Total Knee Arthroplasty
Conditions
Brief summary
The purpose of this study is to find a better way to make patients comfortable after their knee surgery. The investigators compared three ways of providing pain relief, either by use of a nerve block at the femoral and sciatic nerve areas, or with actual injections in the surgical joint area with one of two different medicines, either ropivacaine or liposomal bupivacaine (Exparel®). The hypothesis was that the nerve block at the femoral and sciatic nerve areas would result in lower pain scores and opioid consumption than either of the two injections in the surgical joint area.
Interventions
DRUGPeripheral nerve blocks with Bupivacaine
Subjects received Bupivacaine 0.5% preoperatively, then Bupivacaine 0.2% upon post anesthesia care unit (PACU) arrival via femoral nerve block, then Bupivacaine 0.25% via single-injection sciatic nerve.
DRUGIntra articular injection with Ropivacaine
Subjects received an intra articular injection with Ropivacaine, a total volume of 120 milliliters (mL) injected in the periarticular structures by the surgeon. Ropivacaine dose depended upon body weight: 50-74.9 kg: 200 mg, 75-99.9 kg: 300 mg, 100-125 kg: 400 mg.
DRUGIntra articular injection with liposomal bupivacaine
Subjects received an intra articular injection with liposomal bupivacaine, a total volume of 120 mL injected in the periarticular structures by the surgeon. Patients weighing 50-125 kg received 266mg of Liposomal Bupivacaine.
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Adult patients with an American Society of Anesthesiologists (ASA) physiological status I-III 2. Patients presenting for unilateral primary total knee replacement. 3. No focal neurologic deficit of the surgical lower extremity. 4. Cognitively intact with the ability to sign informed consent
Exclusion criteria
1. Chronic pain syndromes such as fibromyalgia or complex regional pain syndrome 2. History of long term use of daily opioids (\>1 months) with oral morphine equivalent (OME) \>5mg/day. 3. Body mass index (BMI) \> 40 kg/m2 4. Allergies to medications used in this study such as: fentanyl, hydromorphone, ketorolac, ibuprofen, acetaminophen, local anesthetics, oxycodone, OxyContin, tramadol, ondansetron, droperidol, or dexamethasone, celecoxib 5. Major systemic medical problems such as: * Severe renal disorder defined as glomerular filtration rate (GFR) \<50 units/m2 * Cardiovascular disorders defined as congestive heart failure (CHF) New York Heart Association (NYHA) class III-IV * Severe hepatic disorder defined as current or past diagnosis of acute/subacute necrosis liver, acute hepatic failure, chronic liver disease, cirrhosis (primary biliary cirrhosis), fatty liver, chronic hepatitis/toxic hepatitis, liver abscess, hepatic coma, hepatorenal syndrome, other disorders of liver. 6. Impaired cognitive function or inability to understand the study protocol 7. Contraindication to a regional anesthesia technique (e.g., preexisting neuropathy in the operative extremity, coagulopathy \[platelets \< 100,000, International Normalized Ratio (INR) \>1.5\], refusal, etc.). 8. Previous contralateral knee replacement managed with regional or periarticular injection 9. Unable to follow-up at the 3 month interval at Mayo Clinic in Rochester, Minnesota 10. Pregnancy or breast feeding (women of child-bearing potential, must have a negative pregnancy test)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Pain Post-Operative Day (POD) 1 (Morning) | Post-Operative Day 1, approximately 6 am to 12:00 pm | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Pain Post-PACU | Post-operative Day 0, approximately 12 pm to 12 am | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
| Average Pain POD 1 (24 Hours) | POD 1, approximately 12 am to 12 am next day | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
| Maximum Pain POD 1 (24 Hours) | POD 1, approximately 12 am to 12 am next day | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
| Average Pain POD 2 (24 Hours) | POD 2, approximately 12 am to 12 am next day | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
| Maximum Pain POD 2 (24 Hours) | POD 2, approximately 12 am to 12 am next day | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
| Preoperative Daily Opioid Use | baseline | Opioid consumption will be documented in the patient electronic medical record by the nursing staff caring for the patient. |
| Average Pain Post-Postanesthesia Care Unit (PACU) | Post-operative Day 0, approximately 12 pm to 12 am | Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable. |
| PACU Opioid Use | Approximately 2 hours after entry in PACU | Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient. |
| POD 0 Post-PACU Opioid Use | POD 0, approximately 12 pm to 12 am | Additional opioid medications that were taken by subjects (recorded at the same time as the time points for measuring pain). Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient. |
| POD 1 Opioid Use | POD 1, approximately 12 am to 12 am next day | Additional opioid medications that were taken by subjects (recorded at the same time as the time points for measuring pain). Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient. |
| POD 2 Opioid Use | POD 2, approximately 12 am to 12 am next day | Additional opioid medications that were taken by subjects (recorded at the same time as the time points for measuring pain). Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient. |
| Hospital Length of Stay | Approximately 3 days | The hospital length of stay was measured from the date of admittance until the date of discharge. |
| Balance Testing on Operative Leg Using Unipedal Stance Time | baseline, approximately 12 weeks | In order to measure clinical balance, unipedal stance time (UST) was collected as an indicator of balance and fall risk. Timing (in seconds) began upon withdrawal of support and continued until the uplifted foot returned to the floor, the subject required support, or if the subject reached a time limit of 30 seconds. The best performance of three repetitions was recorded for analysis. Normative values for the UST are available. A UST threshold of 30 seconds yields a sensitivity of 95% and a specificity of 58% in identifying those with a history of falls. The first five seconds of unipedal stance is indicative of dynamic balance; inability to maintain unipedal stance for five seconds is a significant predictor of injurious falls. |
| Intraoperative Opioid Use | During the procedure, approximately 2 hours after start of the procedure | Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at Mayo Clinic in Rochester, Minnesota from October 2014 to December 2015.
Participants by arm
| Arm | Count |
|---|---|
| Peripheral Nerve Block (PNB) This group received a continuous femoral nerve block and a single injection sciatic nerve block consisting of the following: Peripheral nerve blocks with Bupivacaine. | 50 |
| Ropivacaine (PAI-R) This group received intra articular injection with Ropivacaine, a total volume of 120 milliliters (mL) injected in the periarticular structures by the surgeon. Following the current, standardized practice for periarticular infiltration, approximately 30 - 40 mL of solution was injected into the posterior capsule just prior to cementing the implants in place and 40 - 50 mL of solution injected into the medial and lateral retinaculum while the cement was hardening and prior to deflation of the tourniquet. The remaining volume of approximately 40 mL was injected into the quadriceps tendon and subcutaneous tissue prior to skin closure. | 55 |
| Liposomal Bupivacaine (PAI-L) This group received Intra articular injection with liposomal bupivacaine, a total volume of 120 milliliters (mL) injected in the periarticular structures by the surgeon. Following the current, standardized practice for periarticular infiltration, approximately 30 - 40 mL of solution was injected into the posterior capsule just prior to cementing the implants in place and 40 - 50 mL of solution injected into the medial and lateral retinaculum while the cement was hardening and prior to deflation of the tourniquet. The remaining volume of approximately 40 mL was injected into the quadriceps tendon and subcutaneous tissue prior to skin closure. | 52 |
| Total | 157 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 3 | 0 | 3 |
| Overall Study | subject expired before surgery | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Peripheral Nerve Block (PNB) | Ropivacaine (PAI-R) | Liposomal Bupivacaine (PAI-L) | Total |
|---|---|---|---|---|
| Age, Continuous | 67 years STANDARD_DEVIATION 9 | 68 years STANDARD_DEVIATION 8 | 67 years STANDARD_DEVIATION 8 | 67.7 years STANDARD_DEVIATION 8.8 |
| Region of Enrollment United States | 50 Participants | 55 Participants | 52 Participants | 157 Participants |
| Sex: Female, Male Female | 25 Participants | 34 Participants | 27 Participants | 86 Participants |
| Sex: Female, Male Male | 25 Participants | 21 Participants | 25 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 55 | 0 / 52 |
| other Total, other adverse events | 2 / 50 | 3 / 55 | 3 / 52 |
| serious Total, serious adverse events | 0 / 50 | 0 / 55 | 0 / 52 |
Outcome results
Primary
Maximum Pain Post-Operative Day (POD) 1 (Morning)
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: Post-Operative Day 1, approximately 6 am to 12:00 pm
Population: Intent-to-Treat Analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Maximum Pain Post-Operative Day (POD) 1 (Morning) | 3 units on a scale |
| Ropivacaine (PAI-R) | Maximum Pain Post-Operative Day (POD) 1 (Morning) | 4 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Maximum Pain Post-Operative Day (POD) 1 (Morning) | 4.5 units on a scale |
p-value: 0.144Wilcoxon (Mann-Whitney)
p-value: 0.016Wilcoxon (Mann-Whitney)
p-value: 0.196Wilcoxon (Mann-Whitney)
Secondary
Average Pain POD 1 (24 Hours)
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: POD 1, approximately 12 am to 12 am next day
Population: Intent-to-Treat Analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Average Pain POD 1 (24 Hours) | 2.5 units on a scale |
| Ropivacaine (PAI-R) | Average Pain POD 1 (24 Hours) | 3.5 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Average Pain POD 1 (24 Hours) | 3.7 units on a scale |
p-value: 0.059Wilcoxon (Mann-Whitney)
p-value: 0.005Wilcoxon (Mann-Whitney)
p-value: 0.214Wilcoxon (Mann-Whitney)
Secondary
Average Pain POD 2 (24 Hours)
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: POD 2, approximately 12 am to 12 am next day
Population: Intent-to-Treat Analysis. For POD 2, data are missing for 5 subjects (1 on Peripheral Nerve Block (PNB) arm, 1 on Ropivacaine (PAI-R) arm, and 3 on Liposomal Bupivacaine (PAI-L) arm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Average Pain POD 2 (24 Hours) | 3.3 units on a scale |
| Ropivacaine (PAI-R) | Average Pain POD 2 (24 Hours) | 3.2 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Average Pain POD 2 (24 Hours) | 3.5 units on a scale |
p-value: 0.958Wilcoxon (Mann-Whitney)
p-value: 0.203Wilcoxon (Mann-Whitney)
p-value: 0.132Wilcoxon (Mann-Whitney)
Secondary
Average Pain Post-Postanesthesia Care Unit (PACU)
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: Post-operative Day 0, approximately 12 pm to 12 am
Population: Intent-to-Treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Average Pain Post-Postanesthesia Care Unit (PACU) | 0.6 units on a scale |
| Ropivacaine (PAI-R) | Average Pain Post-Postanesthesia Care Unit (PACU) | 1.7 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Average Pain Post-Postanesthesia Care Unit (PACU) | 2.4 units on a scale |
p-value: 0.003Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.021Wilcoxon (Mann-Whitney)
Secondary
Balance Testing on Operative Leg Using Unipedal Stance Time
In order to measure clinical balance, unipedal stance time (UST) was collected as an indicator of balance and fall risk. Timing (in seconds) began upon withdrawal of support and continued until the uplifted foot returned to the floor, the subject required support, or if the subject reached a time limit of 30 seconds. The best performance of three repetitions was recorded for analysis. Normative values for the UST are available. A UST threshold of 30 seconds yields a sensitivity of 95% and a specificity of 58% in identifying those with a history of falls. The first five seconds of unipedal stance is indicative of dynamic balance; inability to maintain unipedal stance for five seconds is a significant predictor of injurious falls.
Time frame: baseline, approximately 12 weeks
Population: Intent-to-treat analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Peripheral Nerve Block (PNB) | Balance Testing on Operative Leg Using Unipedal Stance Time | baseline | 24 seconds |
| Peripheral Nerve Block (PNB) | Balance Testing on Operative Leg Using Unipedal Stance Time | 12 weeks | 20 seconds |
| Ropivacaine (PAI-R) | Balance Testing on Operative Leg Using Unipedal Stance Time | baseline | 16 seconds |
| Ropivacaine (PAI-R) | Balance Testing on Operative Leg Using Unipedal Stance Time | 12 weeks | 30 seconds |
| Liposomal Bupivacaine (PAI-L) | Balance Testing on Operative Leg Using Unipedal Stance Time | baseline | 17 seconds |
| Liposomal Bupivacaine (PAI-L) | Balance Testing on Operative Leg Using Unipedal Stance Time | 12 weeks | 23 seconds |
Comparison: Within group comparison of baseline and 3 months (approximately 12 weeks)p-value: 0.623Regression, Cox
Comparison: Within group comparison of baseline and 3 months (approximately 12 weeks)p-value: 0.001Regression, Cox
Comparison: Within group comparison of baseline and three months (approximately 12 weeks)p-value: 0.048Regression, Cox
Secondary
Hospital Length of Stay
The hospital length of stay was measured from the date of admittance until the date of discharge.
Time frame: Approximately 3 days
Population: Intent-to-treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Hospital Length of Stay | 2 days |
| Ropivacaine (PAI-R) | Hospital Length of Stay | 2 days |
| Liposomal Bupivacaine (PAI-L) | Hospital Length of Stay | 2 days |
p-value: 0.768Kruskal-Wallis
Secondary
Intraoperative Opioid Use
Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient.
Time frame: During the procedure, approximately 2 hours after start of the procedure
Population: Intent-to-treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Intraoperative Opioid Use | 10 mg OME |
| Ropivacaine (PAI-R) | Intraoperative Opioid Use | 10 mg OME |
| Liposomal Bupivacaine (PAI-L) | Intraoperative Opioid Use | 10 mg OME |
p-value: 0.807Wilcoxon (Mann-Whitney)
p-value: 0.171Wilcoxon (Mann-Whitney)
p-value: 0.104Wilcoxon (Mann-Whitney)
Secondary
Maximum Pain POD 1 (24 Hours)
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: POD 1, approximately 12 am to 12 am next day
Population: Intent-to-Treat Analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Maximum Pain POD 1 (24 Hours) | 5.5 units on a scale |
| Ropivacaine (PAI-R) | Maximum Pain POD 1 (24 Hours) | 6 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Maximum Pain POD 1 (24 Hours) | 6 units on a scale |
p-value: 0.189Wilcoxon (Mann-Whitney)
p-value: 0.043Wilcoxon (Mann-Whitney)
p-value: 0.357Wilcoxon (Mann-Whitney)
Secondary
Maximum Pain POD 2 (24 Hours)
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: POD 2, approximately 12 am to 12 am next day
Population: Intent-to-Treat Analysis. For POD 2, data are missing for 5 subjects (1 on PNB arm, 1 on PAI-R arm, and 3 on PAI-L arm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Maximum Pain POD 2 (24 Hours) | 5 units on a scale |
| Ropivacaine (PAI-R) | Maximum Pain POD 2 (24 Hours) | 6 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Maximum Pain POD 2 (24 Hours) | 6 units on a scale |
p-value: 0.797Wilcoxon (Mann-Whitney)
p-value: 0.493Wilcoxon (Mann-Whitney)
p-value: 0.299Wilcoxon (Mann-Whitney)
Secondary
Maximum Pain Post-PACU
Pain was measured on a 1-10 numeric pain rating scale (NRS) with 0=no pain, and 10=worst pain imaginable.
Time frame: Post-operative Day 0, approximately 12 pm to 12 am
Population: Intent-to-Treat Analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Maximum Pain Post-PACU | 1 units on a scale |
| Ropivacaine (PAI-R) | Maximum Pain Post-PACU | 4 units on a scale |
| Liposomal Bupivacaine (PAI-L) | Maximum Pain Post-PACU | 5 units on a scale |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.257Wilcoxon (Mann-Whitney)
Secondary
PACU Opioid Use
Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient.
Time frame: Approximately 2 hours after entry in PACU
Population: Intent-to-treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | PACU Opioid Use | 0 mg OME |
| Ropivacaine (PAI-R) | PACU Opioid Use | 0 mg OME |
| Liposomal Bupivacaine (PAI-L) | PACU Opioid Use | 0 mg OME |
Secondary
POD 0 Post-PACU Opioid Use
Additional opioid medications that were taken by subjects (recorded at the same time as the time points for measuring pain). Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient.
Time frame: POD 0, approximately 12 pm to 12 am
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | POD 0 Post-PACU Opioid Use | 0 mg OME |
| Ropivacaine (PAI-R) | POD 0 Post-PACU Opioid Use | 8 mg OME |
| Liposomal Bupivacaine (PAI-L) | POD 0 Post-PACU Opioid Use | 15 mg OME |
p-value: 0.012Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.293Wilcoxon (Mann-Whitney)
Secondary
POD 1 Opioid Use
Additional opioid medications that were taken by subjects (recorded at the same time as the time points for measuring pain). Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient.
Time frame: POD 1, approximately 12 am to 12 am next day
Population: Intent-to-treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | POD 1 Opioid Use | 26 mg OME |
| Ropivacaine (PAI-R) | POD 1 Opioid Use | 38 mg OME |
| Liposomal Bupivacaine (PAI-L) | POD 1 Opioid Use | 45 mg OME |
p-value: 0.202Wilcoxon (Mann-Whitney)
p-value: 0.007Wilcoxon (Mann-Whitney)
p-value: 0.148Wilcoxon (Mann-Whitney)
Secondary
POD 2 Opioid Use
Additional opioid medications that were taken by subjects (recorded at the same time as the time points for measuring pain). Opioid consumption was documented in the patient electronic medical record by the nursing staff caring for the patient.
Time frame: POD 2, approximately 12 am to 12 am next day
Population: Intent-to-treat analysis. For POD 2, data are missing for 5 subjects (1 on PNB arm, 1 on PAI-R arm, and 3 on PAI-L arm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | POD 2 Opioid Use | 23 mg OME |
| Ropivacaine (PAI-R) | POD 2 Opioid Use | 15 mg OME |
| Liposomal Bupivacaine (PAI-L) | POD 2 Opioid Use | 23 mg OME |
p-value: 0.933Wilcoxon (Mann-Whitney)
p-value: 0.169Wilcoxon (Mann-Whitney)
p-value: 0.126Wilcoxon (Mann-Whitney)
Secondary
Preoperative Daily Opioid Use
Opioid consumption will be documented in the patient electronic medical record by the nursing staff caring for the patient.
Time frame: baseline
Population: Intent-to-Treat Analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Nerve Block (PNB) | Preoperative Daily Opioid Use | 15 mg oral morphine equivalents (OME) |
| Ropivacaine (PAI-R) | Preoperative Daily Opioid Use | 15 mg oral morphine equivalents (OME) |
| Liposomal Bupivacaine (PAI-L) | Preoperative Daily Opioid Use | 15 mg oral morphine equivalents (OME) |
p-value: 0.571Wilcoxon (Mann-Whitney)
p-value: 0.991Wilcoxon (Mann-Whitney)
p-value: 0.496Wilcoxon (Mann-Whitney)