Laurence WeinbergStaff 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

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

Intravenous Lignocaine

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

Subcutaneous Lignocaine

• Neuropathic pain• Ischaemic pain

Limited data for ACUTE postoperative pain

Hypothesis

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

Study Design

• Prospective randomised multicentre• Blinded• Inclusion criterion Adults (age > 18 years < 75 years) Elective open radical prostatectomy ASA I-III patients

• Exclusion criterionx Creatinine > 200 umoll/L, Abn LFT’s x Chronic opioid usex Allergy: morphine, LAx Cardiac conduction defects/Class I anti-arrhythmic agents

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/kg2. Maintenance: Volatile anaesthesia: 0.6-1 MAC, Fentanyl infusion 2.5 ug/kg/hr3. 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

Study Design

• Lignocaine group: Pre-induction• Loading dose IV: 1.5 mg/kg• Intraop infusion IV: 1.5 mg/kg/hr

Study Design

• Lignocaine group:• Post-op SUBCUT infusion: 1.5 mg/kg/hr

Study Design

• Control group:• Normal saline: equal volume delivered in the

same way

Study Design

• Primary outcome1. Length of hospital stay

• Secondary outcomes1. GI function2. Time to mobilise3. Rescue analgesia and anti-emetic therapy4. Visual Analogue Scores for pain (VAS) 0 to 100mm5. Morphine consumption: 24 hours 6. Patient satisfaction7. Opioid & lignocaine side effects8. Lignocaine plasma levels: PACU & 24 hours9. Adverse events

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

Consort diagram

Total patients consentedN = 85

Total patients consentedN = 85

Patients excludedN = 10

Laparoscopic retropubic prostatectomy N = 9Procedure aborted (anaphylaxis) N = 1

Patients excludedN = 10

Laparoscopic retropubic prostatectomy N = 9Procedure aborted (anaphylaxis) N = 1

Inclusion critreria metN = 75

Randomised

Inclusion critreria metN = 75

Randomised

Placebo GroupN = 38

Placebo GroupN = 38

Lignocaine GroupN = 37

Lignocaine GroupN = 37

Intention to treatIntention to treat Intention to treatIntention to treat

Demographics

Lignocaine Group Placebo GroupPatients (n) 37 38

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/m2) 28 (5.05, 16.9-42.2) 26 (3.53, 21.2-35.9)

ASA Class - I / II / III 24 / 13 / 0 26 / 12 / 0

Gleason Scores 7 (0.86) 7 (0.62)

PSA 8.7 (5.02) 7.8 (4.85)

* Data presented as SD, range

Hospital Stay

Hospital stay (days) 3.3 (0.80) 4.6 (3.18) -1.3 0.017 -2.40 to -0.25

Lignocaine Placebo Mean (SD) Mean (SD) Difference P 95% CI

Operative variables

Surgery duration (min) 155.7 (34.2) 141.6 (44.6) 0.13 (-4.27, 32.47)

Lowest intraop temp (0C) 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)

Lignocaine Placebo Mean (SD) 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

Postoperative variables

Oral sips (hrs) 7.2 (3.6) 8.6 (4.3) -1.4 0.17 (-3.39, 0.60)

Free fluid (hrs) 9.7 (4.5) 13.6 (5.0) -3.9 0.002 (-6.30, -1.53)

Light diet (hrs) 15.5 (4.9) 20.9 (7.5) -5.4 0.002 (-8.61, -2.13)

Time to mobilise (hrs) 17.4 (3.8) 22.0 (4.4) -4.6 <0.001 (-6.68, -2.52)

Lignocaine Placebo Mean SD 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

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

Lignocaine Placebo P

Post-op Complications

Hypotension requiring medical intervention

5.4% 2.6% 0.6

Other cardiovascular 0.0% 0.0% 1.0

Respiratory depression 0.0% 0.0% 1.0

Pneumonia 0.0% 0.0% 1.0

Intra-abdominal sepsis 0.0% 2.6% 1.0

Wound healing 0.0% 0.0% 1.0

Renal 0.0% 0.0% 1.0

Lignocaine Placebo P

Pain Rest

MEAN

Lignocaine Placebo

19.3 mm 37.3 mm

Difference: 18 mm

95% CI: 7.3 – 28 mm

P = 0.001

Cumulative Morphine

Lignocaine Placebo

38.3 mg 52.3 mg

MEAN

Difference: 13.9 mg

95% CI: 2.2 - 25.7

P = 0.02

Cumulative Morphine

Lignocaine Placebo

1.4 mg/hr 2.0 mg/hr

MEAN SLOPE

Difference: -0.62

95% CI: -0.14 to -0.02

P = 0.02

Adverse events

• SC cannulae: nil complications• Inadvertent administration of lignocaine

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) Range Mean SD P 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 .

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

Future directions

• Plasma levels & pain scores• Cancer recurrence• Chronic pain• Utility in laparoscopic radical prostatectomy

Thank you 谢谢

Future directions

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