Fast Tracking in Ambulatory Surgery Prevention and Management of Anesthesia Awareness October 2004 Fast Tracking in Ambulatory Surgery T. J. Gan, M.D., F.R.C.A. FFARCS(I) Professor and Vice Chairman Director of Clinical Research Department of Anesthesiology Duke University Medical Center ADVANCED AWARENESS TRAINING MODULE

Prevention and Management of Anesthesia Awareness Outline October 2004 Anesthetic techniques Effective management of PONV Pain NMB Monitoring depth of anesthesia PACU fast track and discharge scoring systems ADVANCED AWARENESS TRAINING MODULE

Freestanding ASCs in the United States The number of freestanding ASCs jumped to 5,068 during 2005 Source: Verispan and William Blair & Co., LLC Estimates RS Daniels, Outpatient Surgery;Jan 2006:108-111

Should you use intravenous of inhalational anesthesia?

Inhalational vs. Intravenous Anesthetic – Recovery Profile min * p<0.05 * * * Tang et al. Anesthesiology 1999;91:253-61

Inhalational vs. Intravenous Anesthetic – Recovery Profile min * * p<0.05 * * Tang et al. Anesthesiology 1999;91:253-61

Choice of Anesthetic Agents in Fast-Tracking 51 women undergoing GYN laparoscopy Propofol for induction Randomized to Propofol, sevoflurane and desflurane BIS monitored to keep at 60 Triple antiemetic prophylaxis Local anesthetic infiltration Coloma et al. Anesth Analg 2001;93:112-5

Coloma et al. Anesth Analg 2001;93:112-5 Propofol vs. Sevo vs. Des Coloma et al. Anesth Analg 2001;93:112-5

TIVA (Prop/Remi) versus Desflurane in Children ENT Procedures Remifentanil Propofol Desflurane Nitrous Spon Ventilation 11 ± 4 min 7 ± 3 min Eye Opening 14 ± 7 min Aldrete Score 9 17± 7 min 17 ± 7 min Agitation 44% 80% Grundmann et al. Acta Anesth Scndinavica 1998;42:845-50

Larsen B et al. Anesth Analg 2000;90:168-74

Gupta et al. Anesth Analg 2004;98:632-41 Compared propofol, Isoflurane, Sevoflurane and Desflurane Propofol vs. Isoflurane 18 studies Propofol vs. Desflurane 13 studies Propofol vs. Sevoflurane 11 studies Isoflurane vs. Sevoflurane 6 studies Isoflurane vs. Desflurrane 4 studies Sevoflurane vs. Desflurane 6 studies Gupta et al. Anesth Analg 2004;98:632-41

Systematic Analysis - Results Early recovery Faster with desflurane than propofol and isoflurane Faster with Sevoflurane than isoflurane Intermediate recovery (Home readiness) Sevoflurane faster than isoflurane (5 min) PONV, PDNV, rescue antiemetic and headache Propofol better than inhalational agents Gupta et al. Anesth Analg 2004;98:632-41

General Anesthesia vs. Regional Anesthesia

Chan et al. Anesth Analg 2001;93:1181-4 Outpatient hand surgery Randomized to GA – Propofol/Isoflurane/Fentanyl IVRA – 0.5% lidocaine Axillary Block – lidocaine/chlorrprocaine Regional groups received sedation with propofol Chan et al. Anesth Analg 2001;93:1181-4

Chan et al. Anesth Analg 2001;93:1181-4

Korhonen et al. anesth Analg 2004;99:1668-73 Spinal vs. GA - Outcomes Korhonen et al. anesth Analg 2004;99:1668-73

Spinal Anethesia vs. Desflurane GA Korhonen et al. anesth Analg 2004;99:1668-73

Hadzic A et al. Anesthesiology 2005;102:1001-7 50 outpatients for open rotator cuff repair Randomized to Fast track GA with LA infiltration (bupivacaine 0.25%) Interscalene block (ropivavaine 0.75%) Outcomes: Phase I and II recovery Daily activities up to 2 weeks. Patient satisfaction Hadzic A et al. Anesthesiology 2005;102:1001-7

Hadzic A et al. Anesthesiology 2005;102:1001-7

Management of PONV

Functional Interference Due to Nausea and/or Vomiting White et al. Anesth Analg 2008;107:452-8 Emesis Nausea Functional Interference Patients who reported emesis experienced a median of at least 2 episodes. Patients experienced more frequent nausea than vomiting across all study intervals. Forty-four percent of the study population experienced interference with postoperative functioning due to nausea and/or vomiting during the 3-day post-surgical study period. This interference occurred for 29% of patients in the 0-6 h interval and for 35% in the 6 ‑ 72 h study interval.

PONV Occurring in the PACU* and/or Within 48 Hours After PACU Discharge Carroll p905/T6/A 7+14+24+13=58 patients w/ PONV 7+14+24=45 45/58=78% 7+14=21 21/58=36% 20 40 60 80 100 78% Patients Who Experienced PONV, % 36% Carroll p905/T6/A 7+14+24+13=58 patients w/ PONV 13+24=37 37/58=64% 36% A study designed to evaluate PONV in patients receiving care at outpatient surgery centers provides valuable insight regarding the incidence of PONV. In this study, the incidence of PONV was measured in the recovery room, by telephone the day after discharge, and by a questionnaire patients were instructed to complete 5 days after discharge. The study enrolled adult patients (≥18 years of age) who were scheduled to receive general anesthesia and undergo 1 of 4 selected surgeries: laparoscopy, dilation and curettage (D&C), arthroscopy, or hernia repair. Among the 143 outpatients with complete data, the overall incidence of PONV was 41%.1 As shown in this figure, among patients who experienced PONV, the majority of PONV occurred initially within the first 48 hours after discharge from the postanesthesia care unit (PACU). In fact, only 36% of patients who experienced PONV did so initially in the PACU, whereas 78% of patients who experienced PONV did so initially in the PACU and/or within 48 hours after PACU discharge.1 Some patients who initially experienced PONV within 48 hours after PACU discharge continued to experience PONV for up to 5 days after PACU discharge.1 Also of interest is the emergence of PONV in patients who did not experience PONV in the recovery room. Nearly 65% of patients (37/58) with PONV did not experience symptoms until after discharge from the PACU.1 Carroll p903/A,C; p904/B,C Initial PONV in the PACU (21/58) Initial PONV in the PACU and/or Within 48 Hours After PACU Discharge (45/58) Carroll p903/C; p904/A Carroll p905/T6/A 7+14+24+13=58 patients w/ PONV 58/143=41% Carroll p905/T6/A 7+14+24+13=58 patients w/ PONV 7+14+24=45 45/58=78% 7+14=21 21/58=36% Nearly 65% of patients did not experience PONV symptoms until after discharge from the PACU. Carroll p905/T6/A 7+14+24+13=58 patients w/ PONV 13+24=37 37/58=64% * PACU=postanesthesia care unit. Carroll NV et al. Anesth Analg. 1995;80:903–909. Reference: 1. Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea and vomiting after discharge from outpatient surgery centers. Anesth Analg. 1995;80:903–909.

Wengritzky et al. BJA 2010;104:158-66

Leslie et al. BJA 2009;101:498-505

Apfel C, et al. Acta Anaesthesiol Scand 1998;42:495-501. PONV Risk Scores % Risk Factors Points Female 1 History of PONV/motion sickness Postop Opioid Non-Smoker Apfel C, et al. Acta Anaesthesiol Scand 1998;42:495-501.

ODT – Post Discharge Incidence of Nausea and Emesis % of Patients * Gan et al. Anesth Analg 2002;94:1199-1200

Cumulative Incidence of PONV TDS + Ondansetron vs. Ondansetron 1. Transderm Scop Phase IV Clinical Study Report Page 297-300 Table 14.2.7.1 Gan et al. Anesth Analg 2009;108:1498 –504

Factorial Designed Trial: 6 Interventions for PONV Prevention High-Risk PONV Patients (N=4,123) Results: PONV risk reduction Ondansetron 26% Dexamethasone 26% Droperidol 26% Propofol 19% Nitrogen 12% (nitrous oxide exclusion) Remifentanil not significant Apfel CC, et al. N Engl J Med. 2004;350:2441-2451.

Factorial Designed Trial: Ondansetron, Dexamethasone, and Droperidol Antiemetic Drug Combination Outcomes (N=5,161) 60 50 * † ‡ 40 *† *‡ †‡ Incidence of Postoperative Nausea and Vomiting (%) 30 20 10 3 2 1 No. of Antiemetics Incidence for each antiemetic or combination Average value for each number of antiemetics *Ondansetron; †dexamethasone; ‡ droperidol. Apfel CC, et al. N Engl J Med. 2004;350:2441-2451. Adapted with permission.

Algorithm for PONV Prophylaxis Evaluate risk of PONV in surgical patient and patient’s concerns Low No prophylaxis unless there is medical risk of sequelae from vomiting Moderate High Consider regional anesthesia Not Indicated If general anesthesia is used, reduce baseline risk factors when clinically practical & consider using nonpharmacologic therapies Avoid opioids (IIIA) Avoid N2O (IIA) Avoid high dose reversal agent (IIA) Adequate hydration (IIIA) Propofol anesthetic (IA) Patients at moderate risk Consider antiemetic prophylaxis with monotherapy (adults) or combination therapy (children & adults) Patients at high risk Initiate combination therapy with 2 or 3 prophylactic agents from different classes Gan et al. Anesth Analg 2003;97:62-71Gan JAMA 2002;287:1233-6

Gan et al. A&A 2007;105:1615-28

Management of Pain

Postoperative Pain: All Patients (in Hospital up to 2 Weeks) 1 2 Patients’ worst pain Any pain Slight pain Moderate pain Severe pain Extreme pain 1Apfelbaum, Gan et al. Anesth Analg. 2003;97:534-40; 2Warfield et al. Anesthesiology. 1993

Pavlin et al. Anesth Analg 2002;95:627-34 24% had pain score ≥ 7 24% delayed PACU discharge by pain Maximum pain score predictive of total recovery Lower pain score (by 25%) if LA or NASID were used Pavlin et al. Anesth Analg 2002;95:627-34

Structural Remodeling Long-Term Consequences of Acute Pain: Potential for Progression to Chronic Pain CNS Neuroplasticity Hyperactivity Structural Remodeling Sustained Activation Peripheral Nociceptive Fibers Sensitization Surgery or injury causes inflammation Peripheral Nociceptive Fibers Transient Activation Sustained currents Changes in neuronal function following injury can take place at the level of the periphery, the spinal cord, and the brain, and may increase the magnitude of perceived pain and contribute to the development of chronic pain.1 Peripheral nociceptors can become more sensitive following repeated exposure to noxious stimuli due to release of chemical mediators from damaged cells following injury and inflammation, and alteration of sodium channel activity in the nociceptor membrane.2 Plastic changes in the spinal dorsal horn due to increased afferent input can also play a role in neuronal sensitization.1,2 High-frequency action potentials result in release of neuropeptides from the nociceptor central terminals in the spinal cord and subsequent modification of neuronal membrane excitability.2 The more intense the peripheral noxious stimulus, the higher the frequency and the longer the duration of the train of action potentials activated in the nociceptors.2 During the acute phase of central sensitization, release of transmitters from nociceptor central terminals in the dorsal horn causes changes in synaptic receptor density, as well as changes in the threshold and kinetics of neuronal activation. Together, these changes dramatically increase the efficiency of pain transmission.2 It should be noted that most of the available information regarding modulation of pain perception at the peripheral, spinal, and supraspinal levels is based on animal research. However, the few published human studies indicate that peripheral sensitization and central hyperexcitability may also be important determinants for acute and chronic pain in humans.1 CHRONIC PAIN ACUTE PAIN Woolf. Ann Intern Med. 2004;140:441; Petersen-Felix. Swiss Med Weekly. 2002;132:273-278; Woolf. Nature.1983;306:686-688; Woolf et al. Nature. 1992;355:75-8. Petersen-Felix S, Curatolo M. Neuroplasticity--an important factor in acute and chronic pain. Swiss Med Wkly. 2002;132(21-22):273-478. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451.

Acute Postoperative Pain Has Been Associated With Chronic Pain After Common Procedures Incidence of Chronic Post-Surgical Pain US Surgical Volumes (1000s)1 Amputation 57-62%2 159 Breast surgery 27-48%3,4 479 Thoracotomy 52-61%5,6 Unknown Inguinal hernia repair 19-40%7,8 609 Coronary artery bypass 23-39%9-11 598 Caesarean section 12%12 220 Acute postoperative pain is followed by chronic pain after common procedures, the rate of which varies based on type of surgery. Intensity of acute postsurgical pain has been correlated with the development of chronic postsurgical pain, as have other factors such as nerve injury and inflammation. Factors correlated with the development of post-surgical chronic pain1: Nerve injury Inflammation Intense acute postoperative pain Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367:618-625. Hanley MA, Jensen MP, Smith DG, et al. Preamputation pain and acute pain predict chronic pain after lower extremity amputation. J Pain. 2007 Feb;8:102-109. Carpenter JS, Andrykowski MA, Sloan P, et al. Postmastectomy/postlumpectomy pain in breast cancer survivors. J Clin Epidemiol. 1998;51:1285-1292. Poleshuck EL, Katz J, Andrus CH, et al. Risk factors for chronic pain following breast cancer surgery: a prospective study. J Pain. 2006 Sep;7:626-634. Katz J, Jackson M, Kavanagh BP, et al. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996;12:50-55. Perttunen K, Tasmuth T, Kalso E. Chronic pain after thoracic surgery: a follow-up study. Acta Anaesthesiol Scand. 1999;43:563-567. Massaron S, Bona S, Fumagalli U, et al. Analysis of post-surgical pain after inguinal hernia repair: a prospective study of 1,440 operations. Hernia. 2007;11:517-525. O'Dwyer PJ, Kingsnorth AN, Molloy RG, et al. Randomized clinical trial assessing impact of a lightweight or heavyweight mesh on chronic pain after inguinal hernia repair. Br J Surg. 2005 Feb;92(2):166-70. Steegers MA, van de Luijtgaarden A, Noyez L, et al. The role of angina pectoris in chronic pain after coronary artery bypass graft surgery. J Pain. 2007;8:667-673. Taillefer MC, Carrier M, Bélisle S, et al. Prevalence, characteristics, and predictors of chronic nonanginal postoperative pain after a cardiac operation: a cross-sectional study. J Thorac Cardiovasc Surg. 2006;131:1274-1280. Bruce J, Drury N, Poobalan AS, et al. The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study. Pain. 2003;104:265-273. Nikolajsen L, Sørensen HC, Jensen TS, Kehlet H. Chronic pain following Caesarean section. Acta Anaesthesiol Scand. 2004;48:111-116. 1. Kehlet et al. Lancet. 2006;367:1618-1625; 2. Hanley et al. J Pain. 2007;8:102-10; 3. Carpenter et al. Cancer Prac. 1999;7:66-70; 4. Poleschuk et al. J Pain. 2006;7:626-634; 5. Katz et al. Clin J Pain. 1996;12:50-55; 6. Perttunen et al. Acta Anaesthesiol Scand. 1999;43:563-567; 7.Massaron et al. Hernia. 2007;11:517-525; 8. O’Dwyer et al. Br J Surg. 2005;92:166-170; 9. Steegers et al. J Pain. 2007;8:667-673; 10. Taillefer et al. J Thorac Cardiovasc Surg. 2006;131:1274-1280; 11. Bruce et al. Pain. 2003;104:265-273; 12. Nikolajsen et al. Acta Anaesthesiol Scand. 2004;48:111-116.

Multimodal or balanced analgesia Opioid  doses of each analgesic Improved anti- nociception due to synergistic/ additive effects May  severity of side effects of each drug Potentiation Conventional NSAIDs/coxibs, paracetamol, nerve blocks Kehlet H, et al. Anesth Analg 1993;77:1048–56 Playford RJ, et al. Digestion 1991;49:198–203

Adjunctive Analgesics NSAIDs and COX-2 selective inhibitors (coxibs) Acetaminophen Local anesthetics Ketamine Gabapentin / pregabalin Clonidine / dexmedetomidine Steroids Non pharmacological techniques

Acetaminophen, NSAIDs or COX-2 inhibitors 52 RPCTs (~5000 patients) Acetaminophen, NSAIDs or COX-2 inhibitors Average morphine consumption – 49 mg/24hrs 15-55 % decrease in morphine consumption VAS pain decreased by 1 cm NSAIDs / COX-2 Specific inhibitors ↓ nausea from 28.8% to 22% ↓ Sedation 15.4% to 12.7% ↑ Renal failure 0% to 1.7%

Morphine Consumption – 24 hours Elia et al. Anesthesiology 2005;103:1296-1304

Regional Anesthesia in Ambulatory Surgery 1800 patients receiving upper or lower extremity block with 0.5% ropivacaine Interscelene, supraclavicular, axillary, lumbar plexus, emoral and sciatic block Discharged on the day of surgery Conversion to GA 1-6% No opioid in PACU – 89% to 92% Require opioid up to 7 days – 21% to 27% Persistent parasthesia 0.25%, resolved within 3 months Klein et al. Anesth Analg 2002;94:65–70

Hadzic et al Anesth Analg 2005;100:976–81

Hadzic et al. Anesthesiology 2004;101:127-32

Ambulatory Infusion Pump

Management of Neuromuscular Blockade

Reversal of Rocuronium 0.45 mg/kg 3/25/2017 Recovery times after administration of a single dose of 0.45 mg/kg (1.5 × ED95) rocuronium. In one group (Spont), spontaneous recovery is allowed. In the remaining groups, 70 µg/kg neostigmine is administered 5 minutes after rocuronium or at 1%, 10%, and 25% recovery of the first twitch (T1) from its control value. *P < 0.01 versus spontaneous recovery. Note that times to attain a train-of-four ratio of 0.9 are significantly shorter when neostigmine is administered at T1 = 10% or 25% of control tension. (Figure constructed based on data redrawn from Bevan JC, Collins L, Fowler C, et al: Early and late reversal of rocuronium and vecuronium with neostigmine in adults and children. Anesth Analg 89:333–339, 1999.) Bevan JC et al. Anesth Analg 1999;89:333–339

Cisatracurium vs. Rocuronium TOF  0.9 at EOS 27% 7% TOF at reversal 63  7% 40 19% EOS to TOF = 0.9 10  9 min 18  13 min Cammu et al. Eu J Anaesth 2002;19:129-34

Assessment of NMB Recovery Positive Predictive Value % (95 CI) Negative Predictive Value % (95 CI) TOF<0.7 TOF<0.9 Head lift 19 (15-23) 53 (47-58) 85 (81-89) 58 (52-63) Tongue depressor 28 (23-33) 54 (48-59) 86 (83-90) 56 (51-62) TOF 79 (75-82) 93 (91-94) 87 (84-90) 57 (53-61) DBS 83 (78-86) 97 (95-98) 88 (85-90) (54-62) Debaene et al. Anesthesiology 2003;98:1042-8

Residual Paralysis Debaene et al. Anesthesiology 2003;98:1042-8 Time between the administration of a single dose of NMB and the arrival in the PACU. Debaene et al. Anesthesiology 2003;98:1042-8

Sugammadex Angewandte Chemie 2002:41:266 -270

First Human Exposure to ORG25969 Gijsenbergh et al. 29 healthy men Anesthesia: propofol target-controlled infusion and remifentanil Rocuronium 0.6mg/kg Placebo or sugammadex ranging from 0.1 to 8.0 mg/kg Gijsenbergh, Francois Anesthesiology. 103(4):695-703, 2005.

Phase 1 Gijsenbergh, Francois Anesthesiology. 103(4):695-703, 2005. 3/25/2017 Train-of-four tracing from one volunteer who participated during part 2 of the study. The blue line represents the height of the twitch, and the dashed red line is the value of the train-of-four ratio. The volunteer received 0.6 mg/kg rocuronium (Roc) followed by placebo at 3 min (A) in one treatment period, followed by 8 mg/kg Org 25969 in another treatment period (B). No recurarization was observed in the 90 min during which the neuromuscular block was monitored. Gijsenbergh, Francois Anesthesiology. 103(4):695-703, 2005.

Depth of Anesthesia Monitoring

CLINICAL UTILITY TRIAL: EMERGENCE TIMES Prevention and Management of Anesthesia Awareness CLINICAL UTILITY TRIAL: EMERGENCE TIMES October 2004 minutes * p < 0.001 As a result of decreased drug usage, patients woke up faster, they opened their eyes faster and they responded to verbal command faster. On average, emergence from anesthesia dropped from 10 minutes in the standard practice group to only 6 minutes in the BIS monitored group. A common question is often asked, “what difference does 3 or 4 minutes make in emergence times”? This trial demonstrated that there were benefits beyond shaving a couple minutes off at the end of surgery. The more significant improvements result from reducing the outliers -- those patients that take an unusually long time to wake up Gan TJ, et al. Anesthesiology, Oct. 1997. ADVANCED AWARENESS TRAINING MODULE

CLINICAL UTILITY TRIAL: PACU DISCHARGE TIME Prevention and Management of Anesthesia Awareness CLINICAL UTILITY TRIAL: PACU DISCHARGE TIME October 2004 BIS Patients 16% Faster than Standard Practice As a result of reduced drugs administered, faster emergence times and better global assessment scores in recovery, patients were eligible to leave the PACU 16% faster. Gan TJ, et al. Anesthesiology, Oct. 1997. ADVANCED AWARENESS TRAINING MODULE

CLINICAL UTILITY TRIAL: DRUG USAGE Prevention and Management of Anesthesia Awareness CLINICAL UTILITY TRIAL: DRUG USAGE October 2004 mg In each of the next several slides, the yellow bar represents patients treated using the BIS monitor. The pink bar represents the standard practice group. Looking first at drug usage, the BIS patients, on average, received 23% less propofol. * p <0.001 23% Less Propofol Used Gan TJ, et al. Anesthesiology, Oct. 1997. ADVANCED AWARENESS TRAINING MODULE

CLINICAL UTILITY TRIAL: BLINDED PACU ASSESSMENTS Prevention and Management of Anesthesia Awareness October 2004 * p < 0.001 The patients that were monitored with the BIS during surgery in the multicenter clinical utility trial received a much better overall assessment score from the nurses in the recovery room. Many more BIS patients were rated “excellent to good” compared to “good to fair” in the standard practice group. Excellent Oriented on Arrival Good Fast Recovery Fair Slow Recovery Gan TJ, et al. Anesthesiology, Oct. 1997. ADVANCED AWARENESS TRAINING MODULE

PACU Discharge Criteria

Aldrete JA. J Clin Anesth 1995;7:89-91 PACU Discharge Max 10 Score ≥ 9 Aldrete JA. J Clin Anesth 1995;7:89-91

Chung et al. J Clin Anesth 1995;80:896-902 PADS Max 10 Score ≥ 9 Fit for discharge Chung et al. J Clin Anesth 1995;80:896-902

White et al. Anesth Analg 1999;88:1069-72 Eligible for fast-track Score of ≥12 No score < 1 in any category White et al. Anesth Analg 1999;88:1069-72

Factors Delaying Discharge Preoperative Female Increasing age CHF Intraoperative Long duration of surgery GA Spinal anesthesia Postoperative Pain PONB Drowsiness No escort

Factors delaying discharge Mandatory oral fluid intake Mandatory voiding Risk factors for postop urinary retention Type of surgery (anorectal, hernia, vaginal/pelvic gynecological surgery) Old age Male sex Spinal/epidural Duration of surgery > 60 min Intraoperative fluid > 750 mL

Summary Use short acting drugs IV or inhalational anesthetic are recommended Regional anesthesia can have postdischarge advantages Optimal antiemetic prophylaxis Comprehensive perioperative analgesic regimen Beware of residual paralysis Aggressively adopt bypass and discharge criteria

Prevention and Management of Anesthesia Awareness October 2004 Questions ADVANCED AWARENESS TRAINING MODULE