1. Laurence Weinberg Staff Anaesthetist, Austin Hospital, Victoria Clinical Fellow, Department of Surgery, The University of Melbourne. Length of stay after open radical prostatectomy with intravenous lignocaine followed by 24-hour subcutaneous infusion: blinded, randomized, placebo controlled multicentre trial

2. Acknowledgements o ANZCA: Project Grant o University of Melbourne Story D, Gordon I, Christophi C o Co-investigators Rachbuch C, Beilby D, Trinca J, Howard W, Yeomans M, Yanezas M, James K, McNicol L

3. Intravenous Lignocaine Clear advantages: abdominal surgery Lower pain scores Opioid sparing effects Enhances functional recovery Reduces immune alterations Decreases length of hospital stay

4. Subcutaneous Lignocaine Neuropathic pain Ischaemic pain Limited data for ACUTE postoperative pain

5. Hypothesis Intraoperative IV lignocaine + 24 hrs post-operative SC lignocaine Enhances recovery Shortens length of hospital stay after open radical retropubic prostatectomy

6. Study Design Prospective randomised multicentre Blinded Inclusion criterion Adults (age > 18 years < 75 years) Elective open radical prostatectomy ASA I-III patients Exclusion criterion x Creatinine > 200 umoll/L, Abn LFT’s x Chronic opioid use x Allergy: morphine, LA x Cardiac conduction defects/Class I anti-arrhythmic agents

7. Study Design Human Research Ethics approval Consenting patients randomised 2 groups GA: standardized, no regional anaesthesia All patients: 1.Induction: Propofol: 1-3 mg/kg; Fentanyl 3 ug/kg 2.Maintenance: Volatile anaesthesia: 0.6-1 MAC, Fentanyl infusion 2.5 ug/kg/hr 3.Surgical closure: Paracetamol IV 1 g, Ketorolac 30 mg 4.Postoperatively: Morphine PCA, 1 mg boluses, 5 min lockout QID paracetamol, NSAID, Acute Pain Service

8. Study Design Lignocaine group: Pre-induction Loading dose IV: 1.5 mg/kg Intraop infusion IV: 1.5 mg/kg/hr

9. Study Design Lignocaine group: Post-op SUBCUT infusion: 1.5 mg/kg/hr

10. Study Design Control group: Normal saline: equal volume delivered in the same way

11. Study Design Primary outcome 1.Length of hospital stay Secondary outcomes 1.GI function 2.Time to mobilise 3.Rescue analgesia and anti-emetic therapy 4.Visual Analogue Scores for pain (VAS) 0 to 100mm 5.Morphine consumption: 24 hours 6.Patient satisfaction 7.Opioid & lignocaine side effects 8.Lignocaine plasma levels: PACU & 24 hours 9.Adverse events

12. Statistics analyses Power analyses: based on a PILOT STUDY* for patients undergoing open radical prostatectomy (2007/8) who received PCA morphine alone: mean hospital stay 4.5 days (SD 26.4 hrs) Sample size: 18 hour difference in hospital stay, power 0.8, significance level of 0.05, 38 patients per group Analyses: intention-to-treat bases * Weinberg L, et al. Anaesthesia & Intensive Care 2010; 38: A1116

13. Consort diagram Total patients consented N = 85 Total patients consented N = 85 Patients excluded N = 10 Laparoscopic retropubic prostatectomy N = 9 Procedure aborted (anaphylaxis) N = 1 Patients excluded N = 10 Laparoscopic retropubic prostatectomy N = 9 Procedure aborted (anaphylaxis) N = 1 Inclusion critreria met N = 75 Randomised Inclusion critreria met N = 75 Randomised Placebo Group N = 38 Placebo Group N = 38 Lignocaine Group N = 37 Lignocaine Group N = 37 Intention to treat

14. Demographics Lignocaine GroupPlacebo Group Patients (n)3738 Age * (yrs)61 (6.3, 44-70)60.0 (7.6, 38-71) Weight * (kg)85 (14.1, 52-117)83 (11.9, 60-123) Body mass index * (kg/m 2 )28 (5.05, 16.9-42.2)26 (3.53, 21.2-35.9) ASA Class - I / II / III24 / 13 / 026 / 12 / 0 Gleason Scores7 (0.86)7 (0.62) PSA8.7 (5.02)7.8 (4.85) * Data presented as SD, range

15. Hospital Stay Hospital stay (days) 3.3 (0.80)4.6 (3.18)-1.3 0.017 -2.40 to -0.25 LignocainePlacebo Mean (SD) Difference P 95% CI

16. Operative variables Surgery duration (min) 155.7 (34.2) 141.6 (44.6) 0.13(-4.27, 32.47) Lowest intraop temp ( 0 C) 35.5 (0.5) 35.6 (0.5) 0.41(-0.34, 0.14) Blood loss (ml) 1050.8 (750.9) 940.3 (651.1) 0.50(-218, 439) Blood Tx* (% patients) 5.4%7.9% 1.00*(-16.0%, 10.9%) Colloids (total) 843.9 (926.6) 742.6 (713.8) 0.60(-281, 483) Crystalloids (total) 3281.1 (1094.6) 2552.6 (1173.5) 0.007(206, 1251) LignocainePlacebo Mean (SD) P 95% CI For comparison of means, standard two-sample t-tests were used Uses Fisher's Exact Test due to comparison of proportions with small sample size

17. Postoperative variables Oral sips (hrs) 7.2 (3.6) 8.6 (4.3) -1.40.17 (-3.39, 0.60) Free fluid (hrs) 9.7 (4.5) 13.6 (5.0) -3.90.002 (-6.30, -1.53) Light diet (hrs) 15.5 (4.9) 20.9 (7.5) -5.40.002 (-8.61, -2.13) Time to mobilise (hrs) 17.4 (3.8) 22.0 (4.4) -4.6<0.001 (-6.68, -2.52) LignocainePlacebo Mean SD Difference P 95% CI Two-sample t-test was used for the comparisons of means For the comparison of percentages, Fisher’s exact test was used for the p-values and the Newcombe-Wilson approximation for the confidence intervals

18. Adverse Effects (% patients) Nausea/Vomiting 51.4%44.7% 0.6 Pruritis 16.2%23.7% 0.6 Dizziness 37.1%54.1% 0.17 Visual disturbances 11.4%16.2% 0.7 Peri-oral numbness 5.9%5.4% 1.0 Muscle weakness 2.9%8.1% 0.6 Paraesthesia 9.1%8.1% 1.0 Constipation 10.8%26.3% 0.14 LignocainePlacebo P

19. Post-op Complications Hypotension requiring medical intervention 5.4%2.6% 0.6 Other cardiovascular 0.0% 1.0 Respiratory depression 0.0% 1.0 Pneumonia 0.0% 1.0 Intra-abdominal sepsis 0.0%2.6% 1.0 Wound healing 0.0% 1.0 Renal 0.0% 1.0 LignocainePlacebo P

20. Pain Rest MEAN LignocainePlacebo 19.3 mm37.3 mm Difference: 18 mm 95% CI: 7.3 – 28 mm P = 0.001

21. Cumulative Morphine LignocainePlacebo 38.3 mg52.3 mg MEAN Difference: 13.9 mg 95% CI: 2.2 - 25.7 P = 0.02

22. Cumulative Morphine LignocainePlacebo 1.4 mg/hr2.0 mg/hr MEAN SLOPE Difference: -0.62 95% CI: -0.14 to -0.02 P = 0.02

23. Adverse events SC cannulae: nil complications Inadvertent administration of lignocaine

24. Lignocaine Levels Recovery * 1.36 (0.48) 0.5 – 2.19 < 0.5 0.00<0.001 * (0.63-0.94) 24-hours 3.20 (0.95) 1.1 – 4.96 < 0.5 Lignocaine (ug/mL)Placebo (ug/mL) Mean (SD) RangeMean SDP 95% CI * Uses Mann-Whitney of medians (adjusted for ties) due to non-Normal data Not appropriate for formal analyses of the 24-hour data as all values in placebo were recorded as < 0.5.

25. Conclusions IV lignocaine followed by 24-hr SC infusion Shorter length of stay (1.3 days) Accelerated acute rehabilitation Free fluid (3.9 hrs) Diet (5.4 hrs) Mobilisation (4.6 hrs) Less 24-hour morphine use Lower pain scores Safety factors: paramount

26. Future directions Plasma levels & pain scores Cancer recurrence Chronic pain Utility in laparoscopic radical prostatectomy

27. Thank you 谢谢

28. Future directions Pearson’s correlation is r = 0.09 here, a weak positive correlation (P = 0.6)