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
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 criterion
x
x
x
x
Creatinine > 200 umoll/L, Abn LFT’s
Chronic opioid use
Allergy: morphine, LA
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.
2.
3.
4.
Induction: Propofol: 1-3 mg/kg; Fentanyl 3 ug/kg
Maintenance: Volatile anaesthesia: 0.6-1 MAC, Fentanyl infusion 2.5 ug/kg/hr
Surgical closure: Paracetamol IV 1 g, Ketorolac 30 mg
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 outcome
1. Length of hospital stay
• Secondary outcomes
1.
2.
3.
4.
5.
6.
7.
8.
9.
GI function
Time to mobilise
Rescue analgesia and anti-emetic therapy
Visual Analogue Scores for pain (VAS) 0 to 100mm
Morphine consumption: 24 hours
Patient satisfaction
Opioid & lignocaine side effects
Lignocaine plasma levels: PACU & 24 hours
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 consented
N = 85
Inclusion critreria met
N = 75
Randomised
Lignocaine Group
N = 37
Placebo Group
N = 38
Intention to treat
Intention to treat
Patients excluded
N = 10
Laparoscopic retropubic prostatectomy N = 9
Procedure aborted (anaphylaxis) N = 1
Demographics
Lignocaine Group
Placebo Group
Patients (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)
Lignocaine
Placebo
Mean (SD)
Mean (SD)
Difference
3.3 (0.80)
4.6 (3.18)
-1.3
P
0.017
95% CI
-2.40 to -0.25
Operative variables
Lignocaine
Mean
(SD)
Placebo
Mean
(SD)
P
95% CI
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%
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)
7.9%
• 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
Lignocaine
Oral sips (hrs)
Free fluid (hrs)
Light diet (hrs)
Time to mobilise (hrs)
Placebo
Mean
SD
Mean
SD
Difference
P
95% CI
7.2
(3.6)
8.6
(4.3)
-1.4
0.17
(-3.39, 0.60)
9.7
(4.5)
13.6
(5.0)
-3.9
0.002
(-6.30, -1.53)
15.5
(4.9)
20.9
(7.5)
-5.4
0.002
(-8.61, -2.13)
17.4
(3.8)
22.0
(4.4)
-4.6
<0.001
(-6.68, -2.52)
• 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)
Lignocaine
Placebo
P
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
Post-op Complications
Lignocaine
Placebo
P
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
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
MEAN
Lignocaine
Placebo
38.3 mg
52.3 mg
Difference: 13.9 mg
95% CI: 2.2 - 25.7
P = 0.02
Cumulative Morphine
MEAN SLOPE
Lignocaine
Placebo
1.4 mg/hr 2.0 mg/hr
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
Lignocaine (ug/mL)
Mean (SD)
Recovery* 1.36 (0.48)
24-hours
3.20
(0.95)
Range
Placebo (ug/mL)
Mean
0.5 – 2.19
< 0.5
1.1 – 4.96
< 0.5
SD
0.00
P
95% CI
<0.001*
(0.63-0.94)
• * 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)