1. Assessing and Managing Sedation in the Intensive Care and the Perioperative Settings

2. SEDATION Curriculum Learning Objectives Manage adult patients who need sedation and analgesia while receiving ventilator support according to current standards and guidelines Use validated scales for sedation, pain, agitation, and delirium in the management of these critically ill patients Assess recent clinical findings in sedation and analgesia management and incorporate them into the management of patients in the acute care, procedural, and surgical sedation settings

3. Desirable Properties for Sedatives in Neurological Surgery Preservation of intracranial hemodynamics Hemodynamic stability Noninterference with neurophysiologic monitoring Cooperative sedation (for functional neurosurgery) Controllability (rapid onset and offset of effect) Neuroprotection Antinociception

4. Potential Drawbacks of Sedative and Analgesic Therapy Oversedation Impede assessment of neurologic function Increase risk for delirium Numerous agent-specific adverse events Kollef MH, et al. Chest. 1998;114:541-548. Pandharipande PP, et al. Anesthesiology. 2006;104:21-26.

5. Sedation in Volunteers Regional and Global CBF 9 volunteers were infused with a 1 mcg/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 mcg/kg/h and 0.6 mcg/kg/h Measured hemodynamics and CBF (via PET scan) Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.

6. Cerebral Blood Flow Dexmedetomidine infusion at 2 doses Both low and high doses –Reduced global CBF by one third –Decreased mean systemic BP, HR, and CO 15% to 20% –Increased PaCO 2 no more than 5 mm Hg CBF reduced during infusion Decreased CBF persisted at least 30 minutes Baseline Low Infusion High Infusion30 min post- termination Note: Color intensity correlates with CBF Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.

7. VariableBaseline DEX load (20 min) LOW DEX HIGH DEX DEX off (30 min) n99995 CO (L/min)7.36.1 * 6.3 * 5.9 * 6.0 * MAP (mm Hg)929179 * 81 * 77 * HR (bpm)7360 * 6562 * pH7.39NA7.35 * 7.36 * PaCO 2 (mm Hg)37NA42 * 39 PaO 2 (mm Hg)96NA989698 [DEX] (pg/mL)0.0NA466 * 628 * 380 * Global CBF (mL · 100 g −1 · min −1 ) 90.5NA63.9 * 60.6 * 63.4 * Effects of Treatment on Hemodynamic Variables Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059. * P < 0.05, compared with baseline

8. Treatment CBF (mL · 100 g −1 · min −1 ) CBF (95% CI) P value (vs baseline) Global CBF Baseline91(72–114) DEX-LOW64(51–81)0.0002 DEX-HIGH61(48–76)0.0006 DEX-OFF63(49–83)0.0120 Effect of Sedative on Global CBF Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.

9. Cerebral Blood Flow Velocity, Cerebral Metabolic Rate, and Carbon Dioxide Response in Normal Humans Hypothesis: dexmedetomidine would reduce the CBF/CMR ratio Middle cerebral artery velocity was recorded continuously in 6 volunteers CBFV and CMR were measured at 6 intervals before, during, and after DEX administration Drummond JC, et al. Anesthesiology. 2008;108:225-232.

10. CBFV and CMRe Drummond JC, et al. Anesthesiology. 2008;108:225-232.

11. Sedation Did Not Decrease CBFV/CMR Ratio The expected decrease in CBFV was offset by an unanticipated decrease in CMR, leaving CBFV/CMR unchanged Significant reduction in the slope of the PaCO 2 –CBFV relation during dex administration Conclusion: dex should be further evaluated in patients with neurologic injury

12. Brain Oxygenation Maintained in Neurovascular Surgery Patients Small Case Series Drummond JC, et al. J Neurosurg Anesthesiol. 2010;22(4):336-341. *P < 0.04 from baseline N = 5 patients General anesthesia Sufentanil Sevoflurane N 2 O Dex at time = 0

13. Intracranial Surgery

14. Need for Sedation and Analgesia in Neurosurgical Patients Prevent 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;30:746-752. Weinert C. Curr Opin in Crit Care. 2005;11:376-380. Kress JP, et al. Am J Respir Crit Care Med. 1996;153:1012-1018.

15. Double-Blind Randomized Controlled Trial: Intracranial Tumor Surgery 54 patients scheduled for elective surgery of supratentorial brain tumor were randomized –Placebo –Dex, target plasma conc = 0.2 ng/mL –Dex, target plasma conc = 0.4 ng/mL Dex groups received fentanyl 2 mcg/kg at induction and before the start of the operation; placebo group received 4 mcg/kg Anesthesia maintained with NO 2 in O 2 and isoflurane Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665.

16. Hemodynamics Maximum increases from baseline ** P < 0.01, DEX-0.4 vs DEX-0.2 and placebo ## P < 0.01, DEX-0.2 and DEX-0.4 vs placebo

17. Dex increased median percentage of time points with SD and HR within 20% of comparison values Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665. Hemodynamics Intraoperative cardiovascular variability

18. Dex infusion decreased hemodynamic responses to noxious stimuli and attenuated the emergence from anesthesia – Decreased the immediate hemodynamic response – Decreased the time to removal of the tracheal tube However, the need to treat hypertension or tachycardia was similar in all groups No difference between the groups in the occurrence of bradycardia or hypotension At 2 hours after extubation, there was no difference in the Hudes class or subjective sedation score between the groups Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665. Randomized Controlled Trial of Sedation in IC Tumor Surgery

19. Hemodynamics During Craniotomy Double-blind, placebo-controlled study in patients undergoing intracranial surgery Comparison of patients receiving either sevoflurane- opioid-placebo anesthesia (n = 28) or sevoflurane- opioid-dexmedetomidine anesthesia (n = 28) Data collected: –Hemodynamic variables – systolic blood pressure (SBP) and heart rate (HR) –Administration of sevoflurane, opioids, and/or antihypertensive agents intraoperatively –Time spent in PACU and administration of opioids and/or antihypertensive agents postoperatively Bekker A, et al. Anesth Analg. 2008;107:1340-1347.

20. Hemodynamics During Craniotomy No increase of hypotensive episodes or bradycardia Placebo (n = 28)Dexmedetomidine (n = 28) AUC SBP (mmHg×min/hr)Median (IQR) > 130 mmHg35 (10-101)9 (1-49) ‡ < 90 mmHg27 (8-58)48 (10-96) AUC HR (beats×min/hr) > 90 bpm12 (0-59)8 (0-26) < 50 bpm0 (0-2)0 (0-4) Intraoperative AverageMean (SD) SBP (mmHg)106.5 (9.9)102.2 (9.4) HR (bpm)74.6 (13.0)67.9 (1.7) ‡ ‡ P < 0.05 Bekker A, et al. Anesth Analg. 2008;107:1340-1347.

21. Hemodynamics During Craniotomy Placebo (n = 28)Dexmedetomidine (n = 28) Intraoperative Drugs Sevoflurane, mean (%ET)1.16 (0.38)1.00 (0.37) Fentanyl, μg/kg2.6 (1.9)1.9 (1.0) Remifentanil, μg/kg27 (13)19(11) * Any BP med, n (%)24 (86%)12 (43%) † Postoperative Measures PACU duration (min)130 (27)91 (17) ‡ Times SBP > 130 mmHg2.5 (2.0)1.25 (1.55) * Any analgesic, n (%)18 (64%)15 (54%) Any BP med, n (%)14 (50%)10 (36%) * P < 0.05 compared with placebo † P = 0.0008 compared with placebo ‡ P < 0.0001 compared with placebo Bekker A, et al. Anesth Analg. 2008;107:1340-1347.

22. NeurolCU

23. Managing Traumatic Brain Injury Monitor ICP Diagnosis Urgent surgery when indicated Blood pressure management Hyperosmolar therapy (mannitol, hypertonic saline) Sedation/analgesia Nutrition DVT prophylaxis Prevention of seizure Saiki RL. Crit Care Nurs Clin North Am. 2009;21:549-559.

24. Sedation/Analgesia for Traumatic Brain Injury Goal: reduce ICP by decreasing pain, agitation Saiki RL. Crit Care Nurs Clin North Am. 2009;21:549-559. AgentAdvantagesConsiderations Propofol Short acting Reduces cerebral metabolism, O 2 consumption Improves ICP after 3d Propofol infusion syndrome Barbiturates Reduce ICP Neuroprotection Interfere with neuro exam Hypotension, reduced CBF OCs not improved with severe TBI

25. Traumatic Brain Injury with Reduced PbtO 2 Medical Interventions Bohman LE, et al. Neurocrit Care. 2011;14:361-369.

26. Traumatic Brain Injury with Reduced PbtO 2 Effectiveness of Interventions Bohman LE, et al. Neurocrit Care. 2011;14:361-369. Loraz/Midaz Benefit of PbtO 2 not proven Response Rate/ Overall Patient Response Rate

27. Monitoring ICP After TBI Retrospective analysis 246 TBI patients Classify ICP profiles by time to peak Correlate with outcomes Bremmer R, et al. Neurocrit Care. 2010;12:362-368. 1-2 d peak 3-5 d peak >5 d peak

28. Monitoring ICP After TBI Bremmer R, et al. Neurocrit Care. 2010;12:362-368.

29. Awake Craniotomy Functional Neurosurgery

30. Awake Craniotomy Procedures Bilotta F, et al. Curr Opin Anaesthesiol. 2009;22(5):560-565.

31. Characteristics of Cooperative Sedation Patients easily transition from sleep to wakefulness and task performance when aroused Patients can resume rest when not stimulated Most useful during procedures in which communication with the patient must be maintained, facilitates patient participation in therapeutic maneuvers Reduces risk of drug-induced complications Bekker A, et al. Neurosurgery. 2005;57(1 Suppl):1-10.

32. Current Sedatives for Awake Craniotomy Bonhomme V, et al. Eur J Anaesthesiol. 2009;26(11):906-912.

33. Asleep-Awake-Asleep Overview Anesthesia Surgical Preparation Cooperative Sedation Eloquent Area Mapping Surgery Anesthesia Surgical Closure

34. Sedation During Awake Craniotomy Is Dex Compatible With Neurocognitive Testing? Bekker 2001Bustillo 2002Lotto 2003Ard 2003Ard 2005 Patient Number1511217 IndicationNeoplasmAVM Tumor, epilepsy, aneurysm Pediatric epilepsyTumor, epilepsy Dex Load, μg/kg10 or 110.5 Mean Dex Dose, μg/kg0.813.41.6 Dex Infusion, μg/kg.h0.4, 0.2, 0.10.2–0.70.60.5, 0.2, 0.10.1–0.4 Mean MDZ, mg2.811.7 (in 6 pts) Mean Fentanyl, μg100160100191 (in 16 pts) Other AnesthesiaProp, N 2 O, sevo(flumazenil)PropProp, N 2 O, sevo Cognitive TestLanguageWadaLanguage Test successful?1/10/510/112/217/17 Bekker AY, et al. Anesth Analg. 2001;92(5):1251-1253. Bustillo MA, et al. J Neurosurg Anesthesiol. 2002;14(3):209-212. Lotto M, et al. Anesthesiology. 2003; 99: A356. Ard J, et al. J Neurosurg Anesthesiol. 2003;15(3):263-266. Ard JL, et al. Surg Neurol. 2005;63(2):114-116. AVM = arteriovenous malformation Prop = propofol Sevo = sevoflurane

35. Implanting DBS for PD Sedation is demanding –Recordings of movement-related neurons –Preservation of PD symptoms for DBS localization –Patient cooperation –Halo restricts movement, respiratory depression problematic GABAergic sedatives (MDZ, propofol) not useful –Ameliorate tremor and rigidity (precludes mapping & testing) –Impair consciousness –May cause respiratory depression Rozet I, et al. Anesth Analg. 2006;103(5):1224-1228.

36. Implanting DBS for PD Retrospective study with dexmedetomidine –Control (no sedative) n = 8 patients –Dex (0.1-0.3 mcg/kg.h, more to goal [OAA/S = 4])n = 11 patients Results –MER unimpaired by dex –Surgical time shorter with dex (4 vs 6 h, P = 0.05) –Less intraoperative use of antihypertensives (100% vs 54%, P = 0.048) –Dex preserved clinical signs of PD Tremor Rigidity Bradykinesia Study limitations –Small –Observational –Only perioperative outcomes presented Rozet I, et al. Anesth Analg. 2006;103(5):1224-1228.

37. Implanting DBS (2) Retrospective analysis of 258 procedures (250 patients) Patients with motor disorders, 68% PD Propofol most common sedative, 91% Propofol used almost exclusively in the first 30 to 45 minutes to facilitate head-frame placement Khatib R, et al. J Neurosurg Anesthesiol. 2008;20:36-40.

38. Conscious Sedation for Glioma Resection? Retrospective cohort-matched study Initial and final surgery with propofol/sevoflurane Dex with prn midazolam during resection Peruzzi P, et al. J Neurosurg. 2011;114(3):633-639.

39. Monitoring EEG in Patients with Temporal Lobe Epilepsy Oda Y, et al. Anesth Analg. 2007;105(5):1272-1277. Talke P, et al. J Neurosurg Anesth. 2007;19(3):195-199.

40. Spinal Surgery/AFOI

41. Drugs for Fiberoptic Intubation Agent Class ExampleAdvantagesConsiderations GABA agonist Benzodiazepine Midazolam Quick onset Injection not painful Short duration Not analgesic Airway reflexes persist GABA agonist Benzodiazepine Propofol Quick onsetRespiratory depression Unconsciousness Decreased bp, cardiac output Increased HR OpioidFentanyl Remifentanil Analgesic Cough suppressive Respiratory depression  2 Agonist DexmedetomidinePt easily arousable Anxiolytic Analgesic No respir. depression Transient hypertension Hypotension Bradycardia Summary courtesy of Pratik Pandharipande, MD.

42. Propofol vs Combined Sedation in Flexible Bronchoscopy Randomized non-inferiority trial 200 diverse patients received propofol or midazolam/hydrocodone 1 o endpoints –Mean lowest SaO 2 –Readiness for discharge at 1h Result –No difference in mean lowest SaO 2 –Propofol group had  Higher readiness for discharge score (P = 0.035)  Less tachycardia  Higher cough scores Conclusion: Propofol is a viable alternative to midazolam/hydrocodone for FB Stolz D, et al. Eur Respir J. 2009;34:1024-1030.

43. Dexmedetomidine Increases Comfort in AFOI Double-blinded randomized trial Midazolam +/- dexmedetomidine Awake fiberoptic intubation (AFOI) Patient comfort rated by 2 observers Bergese SD, et al. J Clin Anesth. 2010;22(1):35-40. Total Comfort Score (max = 35) Pre- oxygenation Introduction of scope Introduction of ET tube n = 24 n = 31

44. Sedation for AFOI Study Design 1 Phase 3 multicenter study comparing Dex with placebo (Pbo) in the sedation of nonintubated patients with anticipated difficult-to-intubate airways who were undergoing AFOI Patients randomized –Dex 1 μg/kg loading dose (10 min) and 0.7 μg/kg/hr maintenance infusion –Pbo in normal saline After topical anesthesia (lidocaine) and a Ramsay Sedation Scale (RSS) score ≥ 2 was achieved, nasal or oral intubation using a flexible fiberoptic bronchoscope was performed Bergese SD, et al. Am J Ther. 2010;17(6):586-595.

45. MDZ was administered as required as rescue medication for patients with a RSS score = 1 until target RSS score ≥ 2 Primary endpoint: percentage of patients requiring rescue MDZ to achieve and/or maintain a target sedation level (RSS score ≥ 2) Sedation for AFOI Study Design 2 Bergese SD, et al. Am J Ther. 2010;17(6):586-595.

46. Sedation for AFOI Results Significantly fewer patients in the Dex group required rescue MDZ to achieve and/or maintain sedation compared with the Pbo group –47.3% vs 86.0%, P < 0.001 The total mean supplemental MDZ dose required was significantly lower in Dex-treated patients than in Pbo- treated patients –1.07 mg vs 2.85 mg, P < 0.001 Blood pressure was the most often reported AE –27% of the Dex group had hypotension –28% of the placebo group had hypertension Bergese SD, et al. Am J Ther. 2010;17(6):586-595.

47. Sedation for AFOI MDZ Use 100 90 80 70 60 50 40 30 20 10 0 Patients (%) Dexmedetomidine (n = 55) Placebo (n = 50) Did Not Require MDZ Required MDZ Mean MDZ Dose 1.07 mg 47%* 53% Mean MDZ Dose 2.85 mg 86% 14% % patients receiving MDZ and mean dose both P < 0.001 Bergese SD, et al. Am J Ther. 2010;17(6):586-595.

48. Sedation for AFOI Conclusions Compared to placebo, Dex reduced MDZ requirement in patients with high-risk airways undergoing AFOI –Fewer Dex patients received MDZ –Dex patients requiring MDZ received a lower mean dose Dex is a viable choice for sedation of patients requiring AFOI Bergese SD, et al. Am J Ther. 2010;17(6):586-595.

49. SSEP Amplitude and MEP Voltage Bala E, et al. Anesthesiology. 2008;109(3):417-425. MEPs: dorsal interossei abductor hallucis longus SSEPs: posterior tibial nerve (P37) median nerve (N20)

50. Median Nerve SSEPs Tracings Case Report Left Right Bloom M, et al. J Neurosurg Anesth. 2002;13(4):320-322. Baseline Instrumentation/propofol Closure/dex Baseline Instrumentation/propofol Closure/dex

51. Does Sedation Attenuate tceMEP? Subjects 44 patients with idiopathic scoliosis ProcedurePosterior spine fusion surgery Anesthesia/analgesia N 2 O, sevoflurane, fentanyl, MDZ, remifentanil Primary endpoint Amplitude of transcranial electric motor- evoked potential (tceMEP) Treatment Groups Mahmoud M, et al. Anesthesiology. 2010;112(6):1364-1373.

52. Does Sedation Attenuate tceMEP? 14/40 Dex subjects experienced reduction of tceMEP amplitude (≥ 3/4 muscles affected) –Mean time to recovery (≥ 70% of baseline) = 68 min Dex main effect significant in FDI and TA (P = 0.015 and 0.012) Propofol main effect not significant Mahmoud M, et al. Anesthesiology. 2010;112(6):1364-1373. Percent Change from Baseline in tceMEP Amplitude

53. Does Sedation Attenuate tceMEP? Mahmoud M, et al. Anesthesiology. 2010;112(6):1364-1373. Attenuation of tceMEP varied with Dex dose –High and intermediate group 11/23 (48%) –Low group 2/17 (12%) Increasing the target level of propofol from 2.5 to 5 μg/ml without increasing the level of Dex had no significant effect on the amplitude of the tceMEPs Propofol–Dex interaction was not significant Study limited by early termination, only loading phase analyzed Conclusions Dex can be used as an adjunct to remifentanil-propofol total IV anesthesia when tceMEP and SSEP monitoring is required Target plasma concentrations of 0.4 ng/ml Dex and 2.5 μg/ml propofol seem to have minimal effect on tceMEP amplitude P < 0.025

54. Neurosurgery Summary Neurosurgery presents special challenges for sedation –Preserve cerebral hemodynamic stability –Maintain patient consciousness for some procedures Oversedation presents risks –Delirium –Increased ICU LOS –Lack of patient interaction during procedure Emerging combinations of anesthetic and sedative compounds have attractive properties for addressing these unique requirements