Comparing Two Regional Anesthesia Interventions for Knee Arthroplasty.
Comparing Two Regional Anesthesia Interventions for Knee Arthroplasty.
Osteoarthritis of the knee is a common disease of the elderly and knee arthroplasty is
 indicated in severe cases to improve long term pain and function. Along with perioperative
 quality analgesia, functional recovery is paramount in the postoperative period.Loco-regional
 techniques provide effective analgesia and can mitigate several side effects of systemic
 opioids administration. Also, adequate motor sparing analgesia( to prevent weakness of the
 thigh muscle) following total knee arthroplasty (TKA) is therefore paramount to ensure
 effective rehabilitation, early recovery, readiness to discharge or timely hospital
 discharge.

 There are several motor sparing regional technique described in literature. Adductor canal
 block (ACB), use of intrathecal ( IT) morphine and local infiltration by the surgeons (LIA)
 are such examples. Previous studies have shown the combination of ACB and IT morphine to be
 superior than LIA in providing analgesia.

 Posterior knee infiltration (IPACK), involves blocking the branches of the tibial nerve which
 provides sensory innervation for the posterior aspect of the knee. In combination with ACB, a
 motor sparing analgesic intervention is possible for knee arthroplasty.

 Rationale for doing the study is to evaluate

 1. The effectiveness of IPACK block as a part of multimodal analgesic approach to knee
 arthroplasty surgery.

 2. Enhanced recovery from superior motor sparing analgesia.

 3. early hospital discharge We hypothesize that, following total knee arthroplasty surgery,
 the combination of continuous adductor canal catheter and I-PACK blocks will achieve a
 decrease in the time to readiness to hospital discharge as measured by the following
 four criteria: (1) adequate analgesia; (2) independence from intravenous opioids; (3)
 ability to independently stand, walk 3 m (metres), return, and sit down; and (4)
 independently ambulate 30 m without limitation of time. We postulate this will occur by
 providing superior motor-sparing analgesia compared to LIA for knee arthroplasty
 surgery.
Introduction Osteoarthritis of the knee is a common disease of the elderly and knee
 arthroplasty (TKA) is indicated in severe cases to improve long term pain and function.
 Inadequate perioperative pain control is a strong predictor of persistent pain beyond 3
 months.

 Analgesic modalities for TKA Several analgesia regimes exist for TKA. Multimodal regimens
 including both loco-regional techniques or systemic analgesics. Loco-regional techniques
 provide effective analgesia and can mitigate the side effects of systemic opioids including
 nausea and vomiting, pruritus, respiratory depression and urinary retention.

 Muscle weakness following regional anesthesia technique may induce fall, hinder early
 rehabilitation and prolong hospitalization. Motor sparing analgesic (do not cause weakness of
 muscles) are in vogue due to enhance early rehabilitation and analgesia. Local Infiltration
 Analgesia (LIA), Adductor Canal Block (ACB) and posterior infiltration of the knee (IPACK)
 are examples of motor sparing interventions utilized for TKA surgery.

 LIA involves the injection of high volumes of dilute local anesthetic solution directly into
 the articular and peri-articular tissues during the surgical procedure.

 ACB consists on the administration of local anesthetic in the adductor canal, an aponeurotic
 compartment in the mid-thigh containing the femoral vessels and several distal branches of
 the lumbar plexus that contribute to the innervation of the anterior aspect of the knee.

 Posterior knee infiltration (IPACK), involves ultrasound guided injection of local
 anesthetics in the muscular plane between the popliteal artery and the femoral condyles. This
 involves blocking the branches of the tibial nerve which provides sensory innervation for the
 posterior aspect of the knee Hypothesis We hypothesize that, following total knee
 arthroplasty surgery, the combination of continuous adductor canal catheter and IPACK blocks
 will achieve a decrease in the time to readiness to hospital discharge as measured by the
 following four criteria: (1) adequate analgesia; (2) independence from intravenous opioids;
 (3) ability to independently stand, walk 3 m(metres),return and sit down; and (4)
 independently ambulate 30 m without limitation of time. We postulate this will occur by
 providing superior motor-sparing analgesia compared to LIA for knee arthroplasty surgery.

 Methodology. This will be a multicentric Randomized controlled double blinded study. Proposed
 timeline is three years following ethics approval.

 Study Centre The study will take place in two university hospitals; University Hospital,
 London Health Sciences Centre, London, Ontario and George Elliot Hospital, Warwickshire,
 United Kingdom. These centers have the clinical volume, technical expertise equipment setup,
 previous experience in this area of research, and research support needed to carry out the
 proposed study.

 Research Ethics Board (REB) Approval An application has been submitted to the University
 Health Network, Western University and Leister University Ethics Board for REB approval
 Informed Consent Patients will be identified from operation schedule list from the surgical
 secretaries office a month in advance of their operation.An information package containing a
 letter of introduction, study information and consent form will be posted to the patients
 address as mentioned in power chart a month in advance of OR schedule. Then the patient we
 will contacted by our study team over phone to introduce the study and verbal consent.
 Written consent will happen on the day of admission. The investigator will be a physician and
 will not be participating in the patient's care on the day of surgery.

 Patients will be informed of the procedures involved in the study, the chances of being
 assigned to one of the 2 groups, the risks and benefits of participating, and of their right
 to withdraw from the study at any time without adversely affecting their clinical care. The
 investigators will retain a signed, witnessed consent form. The telephone number of the chair
 of the George Elliot Hospital Research Board and Western University Research Ethics Board
 will be provided to study participants to contact for information on the rights of human
 subjects participating in clinical research.

 Blinding A Pharmacist not directly involved in patient care will prepare all study drugs. The
 patient, anesthesiologist performing the block and looking after the patient in the block
 operating room, surgeons, physiotherapists and the investigator collecting outcome data will
 be unaware of study group allocation. The documentation in the anesthetic chart will be
 written as study interventions instead of the actual procedure.

 Randomization and study groups

 Study participants will be randomly allocated to one of two groups using a computer-generated
 list of random numbers and sealed opaque envelopes using Lawson Redcap. The study groups will
 receive the following interventions:

 Group 1. Spinal Anesthesia + ACB continuous catheter+ IPACK + Sham LIA (100 ml of normal
 saline infiltrated by the surgeons at the end of surgery) Group 2. Spinal Anesthesia + LIA +
 Sham Blocks(20 ml of normal saline ACB and continuous infusion+ IPACK each) Interventions and
 Peri-operative management ACB and continuous catheter placement. ACB will be performed prior
 to surgery in the block room. Monitoring of vital signs will include non-invasive blood
 pressure, electrocardiogram, and pulse oximetry. Supplemental oxygen will be administered.
 After performing a "time-out" procedure including verification of "correct surgical site",
 sedation will be achieved with IV Midazolam in 1 mg increments and IV Fentanyl in 25 mcg
 increments as needed. Ultrasound examination of the thigh will be performed using a high
 frequency linear probe (5-12 MHz range) with either a Philips Sparq or Sonosite Turbo. The
 study participants will be positioned supine with the operative knee slightly flexed and the
 hip externally rotated. Under sterile technique, the adductor canal will be identified as an
 aponeurotic compartment limited by the sartorius muscle antero-medially, the adductor muscles
 posteriorly and the vastus medialis muscle laterally. After skin infiltration of 1 - 3 ml of
 2% lidocaine, a 80 mm, 22 gauge, short-bevel echogenic needle (Sonoplex, Pajunk, Norcross,
 Georgia, Arrow depending on the institution) will be advanced, in plane with the ultrasound
 beam in the mid-thigh, at equal distance from the groin and the patella. 10ml of study
 solution will be injected to surround the femoral artery and the catheter would be placed in
 the adductor canal lateral to the artery. After the placement of the catheter, another 10 ml
 of the study solution will be injected. Continuous infusion of 5mls/hr of 0.2% of ropivacaine
 will be infused till considered ready to discharge. For Group 1 the active study drug will
 consist of 20ml of ropivacaine 0.5% with 1:400,000 epinephrine. In Group 2, study
 participants will receive 20ml of 0.9% saline as a bolus and 5mls/hr of normal saline
 infusion in the postoperative period.

 IPACK Posterior knee infiltration will be performed following ACB. The study participants
 will remain supine with knee flexed and internally rotated. After full asepsis, the
 ultrasound probe will be placed on the superior- lateral surface of the knee joint. On
 visualization of the femoral condyle and popliteal artery, an infiltration of the drug will
 be made in the muscular space between the popliteal artery and the posterior femoral condyle.
 Group 1 receive 20ml of ropivacaine 0.5% with 1:400,000 epinephrine while Group 2 will
 receive 20ml of 0.9%saline.

 Spinal Anesthesia with IT morphine Spinal anesthesia will be performed following the ACB and
 IPACK per standard institutional practice. The study participants will be placed in the
 sitting position and a 25-gauge Whitacre needle will be introduced at the L2-3 or L3-4
 intervertebral levels to enter the intrathecal space under aseptic condition. All patients
 will receive 2-3 ml of 0.75% preservative-free bupivacaine.

 Local Infiltrative Analgesia (LIA) For they study participants in group 2, the knee joint
 will be infiltrated by the surgeon intraoperatively with 300 mg of ropivacaine (100 ml of
 0.3% ropivacaine),30 mg of ketorolac, and 10mg of morphine. Study Participants in Group 1
 will receive local infiltration of 100ml of normal saline as a Sham injection.

 Post-operative Systemic Analgesics

 Standardized perioperative systemic analgesics will be provided to all subjects following
 current standard institutional practice. This will include:

 1. Acetaminophen 3 to 4 g orally daily for 5 days,

 2. Celecoxib 100 to 200 mg orally twice a day (or an alternate non-steroidal
 anti-inflammatory drug for those with sulfa allergy),

 3. Hydromorphone 1-2 mg/morphine 5-10 mg/oxycodone 5-10 mg (or equivalent) orally every two
 hours as needed.

 Intravenous patient-controlled analgesia with hydromorphone or morphine at equivalent doses
 will be prescribed as a "rescue" modality to be started only if oral analgesics fail to
 achieve a pain score of less than 5 as is standard institutional practice. Patients will be
 followed twice daily by the Acute Pain Service team who will be unaware of study group
 allocation and will make changes to the analgesic regimen as required by the clinical
 situation.

 Sample Size Calculation Based of local data, the investigators hypothesize that the
 intervention, for a total of 532 participants (266 per group) the investigators will be able
 to detect a 20% difference in (length of stay)LOS from 2.8 days to 2.24 days. Based on this
 effect size, an alpha of 0.05 and a beta of 0.2, an estimate of sample size to be 532 (266
 patients per group) was calculated.

 Statistical Analysis Normality of continuous outcomes will be assessed visually (using
 histograms of raw and/or transformed data) and numerically (using the Shapiro-Wilk test). If
 the raw or transformed data are approximately normally-distributed, then a parametric method
 (t test) will be used for analysis, otherwise a non-parametric or semi-parametric method will
 be used (0.5 quantile [median] regression for non-time-to-event data and Cox regression for
 time-to-event data). Data will be presented as mean, standard deviation (SD) or median/
 interquartile range (IQR). 95% confidence interval (CI) for the differences between groups
 will be constructed using standard techniques (for normally distributed outcomes) or using
 bootstrapping of 10,000 replications (for non-normally distributed outcomes).

 Categorical outcomes will be analyzed using Fisher's exact test, along with the relative risk
 and its two-sided 95% CI. We will perform regression adjustment for any prognostically
 important differences between groups in baseline variables. A P value of < 0.05 will be
 considered significant.

 Data Monitoring Committee Two researchers from the department of Anesthesia, Dr. Craig
 Railton and Dr. Mahesh Naggapa will form Data Monitoring Committee. They will meet once a
 year to review the results and advice the PI accordingly. None of the members of the Data
 Monitoring Committee will be involved in any other way with the conduct of the trial, except
 the routine, blinded intra or postoperative care of the study participants.

 Confidentiality and DATA sharing All information gathered during the course of the study will
 be stored in a secure, locked filing cabinet, in a locked office of principal investigator. A
 master list with patient identification information (name, birth date, surgeon and surgical
 date) will be maintained separately from a deidentified list. This will allow for review of
 pertinent information if required. When entering and analyzing data, only study subject
 identification numbers will be used to ensure patient confidentiality. All personal
 identification data will be kept in the study regulatory binder, separate from study data.
 Study results will be presented in a way that makes it impossible to identify individual
 participants. The data will be collected in institutional REDCAP accounts and shared within
 institution. Data analysis will be performed by the LHSC Group.
Inclusion Criteria:

 -  ASA Physical Status I-III

 -  18 -70 years of age

 -  BMI 18 - 40

 -  Scheduled for elective unilateral primary total knee arthroplasty under spinal
 anesthesia.

 -  Able to ambulate independently with a standard wheeled walker as maximum mobility aid.

 Exclusion Criteria:

 -  Revision knee arthroplasty

 -  Bilateral knee arthroplasty

 -  Inability to provide informed consent

 -  Patient scheduled for a second knee arthroplasty operation at a later date.

 -  Neuropathic pain or sensory disorders of the surgical limb already diagnosis by a
 physician.

 -  Contraindication to regional anesthesia.

 -  Chronic opioid use defined as > 60 mg of daily oral morphine equivalents.

 -  Patients who did not receive spinal anesthesia with intrathecal morphine or needed
 general anesthetics due to failed spinal anesthesia