-25.6) 21.1 (0.0-23.8) .05 Length of stay in ICU (days) 5.9 (4.5-13.2) 7.9 (6.1-12.9) .08 Length of stay in hospital (days) 13.5 (8.0-23.1) 12.9 (8.9-19.8) .93 Hospital mortality 9 (18%) 14 (25%) .53

40. Implementation challenges Many issues to address Multiple disciplines are involved RN, RT, MD, PT/OT, pharmacist Timing Coordination, collaboration, & teamwork Protocol development Change in culture of workplace Costs Resistance to change

41. Putting it all together

43. Clinical case Male patient, age 74 Hx : Dementia, coronary artery disease, diabetes, hypertension CC : altered mental status, shortness of breath Currently hypoxic and required MV Dx : Septic shock, ARDS, acute renal failure

44. Clinical case Current vent settings : A/C 16, TV 400, PEEP 14, FiO2 80% Current infusions : norepinephrine 10 mcg/min, vasopressin 0.4 units/min, insulin gtt, IVF Assessment : Target RASS -4, actual RASS +1 to -1, displaying vent asynchrony, CAM-ICU positive, bilat rhonchi, pulses present Receiving intermittent boluses of fentanyl and lorazepam Nursing interventions?

45. Clinical case Current vent settings : A/C 16, TV 400, PEEP 5, FiO2 40% Current infusions : propofol 40 mcg/kg/hr, norepinephrine 4 mcg/min, vasopressin 0.4 units/min, insulin gtt, IVF Intermittent fentanyl for analgesia Assessment : Target RASS -1, actual RASS -3, CAM-ICU positive, not breathing over vent set rate, bilat rhonchi, pulses present, moving extremities spontaneously Nursing interventions : for sedation? for delirium? (pharm/nonpharm)

46. Clinical case Current vent settings : PS 5, PEEP 5, FiO2 40%, RR 22 Current infusions : Norepinephrine/vasopressin off, insulin gtt, IVF, propofol off Septic shock resolved, passed SAT/SBT Assessment : Target RASS 0, actual RASS 0, CAM-ICU positive, lungs clear, moves all extremities Nursing interventions : for sedation? for delirium? (pharm/nonpharm)

47. Clinical Case What if the patient had not passed the SBT and was beginning to become agitated? Would you consider pharmacologic treatment for delirium at this point? What if we extubated this patient and he later became agitated?

48. Summary Goals for sedation: Are we on the same page? Daily Sedation Cessation : Did you wake up your patient today? Sedative Choice: What is the best option for my patient right now? Roadmap: How do we put it all together at the bedside?

49. Educational Delirium Website www.ICUdelirium.org [email_address] [email_address]