Intraoperative Lidocaine Infusion for Analgesia (ILIA)
Condition: Elective Total or Subtotal Abdominal Hysterectomy
Study type: Interventional

Summary: 
      The purpose of this study is 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.

      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 approximately 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 levels; intraoperative opioid use

        2. Opioid use in the recovery room

        3. Patient Controlled Analgesia (PCA) morphine requirements postoperatively up to 48 hours

        4. Oral pain controlling medication use up to 48 hours postoperatively if IV PCA
           discontinued before 48 hours

        5. Verbal Analogue Scale (VAS) pain scores in recovery room and during first 2 days
           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.
    

Detailed description: 
      Provide the rationale for the study (see list of references attached separately).

      Provide the rationale for the study (see list of references attached separately).

      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. 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. Considering its low cost, ease of
      administration, and low incidence of side effects, lidocaine presents an attractive
      anesthetic option.

      However, there have been only a few randomized controlled trials to date that have assessed
      the effect of IV lidocaine on a patient's pain control. These trials were small single center
      studies that require independent validation at other institutions and in other surgical
      populations. In the previous trials, the standard anesthetic technique was not as well
      controlled as it will be in this trial. If approved this study will add to the scant but
      promising literature concerning peri-operative lidocaine use for analgesia.

        1. Lidocaine infusion supplements general anesthesia and improves analgesia. Lidocaine has
           been used to supplement general anesthesia for over 50 years (1). It has a MAC sparing
           effect that allows reduction of other anesthetic agents in a balanced anesthetic
           technique (1). Lidocaine infusions improve pain scores in burn patients and provide
           sufficient analgesia without the addition of an opioid analgesic (3). Its use is well
           established in chronic neuropathic and ischemic pain (6,7). Over the last decade, its
           use in the management of acute pain and pre-emptive analgesia has increased. Studies
           demonstrating improved pain scores with movement and at rest in major abdominal
           surgeries and radical retropubic prostatectomy have been published (2,5,8).

        2. IV Lidocaine infusion dose and toxicity (2,3,4,5,6,7,10). Lidocaine toxicity does not
           occur with plasma levels below 5 mcg/mL. Currently reported dosing vary between 'no IV
           bolus' to 3 mg/kg/hr IV bolus followed by 1.5 to 3 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 infusing for 24 hours after the end of surgery with no
           reported side effects attributed to local anesthetic toxicity (4).

           In another lidocaine dose-response study an infusion of 500 mg of lidocaine over one
           hour in 13 patients with neuropathic chronic pain (6) resulted in plasma levels of 2.43
           +/- 1.01 mcg/mL at the initial onset of analgesia. This corresponds to infusion rates of
           approximately 6-7 mg/kg/hr of lidocaine (no bolus). The amount of lidocaine used at the
           onset of analgesia was 123+/-55 mg over ~ 9-20 minutes. Complete analgesia was reported
           in 10 out 13 patients with corresponding plasma levels of 3.79+/- 1.00 mcg/mL with a
           total lidocaine dose of ~ 375 +/- 23mg over 36-54 minutes. 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.

           The dose of lidocaine currently used at the Ottawa Hospital Department of Anesthesia to
           supplement general anesthesia is a bolus of 1-1.5 mg/kg followed by an intraoperative
           infusion of 1.2 to 3 mg/kg/hr. In this study we propose a bolus of 1.5 mg/kg followed by
           3 mg/kg/hr infusion.

        3. Lidocaine infusion reduces opiod consumption. Lidocaine infusions have decreased the
           opioid and NSAID use following major surgery (2,5). A protocol and a case report in burn
           patients demonstrate markedly reduced requirements for opioid analgesia (3). The reduced
           use of opiods should be associated with lower incidence of opiod-related side effects
           and decreased use of medication to treat these side effects.

        4. Lidocaine infusion improves bowel function. Lidocaine use speeds the return of bowel
           function that is a major complication of intra-abdominal operations. In both radical
           prostatectomy and cholecystectomy patients' time to passage of first postoperative bowel
           movement was decreased (4,5).

        5. Lidocaine infusion leads to quicker discharge. Lidocaine use led to faster discharge
           from hospital in-patients undergoing radical prostatectomy (5). This result is likely
           due to the combined beneficial effects as outlined above.

      Protocol:

      Patients will be recruited through multiple mechanisms. These will include, but not be
      restricted to: preoperative assessment clinics, physicians' clinics, and hospital wards.

      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, 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
      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 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. An anesthesia resident or staff not involved with
      care of the patient will open an envelope for that patient and prepare four syringes:

        -  One 10mL Study Drug Bolus syringe containing either Normal Saline or 2% Lidocaine;

        -  Three 20mL Study Drug Infusion syringes containing either Normal Saline or 2% lidocaine.

      Maintenance of confidentiality. All records will be kept confidential. Records will be kept
      in a locked cabinet in the Department of Anesthesiology, Civic Campus for fifteen (15) years
      following enrollment of the last patient. Access will be restricted to study investigators
      and research assistants. Data will be stored on a secure, password-protected computer within
      the Department of Anesthesiology and kept strictly confidential. No information capable of
      identifying a study participant will appear in study reports or publications

      Study design: This is a prospective, randomized, double blinded, 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. 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.

      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 analogue scale (VAS) pain scores for 48 hours;

        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;

        3. Following data will also be analyzed:

             -  Intraoperative lidocaine levels;

             -  Incidence of side effects that can be attributed to local anesthetic toxicity;

             -  Oral pain medications use up to 48 hours postoperatively if IV PCA discontinued
                before 48 hours.

      Baseline Assessment: All patients eligible for the trial will have the following information
      documented preoperatively: age, sex, height, weight, body mass index, serum creatinine,
      calculated creatinine clearance (Cockroft-Gault), 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 40 to ensure adequate anesthetic depth). 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 two points of the study:

        -  30 minutes after the initial bolus

        -  and during surgical closure, just prior to stopping the infusion.

      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 two points of study:

        -  30 minutes after the initial bolus

        -  and during surgical closure, just prior to stopping the infusion.

      Management of inadequate analgesia: Patients in the post anesthesia care unit (PACU) will be
      given their patient controlled analgesia (PCA) after immediate assessment of visual analogue
      scale (VAS) pain scores are complete. They can self administer morphine until their desired
      comfort level is reached with the help of the nurse if needed.

      Management of opioid related side effects: Patients with satisfactory analgesia but
      experiencing unwanted sedation will be assessed by a study physician. Patients experiencing
      hypotension, will be given a 500mL crystalloid bolus and will 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 2 blood samples to test the levels of lidocaine
      in your blood during surgery. 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 PRN q 2 hours. Patients will continue receiving Celebrex 200 PO q12hr with food
      intake and Tylenol 650mg PO q4hr while awake until 72 hours postop.

      Discharge criteria: Patients will be discharged according as per the current discharge
      criteria for the care map of 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. 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.

      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 and every
      8 hours until 48 hours postoperatively. 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 will be
      recorded on departure from the PACU and every 8 hours until 48 hours postoperatively. The
      incidence of opioid related side effects will be recorded. This will include post-operative
      nausea and vomiting, subsequent anti-emetic medication use, time to first flatus and bowel
      movement. This data will be compared between the two groups.

      Lidocaine levels that were measured at 30 minutes intraoperatively and just prior to the end
      of the infusion will also be collected and reported.

      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
      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 will be analyzed with the unpaired student's
      t-test 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.
    

Intervention name(s): Lidocaine Intravenous Infusion
Intervention type(s): Drug
Intervention description(s): 1.5 mg/kg IV bolus on induction, 3 mg/kg/hr infusion from inducation until fascia closure
Intervention MeSH terms: Lidocaine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Intravenous Lidocaine; Lidocaine Infusion; Total Abdominal Hysterectomy; Analgesia; Anesthesia; Adjunct