November 20, 2006 Journal Club

1
November 20, 2006 Journal Club

• 1) Evidence for Lidocaine use in OR
• 2) Study proposal Intraoperative Lidocaine
  Infusion Analgesia for Total Abdominal
  Hysterectomy
• Dr. Jordan Caveno, Dr. Greg Bryson,
• Dr. Dennis Reid, Dr. Ilia Charapov
• Department of Anesthesiology
• University of Ottawa

2
Dues

• Acknowledgments - this presentation
• Dr. Dennis Reid
• idea - RAP
• literature search
• presentation on lidocaine
• Dr. Jordan Caveno
• idea of lidocaine in TAH
• TAH retrospective study data and presentation
• Dr. Greg Bryson
• help with study design

3
Why study lidocaine?

• Current practice at TOH
• common use of lidocaine in Ottawa
• Literature and Lidocaine
• safe, opiod sparing, improved pain scores,
  promotes bowel function, ?decreases hospital
  length of stay?
• Yet, quality of data may not be convincing -
  study designs are problematic

4
Presentation Plan

• Background
• Pharmacology, systemic toxicity
• Proposed mechanisms of action
• Evidence in chronic and perioperative pain
  management
• Study proposal
• Questions

5
Pharmacology of Lidocaine

• amino-amide, sodium channel blocker
• Plasma ½ Life 8 minutes
• Metabolism
• Hepatic 90 of clearance
• rapid cytochrome P450 1A2
• insulin, losec, tobacco
• amiodarone, cimetidine,ciprofloxacin,
  fluoroquinolones, fluvoxamine
• Renal - 10 clearance renal dysfunction -
  metabolites accumuln.
• Metabolites
• monoethylglycinexylidide (MEGX) ½ life 2 hours
• glycinexylidide (GX) ½ life 10 hours
• 1/10 convulsive potency

6
Pharmacology of Lidocaine
Dose and Toxicity

• Steady State - Bolus 1-1.5 mg/kg plus
• - Infusion gt1.0
  mg/kg/hr
• Lightheadedness -5 mcg/ml serum levels
• Unconsciousness -10 mcg/ml
• Seizures -(12-18)mcg/ml
• Respiratory and Cardiac Depression
• -(20-24)mcg/ml
• CD100 HUMANS -(5-7)mg/kg rapid bolus
• CD 50 - HUMANS -(2-4)mg/kg rapid bolus

7
Mechanism of action as systemic analgesic

• Central anti-hyperalgesic and anti-allodynic
• Evidence of central action at postero-lateral
  thalamus
• Action at dorsal horn
• At peripheral A-delta and C fibre mechanical and
  chemical nociceptors
• Higher selectivity for injured nerve fibers
• Tissue injury - major input from chemo-receptors
  to CNS.
• Mechano-insensitive nociceptors
• sensitive to small dose of lidocaine
• prevent central hyperalgesia and improve postop
  pain (Koppert)

8
Evidence for intravenous lidocaine use

• Use in chronic neuropathic pain
• Major abdominal surgery
• Radical prostatectomy

9
Literature and IV lidocaine

• Studies
• Himes 1977 - lidocaine MAC reduction
• Rimback 1990 - lidocaine and bowel function
• Ferrante 1996 - chronic pain - pharmacokinetics
• Groudine 1998 - clinical effects of lidocaine
• Koppert 2004 - clinical effects of lidocaine
• Wu 2005 - DM plus IV lidocaine - potentiation

10
Effect of Intravenous Lidocaine on Volatile
Anesthetic Requirements
Himes et al. Anesthesiology 1977 47 437-440

• Part one prospective cohort study, no controls
• 20 ASA I II patients
• variety of surgeries involving incision of skin
  of trunk
• Premed morphine 8-12 mg
• Constant infusion Lidocaine (3-6)mg/kg/hr
• 90-100 N2O for (60-90) seconds then 30/70 O2/N2O
• Further bolus (2-2.5)mg/kg - then surgery
• Venous plasma levels just before incision
• Observed movement of patients under IV
  lidocaine/N2O GA
• Correlate to blood levels of lidocaine

11
Effect of Intravenous Lidocaine on Volatile
Anesthetic Requirements
Himes et al. Anesthesiology 1977 47 437-440

• Part 2
• animal study 7 Mongrel dogs
• prospective case control
• Given GA with Halothane
• Tail clamp stimulus
• determined MAC for halothane without lidocaine
• Then added Lidocaine infusion
• 0.9 240 mg/kg/hr
• determined effect of lidocaine infusion on MAC of
  halothane

12
Effect of Intravenous Lidocaine on Volatile
Anesthetic Requirements
Results

• Part one human study
• No patient movement above lidocaine plasma level
  of 3.5 mcg/ml
• Part two animal study
• Control animals
• Halothane MAC 0.93
• Lidocaine group MAC of halothane reduced
• by 10-45 between plasma levels of
  (3.5-11.6)mcg/ml
• no decrease in halothane MAC below plasma level
  of 3.0 mcg/ml
• to achieve a level of 3.5mcg/ml
• bolus 1.5mg/kg, infusion 3.0mg/min

13
Effect of Intravenous Lidocaine on Volatile
Anesthetic Requirements
Conclusion lidocaine blood levels of 3.5mcg/ml
0.1MAC Halothane
14
Effect of Intravenous Lidocaine on Volatile
Anesthetic Requirements
Himes et al. Anesthesiology 1977 47 437-440

• One of the first studies to document MAC reducing
  effect of lidocaine
• MAC of halothane reduced by 10-45 between plasma
  levels of (3.5-11.6)mcg/ml

• Non randomized
• no controls (human part)
• small number of subjects

15
Treatment of post-operative ileus by intravenous
lidocaine infusion
Rimback et al. Anesth. Analg. 1990 70(4) 414-9
Study Design

• Molndal, Sweden, RCT, double blinded
• Open cholecystectomy, 30 patients (15 per group)
• Lidocaine bolus 100 mg 30 minutes before
  induction
• 60 kg patient 1.7 mg/kg
• Lidocaine infusion 3mg/min vs saline
• started 30 minutes preoperatively and continued
  for 24 hours
• 60 kg patient 3 mg/kg/hr infusion
• Art line, HR, ECG monitoring 24 hours
• Bowel motility using radiopaque markers

16
Treatment of post-operative ileus by intravenous
lidocaine infusion
segment 1 cecum-transverse colon segment 2 TC
--gt DC segment 3 DC --gt Sigmoid/Rectum
17
Treatment of postoperative ileus by intravenous
lidocaine infusion
Results

• Colonic motility resumption sooner in lidocaine
• B.M. 70 hrs (lidocaine) vs 90 hrs (saline)
• Gas 38 hrs (lidocaine) vs 40 hrs (saline)

Opiod sparing POD 1,2 No difference - nausea
and vomiting - side effects incidence - blood
pressure, HR, - ECG abnormalities Sedation 2
patients in lidocaine group
18
Treatment of postoperative ileus by intravenous
lidocaine infusion
Conclusions

• Small study
• No power analysis
• No levels of lidocaine

• RCT, double blinded
• Lidocaine
• Speeds up bowel function return
• Opiod sparing
• No significant side effects

19
Analgesic response to intravenous lidocaine in
the treatment of neuropathic pain

• Ferrante et al. Anesth, Anal. 1996
• Brigham and Womens Hospital, Harvard Medical
  School
• Prospective cohort study, no controls
• 13 patients studied
• 10 peripheral neuropathic pain
• 3 central neuropathic pain
• patient weights?
• Baseline pain assessment
• Liver and renal disease excluded
• Lidocaine 500mg i.v over 60 minutes (8.35 mg/min
  IV)
• pain scores and venous lidocaine levels every 10
  minutes
• correlate ED50, ED90 to lidocaine blood
  concentrations

20
Analgesic response to intravenous lidocaine in
the treatment of neuropathic pain

• 
  

21
Analgesic response to intravenous lidocaine in
the treatment of neuropathic pain

• 
  

22
Analgesic response to intravenous lidocaine in
the treatment of neuropathic pain Lidocaine
blood levels and analgesia
23
No evidence for prolonged analgesia at 1-2 weeks
no significant side effects
Side effects
(Lidocaine blood levels) - lightheadedness - 6/13
(0.05-3.08 mcg/mL) - feeling drunk - 2/13
(1.5 and 4.01 mcg/mL) - somnolence - 2/13
(2.34 and 4.01 mcg/mL) - vertical nystagmus
1/13 (1.2 mcg/mL) No adjustment of infusion
required due to above No other side effects
24
Analgesic response to intravenous lidocaine in
the treatment of neuropathic pain

• Results
• 10 patients complete relief,3 patients partial
  relief
• 55 40 62
• Complete relief in 8/11 peripheral pain and 2/2
  central pain
• Time to onset of complete analgesia 45_8.6
  minutes
• ED20 330mg ED50 372 mg ED90 416 mg
• ? 70 kg patient ? - ED20 4.7 mg/kg ED50 5.3
  mg/kg ED90 5.9 mg/kg
• Serum concentrations for complete analgesia
  3.79_1.00 mcg/ml

25
Analgesic response to intravenous lidocaine in
the treatment of neuropathic pain
Conclusions

• Analgesic response dramatic
• over a narrow dose and concentration range
• 2.43 mcg/mL onset
• 3.79 mcg/mL complete analgesia (/- 1 mcg/mL)
• few side effects none life-threatening
• no evidence for prolonged analgesia at 1-2 weeks
• 3-4 mcg/mL goal for analgesia?

• small prospective cohort study
• no controls
• chronic pain model

26
Evidence for Lidocaine as a systemic analgesic in
perioperative pain management

• Major abdominal surgery

27
Perioperative Intravenous Lidocaine in Major
Abdominal Surgery
Koppert et al. Anesth. Analg 2004 981050-5

• ? Does Lidocaine decrease post-operative pain
• ? Does it decrease morphine consumption
• ? Side effects
• ? Other discernible benefits

28
Perioperative Intravenous Lidocaine in Major
Abdominal Surgery
Study Design

• Erlangen/Mannheium/Siegen, Germany
• RCT, all staff blinded
• 40 patients (20 per group)
• Lidocaine -bolus 1.5mg/kg
• -infusion 1.5mg/kg/hr
• Incision ½ hour after beginning of protocol
• Termination 1 hour after skin closure
• Control group- saline
• Balanced GA, Fentanyl to up to 6mcg/kg
• PCA morphine - bolus 2mg
• - lockout 10 minutes

29
Perioperative Intravenous Lidocaine in Major
Abdominal Surgery
Study Design outcome

• Dynamic pain rating up to 72 hours postop
• q 2h POD1, q4hPOD 2,3
• Mean lidocaine levels during surgery
• 1 hour post bolus, then q1h
• Opiod sparing effect

30
Perioperative Intravenous Lidocaine in Major
Abdominal Surgery
Results
- Infusion started 50 min before incision -
Plasma levels (1.9 ? 0.7) mcg/ml intraop - Plasma
levels 0.9 mcg/mL 1 hour post d/c - No lidocaine
related side - effects
31
Perioperative Intravenous Lidocaine in Major
Abdominal Surgery
32
Perioperative Intravenous Lidocaine in Abdominal
Surgery
Results
Pain Scores

• Time to PCA same in both groups
• Pain scores at rest same in both groups
• 1-2/10
• Pain scores on movement same in both groups POD1
• 5-6/10
• Pain scores on movement POD 2 and 3
• 4-6/10 vs 3-4/10 in favor of lidocaine group

33
Perioperative Intravenous Lidocaine in Abdominal
Surgery
Results. Morphine requirements

• (103 ?72)mg vs (159 ?72)mg
• opiod sparing in lidocaine group
• Total PCA requests 38 vs 68

34
Perioperative Intravenous Lidocaine in Abdominal
Surgery
Conclusions

• RCT, double blinded
• Good study design
• No justification of power
• is study powered to detect a difference?

• Better pain scores POD 2,3
• Opiod sparing
• No effect on bowel function
• No side effects

35
Intravenous Lidocaine for Radical Prostatectomy
Intravenous lidocaine speeds the return of bowel
function, decreases postoperative pain and
shortens hospital stay in patients undergoing
radical retropubic prostatectomy
Groudine et al. Anesth. Analg. 1998 86(2)
235-239
36
Intravenous Lidocaine for Radical Prostatectomy
Study Design

• Albany, NY
• RCT, double blinded
• 40 patients (20 per group)
• Anesthetic technique flexible but no lidocaine in
  control group.
• All patients to receive ketorolac
• Pain scores, return of bowel function, length of
  stay

37
Intravenous Lidocaine for Radical Prostatectomy
Lidocaine protocol

• Bolus 1.5mg/kg (before induction)
• Infusion 3mg/min gt70kg For 60 minutes
  2mg/min lt70kg postoperatively
• Lidocaine Blood level (1.3 3.7)mcg/ml
• 2 hours post bolus IV bolus

38
Intravenous Lidocaine for Radical Prostatectomy
Management of Pain

• Ketorolac 30mg I.V. plus 15mg I.V. as required
• Parenteral morphine for breakthrough
• RN controlled? (not IV PCA?)
• opiod use calculated from charts
• Pain Score Index average pain score for last 24
  hours multiplied by number of days in hospital
• patients recalled pain experience from last 24
  hours

39
Intravenous Lidocaine for Radical Prostatectomy
Results
40
Intravenous Lidocaine for Radical Prostatectomy
Conclusions

• Underpowered study?
• Accuracy of data collection?
• Opiod use
• pain scores

• RCT, double blinded
• opiod sparing
• early return of bowel function
• better pain scores
• 1-day less LOS

41
Systemic Lidocaine as a Perioperative Analgesic
Conclusions

• Pro
• Con

42
Systemic Lidocaine as a Perioperative Analgesic
Conclusions - pro

• small cohort and RCT studies
• 10 or greater volatile anesthetic sparing effect
  at a plasma level of 3.5mcg/ml
• reduction in narcotic requirements at plasma
  levels between (1.9-3.7)mcg/ml
• improvement in pain scores postop
• quicker return of bowel function postop
• decreased length of stay of 1 day in one study
• analgesic effect through to POD 2-3
• toxicity not an issue at doses presented

43
Systemic Lidocaine as a Perioperative Analgesic
Method of administration

• Bolus 1.5mg/kg at induction
• Infusion (1.5 2.5 mg)/kg/hr
• TOH no bolus - 1 mg/kg bolus
• 1.2-2.4 mg/kg/hr via fentacaine pump (fentanyl
  1-2 mcg/kg/hr, 1.5 lidocaine in 20 cc syringe)
• Variety of procedures - bowel, orthopedics

44
Systemic Lidocaine as a Perioperative Analgesic
Conclusions - con

• Study design lacking
• small
• lack of power analysis
• data collection imprecise

45
New study?

• Literature review done
• suggests an opportunity to do a study
• Review analgesic experience in TAH at TOH
• Dr. Jordan Caveno
• 47 charts review
• power for the study

46
Retrospective study - TAH at TOH

• Is there an ability to improve the analgesic
  experience of TAH patients?
• potential benefit of using lidocaine something
  that could be studied as part of an RCT?
• How many patients would we need?
• Why TAH?
• IV PCA postop for TAH population
• Come up with postop pain model that mimics RAP?

47
TAH at TOH

• Chart review of 53 consecutive patients
• TAH at Civic 2005
• 47 charts included
• GA (38) GAIV lidocaine (9 charts)
• IV PCA postop
• 6 charts excluded
• 2 SAB, 1 no PCA, 1 craniotomy,1 meperidine PCA,1
  sufentanil intra-op
• Data
• Co-analgesics use,NV,opiod use, pain scores,
  length of PCA use, LOS

48
Jordans study -TAH co-analgesic use
49
TAH pain scores morphine consumption
GA 89.6 /- 33 mg GALido 80.9 /- 39 mg
50
TAH duration PCA use stay in hospital
51
TAH pain scores with (n38) and without (n9)
lidocaine infusion
Non significant difference
52
TAH opioid use with and without lidocaine infusion
Fentanyl use PACU Lidocaine 92 mcg No lidocaine
119 mcg
53
Conclusions

• Non significant trend to better pain scores and
  opiod sparing in lidocaine group
• Ketamine is used more often preop (53) than
  NSAIDs (34)
• 75 patients discharged POD3
• IV PCA use stopped 48 hours in most

54
Conclusions power

• to detect an increase in the rate of POD2
  discharge from hospital from 21 to 50
• required number of patients is 42 per group (84
  patients total) - power of 0.8 and 2-sided type I
  error 0.05
• to detect a 30 reduction in postoperative
  morphine use
• required number of patients is 26 patients per
  group (52 patients total) - power of 0.90 and
  2-sided type I error 0.05
• consider enrolling 20 more patients to cover
  protocol violations/withdrawal
• 100 patients between two campuses, 50
  patients/group

55
Intravenous Lidocaine Infusion for Analgesia

• Study proposal
• nothing is finalized
• everything is open to debate
• Compare
• intra-operative fentanyl vs
• fentanyl plus lidocaine infusions
• women having TAH
• Standard general anesthetic
• pre-op tylenol, NSAID, intra-op ketamine
• post-op acetaminophen and NSAID

56
Hypothesis, End points

• Hypothesis
• The addition of an intraoperative lidocaine
  infusion to a balanced anesthetic technique
  result in a 30 reduction in opiod consumption
  during the first 48 hours following total
  abdominal hysterectomy.
• It will result in up to 50 of patients being
  discharged after postoperative day 2 compared
  with the current 21.
• Primary outcome
• total opiod use up to 48 hours postop
• powered to detect a 30 decrease in opiod use
• Secondary outcomes
• POD 2 discharge rate
• powered to detect an increase in POD 2 rate of
  discharge from current 21 to 50

57
Secondary outcomes continued ...

• Secondary continued
• Intraoperative data BIS scores intraoperative
  serum lidocaine level at 60 minutes
  intraoperative opioid use
• Ramsey Sedation Score in PACU
• Lidocaine serum levels in smokers and
  insulin-requiring diabetics
• Opioid use in PACU, Wards
• Verbal Analogue Scale (VAS) pain scores in
  recovery room and during the first 48 hours
  post-operatively - 3 scores/day x 3 days
• Incidence of side effects that can be attributed
  to local anesthetic toxicity
• Incidence of nausea and vomiting and anti-emetic
  use up to 48 hours postoperatively
• Time of first flatus and first bowel movement

58
Secondary outcomes continued

• Secondary outcomes continued
• Subjective indices of recovery
• Brief Pain Inventory Scores prior to discharge
• Quality of Recovery Scores before discharge and
  at one week post discharge

59
Protocol

• Prospective, Double Blinded, RCT
• 100 patients between Civic and General Campus
• Recruitment and study completion in 2007
• Eligibility
• Age 30-69 inclusive
• ASA class I or II
• Body Mass Index (BMI) of 18.5-35

60
Exclusion criteria

• under age 30 or over age 70
• ASA III, IV and V class patients
• Obese class II (BMIgt35) or undernourished
  (BMIlt18.5)
• Unable to use patient controlled analgesia
• Any history of liver dysfunction - abN LFTs
• Renal insufficiency CrCl lt50mL/min
• Seizure disorder
• Hypersensitivity or allergy to amide type local
  anesthetics
• Hypersensitivity or allergy to any of the
  following opiods morphine, hydromorphone,
  meperidine, fentanyl
• Any chronic pain syndromes or opioid use more
  than 7 days of daily use
• Medication use that affects cytochrome P450-3A4
  or P450-1A2 metabolism (insulin and tobacco use
  ok)

61
Protocol

• Recruitment - via PACU
• Premed - Tylenol 30 mg/kg, NSAID
• Balanced GA
• Before induction midazolam 15mcg/kg IV
• After induction dexamethasone 100 mcg/kg IV,
  ketamine 150mcg/kg IV
• rocuronium / fentanyl 3 mcg/kg / propofol 1-4
  mg/kg
• fentanyl 2 mcg/kg/hr air/oxygen desflurane to
  BIS 45-50
• morphine/fentanyl IV PRN
• PACU - IV PCA
• Control group
• saline bolus and infusion
• Experimental
• lidocaine 1.5 mg/kg bolus on induction --gt
  infusion 3 mg/kg/hr. Stop on skin closure

62
Study protocol check list pre-calculated MS
Excel spreadsheet
63
Study protocol check list pre-calculated MS
Excel spreadsheet continued ...
64
(No Transcript)
65
Current status

• OHREB application July 2006
• Revision 1 Sept 2006
• Revisoin 2 October 2006
• Revision 3 November 2006
• Revision 4 - ongoing
• Anticipate approval end of November 2006
• Funding application pending - Chairmans Research
  Fund

66
Study information

• www.ottawa-anesthesia.org/lido/

67
Future

• Future studies
• dose response study
• lidocaine IV vs SAB
• lidocaine IV vs epidural

68
Questions
69
(No Transcript)