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)