Updated: December 18, 2007

Intraoperative Lidocaine Infusion Analgesia trial.

A prospective evaluation of the addition of intraoperative intravenous lidocaine infusion to general anesthetic in Total Abdominal Hysterectomy.

Dr. Ilia Charapov, Dr. Dennis Reid, Dr. Greg Bryson, Dr. Gregory Krolczyk, Dr. Jordan Caveno

Please note – your input into the study design and protocol is welcome. Email
charapov [at] rogers.com

Current Application progress – approved by OHREB December 27, 2006. Funding assured.

Study start date Recruitment started May 29, 2007. To-date, over 30 patients have gone through the protocol.

Recruitment and patient follow-up and data collection – recruitment started at via PAU at Civic and General campuses of TOH; Study Personnel and Study Nurse will interview patients and collect data. Study personnel will also follow patients on a daily basis and assure appropriate patient discharge together with the Gynecology team.

Purpose and Outcomes:

Purpose: To evaluate the efficacy of intravenous lidocaine infusion administered during general anesthesia in:

  1. Reducing length of hospital stay following total abdominal hysterectomy;
  2. Reducing postoperative analgesic requirement following total abdominal hysterectomy.

Study design: This is a prospective, randomized, triple-blinded (patients/physicians/study team), clinical trial comparing intravenous lidocaine infusion plus general anesthesia with general anesthesia alone. The intervention group will receive a balanced anesthetic with the addition of lidocaine as outlined in the anesthetic protocol outlined in Appendix 2 (1.5 mg/kg lidocaine bolus IV, followed by infusion of 3 mg/kg/hr, stopped on skin closure). The control group will receive a balanced anesthetic with the addition of normal saline as outlined in the Appendix 2. The patients, clinicians, and study personnel will be blinded to group allocation.

Hypothesis: The addition of an intraoperative lidocaine infusion to a balanced anesthetic technique will result in up to 50% of patients being discharged after postoperative day 2 compared with the current 21%. Also, it will result in a 30% reduction in opiod consumption during the first 48 hours following total abdominal hysterectomy.

Assumption: Patients in the intervention and control groups will be titrated to equal analgesia because they will self-administer enough pain-controlling medications to make their postoperative pain experience the same.

Primary outcomes:

  1. Length of hospital stay;
  2. Total opioid use at 48 hours postoperatively.

Secondary outcomes. The following data will be collected and analyzed:

  1. Intraoperative data: BIS scores (to control depth of anesthesia); intraoperative serum lidocaine level at 60 minutes; intraoperative opioid use;
  2. Opioid use in the recovery room;
  3. Patient Controlled Analgesia (PCA) morphine requirements in OR, PACU, at 6, 24, 48 hours;
  4. Oral pain controlling medication use up to 48 hours postoperatively if IV PCA discontinued before 48 hours;
  5. Numerical Rating Scale, (NRS) pain scores in recovery room and at 6, 24, 48 hours post-operatively;
  6. Incidence of side effects that can be attributed to local anesthetic toxicity;
  7. Incidence of nausea and vomiting and anti-emetic use up to 48 hours postoperatively;
  8. Time of first flatus and first bowel movement.
  9. Brief Pain Inventory Scores prior to discharge
  10. Quality of Recovery Scores – before discharge and at one week post discharge
  11. Ramsey Sedation Score in PACU
  12. Lidocaine serum levels in smokers and insulin-requiring diabetics.


Intraoperative Lidocaine Infusion Analgesia: Study background and Rationale


Adequate postoperative pain control is still a major problem for many surgical patients. Identifying better ways of controlling pain during and after surgery remains an ongoing goal of research in anesthesia. Continuous infusion of IV lidocaine has been identified in the anesthetic literature as a valuable supplement to general anesthesia. Considering its low cost, ease of administration, and low incidence of side effects, lidocaine is an attractive anesthetic option.

However, to date there have been only few randomized controlled trials that assessed effect of IV lidocaine on a patient’s pain control. These trials were small single-center studies that still require independent validation at other institutions and in other surgical populations.

Proposed mechanism of action of lidocaine:

Lidocaine is amide-type local anesthetic acting on Na+ channels. It’s been noted that apart from being an effective Na-channel blocker, lidocaine also interacts with other cellular systems – dorsal horn neurons, muscarinic/dopaminergic/K/nicotinic and many other tissue receptors. These interactions may occur at the lidocaine serum concentrations that are 1000-5000 times less than those required for Na-channel blockade. This may explain lidocaine nociceptive properties at the low serum concentrations (i.e. < 5 mcg/mL) that are achieved with epidural and intravenous lidocaine infusions (Hollman).

It’s been suggested that lidocaine provides a multi-modal analgesia in acute pain setting.

It reduces neural response to pain by blockade and inhibition of nerve conduction. It is achieved through suppression of neuronal excitability in dorsal horn neurons and depression of spike activity/amplitude/and conduction in myelinated A-delta and unmyelinated C nerve fibers. Lidocaine was shown to suppress spinal cord sensitization, and inhibit spinal visceromotor neurons. Lidocaine also has significant anti-inflammatory properties that may improve postoperative pain experience. Lidocaine has direct excitatory effect on intestinal smooth muscles, which may be the result of a blockade of inhibitory impulses from myenteric plexus. These inhibitory impulses are activated with surgical stimulation of parietal peritoneum (Wu, Hollman, and Groudine).

IV Lidocaine infusion dose and toxicity.

Lidocaine has short plasma ˝ life of 8 minutes. It undergoes mostly hepatic metabolism (90% of clearance), that is rapid and depends on the function of cytochrome P450 1A2 enzyme system. There are a number of medications that affect this system. Insulin and tobacco up-regulate cytochrome P450 1A2. This would result in a faster clearance of lidocaine. Other commonly used medications such as losec, amiodarone, cimetidine, fluoroquinolones, and fluvoxamine down-regulate cytochrome P450 1A2. This would result in delayed clearance of lidocaine. A complete list of medications affecting cytochrome P450 1A2 is presented in attached Appendix 9.

Renal system is responsible for 10% clearance of lidocaine and its metabolites. Renal dysfunction leads to mostly accumulation of metabolites such as monoethylglycinexylidide (MEGX, equal potency with lidocaine and a ˝ life of 2 hours), as well as glycinexylidide (GX, with a ˝ life 10 hours and 10% convulsive potency compared to lidocaine).

Steady State is achieved with a bolus of 1-1.5 mg/kg plus infusion of >1.0 mg/kg/hr.


Lightheadedness is a first sign of toxicity and can be seen with blood levels of > 5 mcg/mL. Unconsciousness may result at serum levels of > 10 mcg/mL, followed by seizures at 12-18 mcg/mL, and finally respiratory and cardiac depression at 20-24 mcg/mL. CD100 (convulsant dose) in humans is 5-7 mg/kg with rapid IV bolus. CD 50 is 2-4 mg/kg with rapid IV bolus. Lidocaine toxicity does not occur with plasma levels below 5 mcg/mL.


Currently reported dosing varies between ‘no IV bolus’ to 1-1.5 mg/kg IV bolus followed by 0.9 to 3.6 mg/kg/hr infusion rates. These doses generally result in plasma levels of 1.3-3.7 mcg/mL. There is no increase in local anesthetic toxicity at these plasma levels compared to placebo. In one study up to 2.6 mg/kg/hr of lidocaine had been infused for 24 hours after the end of surgery with no reported side effects attributed to local anesthetic toxicity.

In clinical settings, IV lidocaine found usefulness in both chronic and acute pain models.

Chronic pain

Lidocaine was found to be an efficient reliever of neuropathic pain (Ferrante, Boas).

Ferrante conducted a lidocaine dose-response study in 13 adult patients with neuropathic chronic pain. 500 mg of IV lidocaine was infused over one hour. This corresponds to infusion rates of 6-7 mg/kg/hr of lidocaine (no bolus). VAS pain scores were obtained q10 minutes. Plasma levels, time of infusion, and the amount of lidocaine infused were noted at the following end-points: 1) onset of analgesia; 2) complete analgesia reported by patient.

Initial onset of analgesia was achieved with 123+/-55 mg of lidocaine infused over 9-20 minutes that corresponded with plasma levels of 2.43 +/- 1.01 mcg/mL.

Complete analgesia was reported in 10 out of 13 patients with a total lidocaine dose of ~ 375 +/- 23mg over 36-54 minutes corresponding to plasma levels of 3.79+/- 1.00 mcg/mL. This analgesic effect did not persist beyond 1 week after treatment.

In 3 patients there was a significant reduction in pain but no complete analgesia.

Light-headedness at some time during infusion was reported in 6 out of 13 patients and their lidocaine levels ranged from 0.9 to 3.08 mcg/mL. At no time did the infusion need to be adjusted because of subjective complaints of toxicity

This study can be criticized due to lack of control and small number of participants. It is also a chronic pain setting, which may not be applicable to the acute peri-operative state. It is also a different pharmacokinetic model – as no bolus was used and higher amounts of lidocaine were used during infusion.

However, the usefulness of this study lies in the dose-response data that was obtained confirming that analgesic blood level of lidocaine is probably around 3.5 mcg/mL. It was also confirmed that no significant side effects were observed at these blood levels.

Acute pain

IV lidocaine had been studies in several surgical populations including major abdominal surgery, laparascopic cholecystectomy, and retropubic radical prostatectomy. The analysis of these studies follows below.

A literature review was undertaken that identified the following five studies that addressed effect of IV lidocaine on the post-operative pain control and ileus:

Himes 1977 (lidocaine MAC reduction); Rimback 1990 (lidocaine speeds up bowel function after laparotomy); Groudine 1998 (improved pain scores and earlier discharge from hospital); Koppert 2004 (improved pain scores and opiod sparing); Wu 2005 (potentiation of Dextromethorphan and IV lidocaine in terms of postoperative pain control).

We will briefly review above studies and point out the significance of their findings.

1) A study by Himes (1977) was one of the first studies to document MAC reducing effect of lidocaine. It was a prospective cohort study involving 20 ASA 1-2 human subjects undergoing variety of surgeries involving incision of skin of trunk. There were no controls in human-part of the experiment. Each patient was pre-medicated with morphine 8-12 mg, then a constant infusion of lidocaine 3-6 mg/kg/hr was started. Patients were given 90-100% N2O for 60-90 seconds followed by 30%/70% O2/N2O.

Before incision, a lidocaine bolus 2-2.5mg/kg IV was given and venous plasma levels were obtained. Investigators observed movement of patients under IV lidocaine/N2O GA and correlated those to blood levels of lidocaine.

No patient movement was observed above lidocaine plasma level of 3.5 mcg/ml – likely a threshold for the analgesic effect of lidocaine. This corresponds to the 0.1 MAC value of Halothane. To achieve this blood levels study recommended a bolus of 1.5 mg/kg of lidocaine followed by 3 mg/min IV infusion.

In the second part of the experiment (prospective case control animal study) seven Mongrel dogs were given GA with Halothane. Tail clamp stimulus was used to determine MAC for halothane without lidocaine (0.93%). A lidocaine infusion was then added ranging between 0.9–240 mg/kg/hr and venous blood lidocaine levels were obtained. An effect of lidocaine infusion on MAC of halothane was analyzed.

In dogs MAC of halothane was reduced by 10-45% between plasma levels of lidocaine of 3.5-11.6 mcg/mL

Overall, it was a small study, with no controls in the human part of the experiment. However, it did confirm a MAC-sparing effect of lidocaine, identified an analgesic blood levels of lidocaine, and suggested a dosing regimen for IV lidocaine infusions (followed by most of the follow-up studies, although on the lower end of dosing scale).

2) Another study on IV lidocaine is by Rimback (1990) coming from Molndal, Sweden. This study confirmed that lidocaine speeds up the return of bowel function after open laparotomy as well as has an opiod sparing effect.

This double-blinded randomized-controlled trial looked at the return of bowel function with and without IV lidocaine in 30 patients (15 per group) undergoing open cholecystectomy. Both groups received GA.

In addition, 30 minutes before induction experimental group received a lidocaine bolus of 100 mg (for a 60 kg patient ~ 1.7 mg/kg) followed by IV lidocaine infusion at 3mg/min (e.g. 60 kg patient ~ 3 mg/kg/hr infusion). Control group received normal saline bolus/infusion. Saline/lidocaine infusions continued for 24 hours. Patients were monitored in PACU with art line, HR, ECG monitoring. Bowel motility was assessed using radio-opaque markers.

Colonic motility was noted to resume much sooner in lidocaine group (bowel movement in 70 hrs (lidocaine) vs 90 hrs (saline)). Opiod sparing was also noted on POD 1 and 2. There was no difference between the two groups in terms of nausea and vomiting, incidence of side effects, hemodynamic parameters.

Overall, it was a small study (30 patients). No blood levels of lidocaine had been obtained. There was no power analysis carried out to justify sample size. However, it was a good quality double-blinded randomized-controlled that showed improved return of bowel function following open laparotomy, as well as an opiod sparing effect. It also confirmed safety of using prolonged lidocaine infusions.

3) Koppert (2004) studied effect of perioperative intravenous lidocaine on postoperative pain and opiod consumption after major abdominal surgery (prostatectomy, nephrectomy, cystectomy, and colectomy). This small but well-designed triple-blinded randomized controlled trial out of Erlangen/Mannheim/Siegen (Germany) involved 40 patients (20 per group).

Patients were given balanced GA with intraoperative fentanyl up to 6mcg/kg. 30 minutes before incision experimental group was given a bolus of IV lidocaine 1.5mg/kg, followed by an infusion of 1.5mg/kg/hr. Infusion was stopped 1 hour after skin closure. Control group received saline bolus. Postop-op opiod consumption was tracked via IV PCA morphine. Dynamic pain scores were collected up to 72 hours postop (q 2h POD1, q4hPOD 2,3). Mean lidocaine levels were done during surgery at 1-hour post bolus, then q1h up to 1 hour after stopping the infusion. Mean duration of infusion was ~ 6 hours. Lidocaine plasma levels were found to be 1.9 +/- 0.7 mcg/ml during infusion, then dropping to 0.9 mcg/mL 1-hour after stopping infusion. Duration of hospital stay was 12 days in experimental and 14 days in control group. There were no lidocaine-related side effects. There was no difference in the speed of return of bowel function between the groups.

Total opiod sparing was noted in lidocaine group: 103+/-72 mg vs 159+/-72 mg. Time to PCA was same in both groups. However a total number of PCA requests was fewer in lidocaine group 38 vs 68. Pain scores on POD 1 at rest and with movement were the same in both groups (1-2/10 rest, 5-6/10 movement). However, pain scores on movement POD 2 and 3 were in favor of lidocaine group (4-6/10 vs 3-4/10).

Overall, it is one of the best-designed and conducted studies on lidocaine with appropriate controls which showed opiod sparing effect of lidocaine and pain scores improvement on POD 2,3. Serum lidocaine levels were likely sub-therapeutic (below 3.5 mcg/mL). Still, there were differences in opiod consumption and pain scores with movement on POD days 2 and 3 in favor of lidocaine group.

As far as shortcomings, it was a small study and authors did not provide justification for chosen sample size. Was the study powered to detect a difference?

Also, patient’s length of hospital stay seems somewhat prolonged in both groups (almost 2 weeks after laparotomy) – is this patient population similar to the one in North America?

4) In a double-blinded randomized controlled trial out of Albany, NY, Groudine (1998) studied pain scores, return of bowel function, and length of hospital stay in 40 patients (20 per group) undergoing retropubic radical prostatectomy. All patients received "flexible anesthetic technique" with no lidocaine in control group. Experimental group received a lidocaine bolus of 1.5mg/kg before induction followed by an infusion at 3 mg/min (for patients >70kg) or 2mg/min (for patients <70kg). Infusion was stopped 60 minutes after skin closure.

For postop pain control all patients received 30 mg IV ketorolac in PACU, then 15 mg IV q6h PRN. Nurse would administer parenteral morphine for breakthrough pain.

Total ketorolac and opiod use was calculated from charts. Both groups received the same amount of postoperative pain medications. A blind observer recorded pain scores, return of bowel function, and length of hospital stay. Patients were asked to recall pain experience for the preceding 24 hours. Patients were then asked to assign a number from 1-10 that would describe an "average pain experience" for the last 24 hours. A "total pain score" was calculated for each patient (an average pain score for last 24 hours "multiplied by" number of days in hospital)

Groudine’s triple-blinded randomized controlled trial study demonstrated benefits of lidocaine in terms of improved postoperative pain experience, faster return of bowel function, and earlier discharge from hospital. Blood levels of lidocaine were probably sub-analgesic for some patients (below 3.5 mcg/mL).

However this study has some significant shortcomings in terms of design. There is no justification of sample size - is it an underpowered study? Accuracy of data collection is a concern, since patients were asked to recall and assign a single number to a 24-hour pain experience. Opiod data is potentially a suspect as well, as it was essentially a nurse-controlled analgesia. Did all the patients requiring pain control receive morphine bolus? Was this morphine given on time? These are all significant concerns that undermine the study findings.

In addition, TOH experience tells us that radical prostatectomy patients are discharged home significantly sooner (POD2) and require much less PRN pain control postop.

This leads to a question – is Albany, NY study population/surgical-nursing care dissimilar to the TOH setting? Can we trust this study data without doing our own in-house validation study?

5) Wu (2005) studied an interaction between dextromethorphan and IV lidocaine in 100 ASA1-2 patients undergoing laparascopic cholecystectomy (hospitals in Taiwan). These patients were randomized to 4 groups (25 per group). At 30 minutes before incision:

No blood lidocaine levels were analyzed. The following data was analyzed – postoperative pain scores, recovery of bowel function, opiod sparing.

All results below were statistically significant (p-value <0.05) except for some of the results in DM+lidocaine group.

It was an interesting well-designed study that attempted to address potentiation of pain control and return of bowel function between two co-analgesics (DM and lidocaine IV). It did demonstrate faster return of bowel function, reduced pain scores, and opiod sparing in both DM and lidocaine groups. These effects were not significant in DM+lidocaine group (with exception of first flatus). No lidocaine bolus was administered. Given very short plasma half-life of lidocaine (8 minutes), we wonder if blood levels of 3.5mcg/mL were achieved. As with other studies, no power analysis was mentioned in planning of this study. Is this an underpowered study?

To summarize above studies:

Systemic lidocaine as a perioperative analgesic was studied in several small (15-25 patient per group) double-blinded RCT studies (with exception of Himes study). What we know about lidocaine:

However, there are some serious concerns about study designs in the reviewed literature:

  1. They are all small single center trials (15-25 per group) that lack power analysis for sample size calculation. This raises the question – are they powered to detect a difference?
  2. Data collection is imprecise in the study by Groudine – which is commonly cited to justify lidocaine use.
  3. Lidocaine dose used in some of these studies tended to be on low end of safe dosing spectrum. This resulted in blood lidocaine levels of less than 3.5 mcg/mL in some studies – a level found to be analgesic by Himes study. I.e. an effect of 1.5mg/kg bolus followed by a 3mg/kg/hr infusion was not reproducibly studied.
  4. Some of the surgical population studied appears dissimilar to The Ottawa Hospital, such 12-14 day hospital stays for laparotomy in Koppert study and 4-5 day stay in prostatectomy patients in Groudine study. Are conclusions of these studies drawn from these populations applicable to Ottawa?

Overall, however, there is a definite benefit of lidocaine in terms of opiod sparing, improving postoperative analgesia, and speeding up return of bowel function. This has led to the adoption of IV lidocaine technique in some centers in North America.

Perhaps study design problems of studies reviewed preclude a universal acceptance of adjuvant use of IV lidocaine in OR.

Ottawa Experience:

A common practice at The Ottawa Hospital is to use a bolus of 0-1 mg/kg followed by a 0.9-2.4 mg/kg/hr infusion with an addition of fentanyl or sufentanil for a variety of procedures in orthopedics and general surgery.

As an example, we examined total abdominal hysterectomy population at TOH. Majority of Trans-Abdominal Hysterectomy (TAH) patients typically receive GA. Minority receives SAB. Approximately 20% of all total abdominal hysterectomies at The Ottawa Hospital today are done using a continuous IV lidocaine infusion in addition to general anesthesia.

A recent retrospective review of postoperative pain experience in TAH patients by Dr. Caveno revealed that there is a definite room for improvement in terms of pain control in this population. Suboptimal pain control in TAH patients also had been echoed by informal discussions with APS director and PACU staff. In this study 47 charts of patients who had undergone TAH at TOH in 2005 were reviewed. Of the 47 patients - 38 received GA alone, and 9 received GA plus "some’ IV lidocaine (0-1 mg/kg bolus followed by 0.9-2.4 mg/kg infusion)

It was revealed that NSAID and co-analgesic (ketamine) use was not consistent: only 35% of patients received NSAID pre-operatively and 53% received ketamine before induction. More than half the patients had pain score ranging from >3 to 7 and above (i.e. moderate-to-severe). Almost all patients required IV PCA postop. Most patients were discharge on POD 3.

To contrast to TAH population in patients after radical prostatectomies (who receive GA+SAB) the postoperative experience is superior to that of TAH. Radical prostatectomy patients do not require IV PCA postop and are routinely discharged on POD 2. Unfortunately, there is up to 10% incidence of syncopal episodes with GA+SAB in radical prostatectomy patients on POD1, so this protocol is being re-examined at this point by Dr. Penning. A trial of intraoperative lidocaine epidural infusion (stopped after skin closure) is being examined to replace SAB.

Question arises – can we improve pain experience of TAH population and make it similar to that of the radical prostatectomy patients?


Relevance - Unanswered questions:

We believe that above analysis opens a door for a well-designed study.

  1. Reviewed literature is flawed in terms of study design. We believe that beneficial effects of lidocaine still require independent validation at other institutions and in other surgical populations.
  2. It is still not clear if administering maximum therapeutic and safe dose of lidocaine peri-operatively (1.5mg/bolus followed by 3mg/kg/hr infusion) and achieving blood levels of > 3.5 < 5 mcg/mL affects maximum possible opiod sparing? Are pain scores maximally reduced as well?
  3. We would like to examine an outcome other than analgesia - length of hospital stay.
  4. It is one of the most clinically significant outcomes of intervention. Only one study so far (Groudine 1998) examined effect of lidocaine on length of hospital stay. However, data collection in this study likely was not precise. In addition, the type of population studied may not apply to the Ottawa experience with radical prostatectomy: much shorter hospital stay in Ottawa, and much less analgesic requirements postop.

    Decreasing hospital stay is a surrogate measure of how fast patients’ wellbeing is restored after surgery and we think it is more clinically relevant compared to the opiod use in the hospital. We agree that Length of Stay is more difficult to accurately measure if we rely on the gynecology team for data collection. Therefore we are going to follow patients ourselves, collect study data, and be closely involved in the patients’ discharge together with the gynecology team.

  5. Can we use IV lidocaine as GA adjuvant intervention in TAH population?
  6. This surgical population appears to require improvement in terms of post-operative pain experience. This is based both on the informal feedback from the PACU staff and APS director. In addition, a retrospective review done by Dr. Caveno highlighted same need for better postop pain control in TAH patients.

    This study also found a non-significant trend towards opiod sparing in the TAH patients receiving GA+IV lidocaine. Since it was an underpowered retrospective study, we cannot draw any conclusions. However, we can use this study to power a well-designed RCT. This may lead to a protocol that works in TAH patients and provides them with better pain experience and sooner discharge from hospital.

  7. Finally, in terms of follow up research – it would be very interesting to compare epidural or spinal lidocaine (with and without addition of epimorphine) with Intravenous lidocaine for elective laparotomy. Extending use of IV lidocaine infusions in PACU or as part of the APS is another idea.

Lidocaine Literature Review - Journal Club Presentation November 20 2006

IV Lidocaine Literature Review and Study Proposal Presentation - by Dr. Ilia Charapov, MD

Sample size:

A retrospective chart review of 47 patients who had elective total abdominal hysterectomies under general anesthesia in 2004 at The Ottawa Hospital (Civic campus) was completed in May 2006. It was used as an initial study to gather information to help design this prospective trial. Although the results were not statistically significant there was a trend toward reduced morphine consumption in patients who received a lidocaine infusion. The mean amount of total postoperative opioid consumed in the first 48 hours from the start of anesthesia was 89.6 mg per patient (SD 33 mg). The rate of postoperative-day two discharge from hospital was 21%. The data from this study was also used to help determine the sample size for this trial.

The study will also be powered to detect an increase from 21 to 50% in the rate of postoperative-day two discharge from hospital with a power of 0.80 and a two-sided type I error of 0.05. The study will also be powered to look for a 30% reduction in total hospital morphine use with a power of 0.90 and a two-sided type I error of 0.05.

Based on the formula for normal theory (11) and assuming two-sided type I error of 0.05 and a power of 0.80, to detect an increase in the rate of postoperative-day two discharge from hospital from 21% to 50% the required number of patients is 42 per group (84 patients total).

Using the same formula, and assuming two-sided type I error of 0.05 and a power of 0.90 to detect a 30% reduction in postoperative morphine use the required number of patients is 26 patients per group (52 patients total).

In order to ensure that enough patients will be included in the analysis despite possible withdrawal from the study and protocol violations, we will enroll 20% more patients for a total of 100 patients (50 patients per group) between two campuses (General and Civic).

Inclusion Criteria - Patients undergoing elective total abdominal hysterectomy at The Ottawa Hospital and able to give informed consent. Plus:

  1. Age 30-69 inclusive;
  2. ASA class I or II patient;
  3. Body Mass Index (BMI) of 18.5-35 (Includes 18.5 to 25 – healthy range; >25-30 overweight; >30-35 Obese Class I)(reference 14)

Exclusion Criteria - Patients unable to give informed consent, unable to provide informed consent, or unable to use patient controlled analgesia. Plus:

  1. Patients under age 30 or over age 70;
  2. ASA III, IV and V class patients ;
  3. Obese Class II patients (BMI>35) (ref. 14), or undernourished (BMI<18.5) (ref.9);
  4. Unable to use patient controlled analgesia;
  5. History of Liver dysfunction
  6. Renal insufficiency defined as a creatinine clearance <50mL/min as calculated using the Cockroft-Gault formula (10);
  7. History of seizure disorder;
  8. Hypersensitivity or allergy to amide type local anesthetics;
  9. Hypersensitivity or allergy to fentanyl;
  10. Any chronic pain syndromes defined as:


- daily use of any opiods for greater than seven consecutive days

11) Medication use that affects cytochrome P450-3A4 or P450-1A2 metabolism excluding insulin and tobacco: see Appendix 9. for a complete list.

Note: We will allow recruitment of smokers and insulin users into the study.

Tobacco and insulin are common medications seen in anesthetic practice. Lidocaine infusions currently run in OR at the TOH are given to patients without regard to their insulin and tobacco use. Over years, such use at TOH main OR had been safe. There are no reports showing toxicity with combination of lidocaine and tobacco and insulin in the literature.

By excluding patients who smoke or use insulin we would significantly limit the number of patients eligible for the study. Most importantly, tobacco and insulin are CYT P450-1A2 inducers (likely mild). As such, they will not predispose patients to higher then expected levels of serum lidocaine (i.e. no risk of toxicity). The opposite may well be true – insulin-requiring diabetic patients and smokers may have lower serum concentrations of lidocaine and require more pain control. To test this hypothesis we will analyze these patients as a subgroup.

Primary objectives:

1) To study the effect of the addition of intraoperative intravenous lidocaine infusion (1.5 mg/kg IV bolus followed by 3 mg/kg/hr infusion) to a balanced general anesthetic on length of hospital stay after total abdominal hysterectomy;

2) To study the effect of the addition of intraoperative intravenous lidocaine infusion (1.5 mg/kg IV bolus followed by 3 mg/kg/hr infusion) to balanced general anesthetic on opioid requirements intraoperatively, in the recovery room, and up to 48 hours post operatively.

Secondary objectives:

1) Post-operative visual NRS pain scores for 48 hours; Ramsey Sedation Scores on arrival and discharge from PACU.

2) Incidence of opioid related side effects including: (a) post-operative nausea and vomiting (b) subsequent anti-emetic medication use (c) decreasing time to first flatus and bowel movement;

  1. Following data will also be analyzed:

- Intraoperative lidocaine level at 60 minutes;

  1. Lidocaine serum levels in smokers and insulin-requiring diabetics.

Patient Recruitment:

Patients will be recruited through Pre-Admission Unit. Study Nurse and Study Inverstigators will recruit patients.

Anesthesia physicians, Obstetrics and Gynecology physicians, residents, and nurses involved in the care of potential total abdominal hysterectomy (TAH) candidates will be be informed about the study by primary investigators through memos, presentatations, departmental meetings. Potential subjects will be identified by these physicians, residents, and nurses involved in the care of TAH patients. Study personnel will be contacted to determine patient eligibility for the study.

Primary investigators at the Civic and General campuses of Ottawa Hospital and physicians at the Preoperative Assessment Unit (PAU) at both campuses will identify patients undergoing elective total abdominal hysterectomy. These patients will be offered an opportunity to participate in the study during standard pre-anesthetic assessment at the Pre-Admission Unit by an anesthesiologist. During this assessment a full medical history with current medications, a complete physical exam, and appropriate investigations will be carried out.

If a patient is willing to consider participation, a study investigator or their delegate (Study Nurse) will discuss the study. The study information sheet will be provided to the patient. The rationale for the study and the study protocol would be discussed using the language appropriate for the patient's background. A discussion of benefits and risks associated with the study and possible anesthetic techniques will be carried out and all questions answered at this time.

Patient consent. Once identified and their eligibility confirmed patients will be asked to provide informed written consent using the Information sheet and Consent form (Appendix 1). Participation will be entirely voluntary. Patients will neither be coerced nor offered incentives to participate.

If the patient decides to participate a Study Checklist form (Appendix 2) will be completed by research personnel and placed on patient’s chart. The Study Checklist form will contain pre-calculated doses of medications for that particular patient as well as concise protocol checklist for the attending anesthetist.

Randomization. Patients will be randomized using a computer generated random number table. All patients randomized will be followed and analyzed in the group to which they are allocated. All patients will be randomized as close to the time of surgery as possible to avoid randomizing patients who subsequently have surgery postponed or cancelled.

Allocation concealment: Allocation to intervention or control groups will be printed on cards placed in sealed, opaque, sequentially-numbered envelopes. Trial envelopes will be kept with research personnel and opened in numerical order when the patient has met the eligibility criteria and is ready to be randomized. The Pharmacy department will prepare a 60ml syringe of study drug that will contain either Normal Saline or 2% Lidocaine and be given as bolus and infused according to the study protocol.

Baseline Assessment: All patients eligible for the trial will have the following information documented preoperatively: medication list, age, sex, height, weight, body mass index, serum creatinine, calculated creatinine clearance (Cockroft-Gault), Liver Function Tests (AST, ALT, Total Bilirubin), primary diagnosis, and scheduled procedure.

Management of anesthesia: All patients will undergo a standardized anesthetic according to the Study Checklist (Appendix 2) that will be completed as soon as the patient is enrolled in the study. The Study Checklist will accompany the anesthetic record and the patient to the OR. This Study Checklist will form the basis for the dosing of all the medications for the anesthetic and the order the protocol is to be completed in. The drugs that are variable in their dosing will include: propofol (will be given to the desired effect at anesthesia induction); rocuronium (will be given to the desired effect of muscle relaxation); and desflurane (will be titrated to a BIS reading of 45-50 to ensure adequate anesthetic depth, ref. 16,17). If needed, morphine will be available to the attending anesthesiologist should the patient demonstrate clinical signs of inadequate analgesia during the anesthetic.

Management of intervention group: Patients in the intervention group will receive lidocaine 1.5 mg/kg as part of their induction. The lidocaine bolus will be followed be a continuous intravenous infusion at 3.0 mg/kg/hr. The rate is pre-calculated and appears on the Study Checklist (Appendix 2). The infusion of lidocaine and fentanyl will be stopped upon skin closure.

Serum lidocaine levels will be collected at 60 minutes (+/- 5 minutes) after beginning of anesthetic. Time of collection will be documented.

Management of control group: Patients in the control group will receive normal saline as part of their induction. The normal saline bolus will be followed be a continuous intravenous infusion. The rate is pre-calculated and appears on the Study Checklist (Appendix 2). The infusion of normal saline and fentanyl will be stopped upon skin closure.

Serum lidocaine levels will be collected at 60 minutes (+/- 5 minutes) after beginning of anesthetic. Time of collection will be documented.

Management of inadequate analgesia: On arrival to PACU an immediate assessment of visual analogue scale (VAS) pain scores and Ramsey Sedation Scale will be done by PACU RN and documented on chart. Patients in the post anesthesia care unit (PACU) will then be given their patient controlled analgesia (PCA). They can self administer morphine until their desired comfort level is reached with the help of the nurse if needed.

PACU RN has discretion to use ketorolac 10 mg IV q 6 hours PRN for breakthrough pain in addition to IV PCA.

No incision infiltration with local anesthetic by surgeon will be allowed in either group.

Management of opioid related side effects: a study physician will assess patients with satisfactory analgesia but experiencing unwanted sedation. Patients experiencing hypotension will be given a 500mL crystalloid bolus and will be assessed by a study physician. Patients with significant respiratory depression will be given naloxone in 40μg boluses until respiratory rate is >10 and will be sedation will assessed by a study physician. Patients experiencing pruritis, nausea, or insomnia will be managed with the medications outlined in the Study Checklist (Appendix 2) and these orders will be on the APS order sheet that will have been completed with the Study Checklist at the time of enrollment.

Postop care: Patients will be discharged to the ward with care as per current Total Abdominal Hysterectomy (TAH) care map.

Description of Tests: In addition to the usual bloodwork involved during this type of procedure, the anesthesiologist will collect 1 blood sample to test the blood lidocaine levels at 1 hour (+/- 5 minutes) after start of anesthetic. There will be no further tests.

Switching to oral analgesia: Patients who are nearing discharge criteria and being able to tolerate medications PO will be offered discontinuation of IV PCA and a switch to PO morphine 5-10 mg PO q 2 hours PRN. Patients will continue receiving Celebrex 200 PO q12hr and Tylenol 650mg PO q4hr while awake until 72 hours postop.

Discharge criteria: Patients will be discharged as per the current discharge criteria for the care map of the TAH patient at The Ottawa Hospital.

  1. Adequate pain control
  2. Vital signs stable
  3. Afebrile (no fever)
  4. Passing flatus (passing gas)
  5. No or scant vaginal discharge
  6. Incision clean, dry, intact, and edges approximated
  7. Tolerates diet as ordered
  8. Understands: staple removal instructions if applicable; New medications; discharge instructions per patient information booklet; follow-up plan with Gynecology physician
  9. Understands there will be a follow up phone call in about one week by one of study investigators to assess level of satisfaction

The Gynecology physicians will make assessment for discharge eligibility daily in the first half of the day. Study investigators will also do daily follow-up of patients and assess readiness for discharge. Should the patient discharge be delayed due to logistical reasons (e.g. was ready for discharge on POD2, but seen late on POD2 and discharged home POD3) – a note of that will be made by study nurse in the study data sheet for that patient.

Post discharge follow-up: patients will be contacted by study coordinator or study nurse in approximately one week by phone to evaluate patient satisfaction with the overall experience. A second Quality of Recovery Score, Appendix 6 will be obtained over the phone. This score will allow evaluation of satisfaction with recovery beyond 48 hours after surgery.

Outcome assessment:

Primary outcome measure: The length of hospital stay in days will be recorded. The morphine consumption will be recorded from the PCA pump database on departure from the PACU, at 6, 24, and 48 hours. Any other opioid medication used for weaning off PCA will also be recorded and converted to morphine equivalents for analysis during the first 48 hours. This data will be compared between the two groups.

Secondary outcome measures: Post-operative visual analogue scale (VAS) pain scores in PACU (arrival and departure) and at 6, 24, 48 hours will be recorded. Ramsey Sedation Scores will be obtained on arrival to PACU to assess sedation levels. The incidence of opioid related side effects will be recorded. Also post-operative nausea and vomiting, subsequent anti-emetic medication use, time to first flatus and bowel movement, Quality of Recovery Score, Appendix 6 (obtained prior to discharge and during one week follow-up interview) as well as Brief Pain Inventory, Appendix 10 – data will be compared between the two groups.

Lidocaine levels will be measured at 60 minutes intraoperatively – time of collection and levels in mcg/mL will also be collected and reported.

Data collection: post-operative opiod use, visual analogue pain scores (VAS), and other postoperative data will be collected by the primary investigators (Dr. Ilia Charapov, Dr. Jordan Caveno) together with the study nurse. This will be done via once daily ward follow-up during which VAS score will be obtained and VAS, opiod use, and other data collected during preceding 24 hours (3 shifts) will be documented.

Data analysis: The number of patients discharged on post-operative day 2 will be analyzed with a chi-square analysis. The morphine consumption at 24 and 48 hours will be analyzed with the unpaired student’s t-test. Post-operative visual analogue scale (VAS) pain scores and Ramsey Sedation Scores will be analyzed for statistical difference using an unpaired student’s t-test. Analyses of secondary outcomes such as immediate post-operative nausea and vomiting, subsequent anti-emetic usage, time to first bowel movement, and Quality of Recovery and Brief Pain Inventory scores will be analyzed with the unpaired student’s t-test or other statistical analysis when appropriate. Statistical significance will be assigned a probability of <0.05 for all analyses.

Data management. Data will be recorded on standardized data collection forms. Data will be transferred from the forms to an Excel 2002 spreadsheet (Microsoft Corp, Redmond WA) at which time patients will be assigned and identified by a unique trial number. Data will be exported to SPSS 11.0.1 (SPSS Inc, Chicago Il) for analysis.


Approximately 20% of all the total abdominal hysterectomy surgeries performed at The Ottawa Hospital at this time are safely performed using both intravenous lidocaine and general anesthesia. In addition, at least half of the anesthesiologists at The Ottawa Hospital routinely include intravenous lidocaine at the start of the anesthetic to put patients asleep (so called "induction of anesthesia".

Common side effects: none as patient will be asleep during administration of a medication.

Common risks associated with intravenous lidocaine administration (approximately 1 in 4) usually occur in awake patients which is not the case in this study. These common reactions are not dangerous and include minor anxiety, dizziness, ringing in the ears, palpitations, taste of metal in the mouth. These can be avoided or minimized completely with the the slow administration of the lidocaine as well as with premedication with other sedative drugs that are commonly used for this procedure.

Uncommon side effects: serious complications such as low blood pressure, shock, seizure, and loss of consciousness are uncommon and are only associated with higher blood levels of lidocaine. These dangerous blood levels of lidocaine are not expected at the dosages used in this study. Anesthesiologists are always aware of these uncommon side effects and will be ready to give you prompt treatment while you are undergoing general anesthetic.

Patients will not be aware of these side effects as well because you they will be asleep.

Rare side effects: risks associated with receiving any anesthetic are dying, brain injury, significant health problems are very rare - less than 1 in 10,000-50,000.




Appendix 1 – Patient Information Sheet and Consent form

Appendix 2 – Microsoft Excel file with Study Protocol and Check List

Appendix 4 – PACU data sheet

Appendix 5 – Adverse Outcome Form

Appendix 6 – Quality of Recovery Score

Appendix 7 – Study Protocol Outline

Appendix 8 – Study Flow chart

Appendix 9 – List of medications affecting cytochrome P450

Appendix 10 – Brief Pain Inventory

Appendix 11 – Complete Study Protocol

Appendix 12 – Patient Diary POD 0

Appendix 13 – Screening form

Appendix 14 – Patient Diary POD 1

Appendix 15 – Patient Diary POD 2

Appendix 15 – Patient Diary POD 7


1. Himes Jr. RS, et al. Effects of Lidocaine on the Anesthetic Requirements for Nitrous Oxide and Halothane. Anesthesiology 1977; 47:437-40.
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2. Koppert W, et al. Perioperative Intravenous Lidocaine has Preventative Effects on Postoperative Pain and Morphine Consumption after Major Abdominal Surgery. Anesth Analg 2004; 98:1050-5.
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3. Cassuto J, et al. Potent Inhibition of Burn Pain Without Opiates. Burns 2003; 23:163-66.

4. Rimback G, et al. Treatment of Postoperative Ileus by Intravenous Lidocaine Infusion. Anesth Analg 1990; 70:414-19.
Download PDF file

5. Groudine SB, et al. Intravenous Lidocaine Speeds the Return of Bowel Function, Decreases Postoperative Pain, and Shortens Hospital Stay in Patients Undergoing Radical Retropubic Prostatectomy. Anesth Analg 1998; 86:235-9.
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 6. Ferrante et al, The analgesic response to intravenous lidocaine in the treatment of neuropathic pain. Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. Anesth Analg. 1996 Jan;82(1):91-7.  PebMed ID: 8712433;
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7. Boas et al, 1982, Analgesic responses to i.v. lignocaine, British Journal of Anesthesia, Vol 54, issue 5 501-505
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8. Wu et al, 2005, The Interaction Effect of Perioperative Cotreatment with Dextromethorphan and Intravenous Lidocaine on Pain Relief an Recovery of Bowel Function after laparascopic cholecystectomy, Anesthesia and Analgesia, volume 100(2), Feb 2005, pp 448-453
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9. National Institute of Diabetes, Digestive and Kidney Diseases, (USA), http://win.niddk.nih.gov/publications/glossary.htm

10. http://www.clinicalculator.com/english/nephrology/cockroft/cc.htm

11. “Inference for Means: Comparing Three Independent Samples”



12. The Utility and Validity of the Modified Brief Pain Inventory in a Multiple-Dose Postoperative Analgesic Trial  Tito R. Mendoza et al, Clin J Pain 2004;20:357–362

13. R. Stoelting, Pharmacology and Physiology in Anesthetic Practice, 2nd edition, 1991, page 345

14. British Nutrition Foundation http://www.nutrition.org.uk/

15. The Ottawa Hospital Laboratory Medicine LFT normal levels.

16. Gan, Tong et al, Bispectral Index Monitoring Allows Faster Emergence and Improved

Recovery from Propofol, Alfentanil, and Nitrous Oxide Anesthesia

Anesthesiology, Volume 87(4), October 1997, pp 808-815

17. Monk, T.G. et al, Anesthetic Management and One-Year Mortality After Noncardiac Surgery, Anesthesia Analgesia, Volume 100(1) January 2005, pp 4-10

18. Hollman et al, Local Anesthetics and the Inflammatory Response: A new Therapeutic Indication? (Review), Anesthesiology Sept 2000, vol 93 (3), pp.858-875