1. Sedation, Analgesia and Paralysis in ICU Mazen Kherallah, MD, FCCP

2. ICU Sedation ICU sedation is a complex clinical problem Current therapeutic approaches all have potential adverse side effects Agitated patients are often hypertensive, increase stress hormones, and require more intensive nursing care

3. The Need for Sedation Anxiety Pain Acute confusional status Mechanical ventilation Treatment or diagnostic procedures Psychological response to stress

4. Patient comfort and Control of pain Anxiolysis and amnesia Blunting adverse autonomic and hemodynamic responses Facilitate nursing management Facilitate mechanical ventilation Avoid self-extubation Reduce oxygen consumption Goals of sedation in the ICU

5. Characteristics of an ideal sedation agents for the ICU Lack of respiratory depression Analgesia, especially for surgical patients Rapid onset, titratable, with a short elimination half-time Sedation with ease of orientation and arousability Anxiolytic Hemodynamic stability

6. The Challenges of ICU Sedation Assessment of sedation Altered pharmacology Tolerance Delayed emergence Withdrawal Drug interaction

7. Sedation Sedatives Causes for Agitation

8. Undersedation Sedatives Causes for Agitation Agitation & anxiety Pain and discomfort Catheter displacement Inadequate ventilation Hypertension Tachycardia Arrhythmias Myocardial ischemia Wound disruption Patient injury

9. Oversedation Sedatives Causes for Agitation Prolonged sedation Delayed emergence Respiratory depression Hypotension Bradycardia Increased protein breakdown Muscle atrophy Venous stasis Pressure injury Loss of patient-staff interaction Increased cost

10. Correctable Causes of Agitation Full bladder Uncomfortable bed position Inadequate ventilator flow rates Mental illness Uremia Drug side effects Disorientation Sleep deprivation Noise Inability to communicate

11. Causes of Agitation Not to be Overlooked Hypoxia Hypercarbia Hypoglycemia Endotracheal tube malposition Pneumothorax Myocardial ischemia Abdominal pain Drug and alcohol withdrawal

12. Altered Pharmacology Midazolam and Age Harper et al. Br J Anesth, 1985;57:866-871

13. Delayed Emergence Overdose (prolonged infusion) –pK derived from healthy patients –Drug interaction –Individual variation Delayed elimination –Liver (C p450 ) –Kidney dysfunction –Active metabolites

14. Morphine Metobolism 80%10%

15. Withdrawal Withdrawal from preoperative drugs Sudden cessation of sedation –Return of underlying agitation Hyperadrenergic syndrome –Hypertension, tachycardia,sweating Opioid withdrawal –Salivation, yawning, diarrhea

16. Drug Interactions Diazepam-Morphine Interaction Synergism Antagonism Morphine Diazepam ED 50 isobologram Righting reflex In rats Kissin et al. Anesthesiology. 1989, 70:689-694

17. Strategies for Patient Comfort Set treatment goal Quantitate sedation and pain Choose the right medication Use combined infusion Reevaluate need Treat withdrawal

18. Set Treatment Goal SedationAnalgesia AmnesiaAnxiolysisHypnosis Patient Comfort

19. Quantitate Sedation & Analgesia Subjective measure Objective measures

20. Sedation Scoring Scales Ramsay Sedation Scale (RSS) Sedation-agitation Scale (SAS) Observers Assessment of Alertness/Sedation Scale (OAASS) Motor Activity Assessment Scale (MAAS) BMJ 1974;2:656-659 Crit Care Med 1999;27:1325-1329 J Clin Psychopharmacol 1990;10:244-251 Crit Care Med 1999;27:1271-1275

21. The Ramsay Scale ScaleDescription 1Anxious and agitated or restless, or both 2Cooperative, oriented, and tranquil 3Response to commands only 4Brisk response to light glabellar tap or loud auditory stimulus 5Sluggish response to light glabellar tap or loud auditory stimulus 6No response to light glabellar tap or loud auditory stimulus

22. The Riker Sedation-Agitation Scale ScoreDescriptionDefinition 7 Dangerous agitationPulling at endotracheal tube, trying to strike at staff, thrashing side to side 6 Very agitatedDoes not calm despite frequent verbal commands, biting ETT 5 AgitatedAnxious or mildly agitated, attempting to sit 4 Calm and cooperative Calm, awakens easily, follows commands 3 SedatedDifficult to arouse, awakens to verbal stimuli, follows simple commands 2 Very sedatedArouse to physical stimuli, but does not communicate spontaneously 1 UnarousableMinimal or no response to noxious stimuli

23. The Motor Activity Assessment Scale ScoreDescriptionDefinition 6 Dangerous agitationPulling at endotracheal tube, trying to strike at staff, thrashing side to side 5 AgitatedDoes not calm despite frequent verbal commands, biting ETT 4 Restless and cooperative Anxious or mildly agitated, attempting to sit 3 Calm and cooperative Calm, awakens easily, follows commands 2 Responsive to touch or name Opens eyes or raises eyebrows or turns head when touched or name is loudly spoken 1 Responsive only to noxious stimuli Opens eyes or raises eyebrows or turns head with noxious stimuli 0 UnresponsiveDoes not move with noxious stimuli

24. What Sedation Scales Do Provide a semiquantitative “score” Standardize treatment endpoints Allow review of efficacy of sedation Facilitate sedation studies Help to avoid oversedation

25. What Sedation Scales Don’t Do Assess anxiety Assess pain Assess sedation in paralyzed patients Predict outcome Agree with each other

26. BIS Monitoring

28. BIS Range Guidelines Awake Responds to loud commands or mild prodding/shaking Low probability to explicit recalls Unresponsive to verbal stimuli Burst suppression Flat line EEG Responds to normal voice Axiolysis Moderate sedation Deep Sedation 100 80 60 40 20 0 BIS

29. Pain Assess Pain Separately

30. Visual Pain Scales 0 1 2 3 4 5 6 7 8 9 10 No pain Worst possible pain

31. Signs of Pain Hypertension Tachycardia Lacrimation Sweating Pupillary dilation

32. Principles of Pain Management Anticipate pain Recognize pain –Ask the patient –Look for signs –Find the source Quantify pain Treat: –Quantify the patient’s perception of pain –Correct the cause where possible –Give appropriate analgesics regularly as required Remember, most sedative agents do not provide analgesia Reassess

33. Nonpharmacologic Interventions Proper position of the patient Stabilization of fractures Elimination of irritating stimulation Proper positioning of the ventilator tubing to avoid traction on endotracheal tube

34. Choose the Right Drug Benzodiazepines Propofol Opioids  -2 agonists

35. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis Benzodiazepines

36. OnsetPeaksDuration Diazepam2-5 min5-30 min>20 hr Midazolam2-3 min5-10 min30-120 min Lorazepam5-20 min30 min10-20 hr

37. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis Propofol

38. OnsetPeaksDuration Propofol30-60 sec2-5 minshort

39. Propofol Dosing 3-5  g/kg/min antiemetic 5-20  g/kg/min anxiolytic 20-50  g/kg/min sedative hypnotic >100  g/kg/min anesthetic

40. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis Opioids

41. Pharmacology of Selected Analgesics AgentDose (iv)Half-lifeMetabolic pathwayActive metabolites Fentanyl 200  g 1.5-6 hrOxidationNone Hydromorphone1.5 mg2-3 hrGlucuronidationNone Morphine10 mg3-7 hrGlucuronidationYes (Sedation in RF) Meperidine75-100 mg 3-4 hrDemethylation & hydroxylation Yes ( neuroexcitation in RF) Codeine120 mg3 hrDemethylation & Glucuronidation Yes ( analgesia, sedation) Remifentanil3-10 minPlasma esteraseNone Keterolac2.4-8.6 hrRenalNone

42. Opioids Lipid Solubility Histamine Release Potency Morphine+/-+++1 Hydromorphone++5 Fentanyl+++-50

43. Opioids OnsetPeaksDuration Morphine2 min20 min2-7 hr Fentanyl30 sec5-15 min30-60 min

44. Problems with Current Sedative Agents MidazolamPropofolOpioids Prolonged weaningX-X Respiratory depressionX-X Severe hypotensionXX- ToleranceX-X Hyperlipidemia-X- Increased infection-X- Constipation--X Lack of orientation and cooperation XXX

45. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists

46. Alpha-2 Receptors Brain (locus ceruleus) Spinal Cord Peripheral vasculature Sedation Anxiolysis Sympatholysis Analgesia Vasoconstriction

47. DEX: Dosing Loading infusion 0.25-1  g/kg (10-20 min) Maintenance infusion 0.2-0.7  g/kg/hr

48. Use Continuous and Combined Infusion Plasma Level Load Maintenance

49. Repeated Bolus Plasma levels

50. Opioid + Hypnotic Infusion Fentanyl + Midazolam or Propofol Analgesia Amnesia Anxiolysis Hypnosis

51. Continuous Infusion Regimens Fentanyl 25-250  g/h Midazolam 0.5-5 mg/hr Propofol 15-50  g/kg/min

52. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct sedation Propofol

53. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct sedation Midazolam

54. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct analgesia Morphine

55. Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct analgesia Fentanyl

56. Reassess Need Use sedation score as endpoint Initiate sedation incrementally to desired level Periodically (q day) titrate infusion rate down until the patient begins to emerge Gradually increase infusion rate again to desired level of sedation Barr, Donner. Crit Care Clin. 1995;11827

57. Treat Withdrawal Acute management –Resume sedation –Beta-blockade, dexmedetomidine Prolonged management –Methadone 5-10 mg VT bid –Clonidine 0.1-0.2 mg VT q8h –Lorazepam 1-2 mg IV q8h