Liposomal Bupivacaine Infiltration Versus Bupivacaine Hydrochloride for the Management of Unilateral Total Knee Arthroplasty in Geriatric Patients at a 287-Bed Community Hospital

Abstract

Introduction: Geriatric patients receiving total knee arthroplasty (TKA) are found to have similar postoperative complications, functional scores, and perioperative mortality, as compared to younger patients. Conversely, geriatric patients often have longer lengths of stay. Periarticular injection (PAI) of liposomal bupivacaine (LB) as part of the multimodal pain management strategy is thought to improve recovery, however, mixed comparative efficacy data exists for its use in TKA.2-5. Methods: A retrospective, chart review was conducted at a 287-bed community teaching hospital. Orthopedic surgical patients who received an infiltration with liposomal bupivacaine versus bupivacaine HCl for unilateral TKA were compared. Patients identified in the electronic medical record by Diagnosis Related Group (DRG) 470—major joint replacement or reattachment of lower extremity without major complication or comorbidity codes were utilized. Patients who meet the following criteria were included: age 65 and older who underwent a TKA between 8/1/2018 to 7/31/2019 were discharged to home. Patients who have contraindications or hypersensitivity to bupivacaine formulations or a history of opioid dependence were excluded. The primary outcome is to identify whether patients who received an infiltration with liposomal bupivacaine had a lower total opioid consumption during their hospital stay. Results: A total of 114 patients who had a DRG 470 code and were above the age of 65 years were studied. There was no statistically significant difference in mean total opioid consumption (oral morphine equivalents) between the bupivacaine HCl (n = 25) and liposomal groups (n = 85) respectively, 93.76 versus 83.72 mg; P = .569. In addition, patients in both groups had similar lengths of hospital stay, 2.5 versus 3 days; P = .529 and mean pain scores until discharge 3.7 versus 4.34 on VAS; P = .305. Conclusion: The results of this drug utilization evaluation do not support a strong clinical advantage with local infiltration of liposomal bupivacaine over bupivacaine HCl in geriatric patients undergoing primary TKA surgery at this institution. There was not a statistically significant difference in mean total opioid consumption between the 2 groups. Additionally, the use of non-opioid analgesics, mean pain scores, and hospital lengths of stay were similar in both groups.

Introduction

Total knee arthroplasty (TKA) is a common elective procedure with reliable functional outcomes and good long term survivorship. Conservative estimates project the incidence of primary knee arthroplasty in the United States to increase up to 1.5 million cases per year by 2050. ¹

According to the Centers for Disease Control and Prevention, 128 people die of an opioid overdose daily in the United States. ² This is a combined value for those who use prescription and illicit opioids. The Diagnostic and Statistical Manual of Mental Disorders (5th edition), defines opioid dependence as problematic opioid use behavior contributing to clinically significant impairment or distress. The primary hurdle for early recovery following TKA is postoperative pain control. Multimodal pain control approaches are often utilized and continue to evolve to meet the demands of patient satisfaction and bundled reimbursement programs. There is a growing amount of literature supporting multimodal analgesia and its benefits of superior pain relief, promotion of recovery of the knee, and reduced opioid consumption and related adverse effects for patients undergoing TKA. ³

Liposomal bupivacaine, a local anesthetic in a lipid encapsulated formulation, is widely used by orthopedists as a component of their multimodal analgesic approach. The potential advantages include a longer duration of analgesia after intraoperative infiltration due to the DepoFoam sustained-release parenteral drug delivery system, reduced opioid use, and lower incidence of opioid-related adverse events. ⁴ There have been retrospective and prospective trials comparing liposomal bupivacaine to traditional periarticular injections (PAI) or various regional anesthetic approaches in the literature with conflicting results.^5-12 Recently, an updated meta-analysis of randomized controlled trials found no clinical benefit on the visual analogue scale for liposomal bupivacaine compared with traditional PAI after TKA. However, liposomal bupivacaine was preferred in terms of lower consumption of morphine equivalents 24 to 72 hours postoperatively, with subsequent lower incidence of nausea and vomiting after TKA. ¹³

Geriatric patients receiving total knee arthroplasty (TKA) are found to have similar postoperative complications, functional scores, and perioperative mortality, as compared to younger patients. Conversely, geriatric patients often have longer lengths of stay. ¹⁴ The purpose of this retrospective review is to evaluate whether infiltration with liposomal bupivacaine offers a clinical advantage over bupivacaine hydrochloride (HCl) in geriatric patients receiving unilateral TKA. We tested the null hypothesis that patients who received local infiltration with liposomal bupivacaine for TKA would not result in a significant difference of total opioid consumption during their hospital stay compared to local infiltration with bupivacaine HCl.

Materials and Methods

A retrospective, single center, chart review was conducted at a 287-bed community teaching hospital. The retrospective chart review and data collection was conducted by a single reviewer. An independent reviewer verified patients who met inclusion criteria prior to data collection. Orthopedic surgical patients who received an infiltration with liposomal bupivacaine versus bupivacaine HCl for unilateral TKA were compared. Patients identified in the electronic medical record by Diagnosis Related Group (DRG) 470—major joint replacement or reattachment of lower extremity without major complication or comorbidity codes were utilized. Patients who met the following criteria were included: age 65 and older who underwent a TKA between August 1st, 2018 and July 31st, 2019 and were discharged to home. Patients were placed into the bupivacaine HCL or liposomal bupivacaine group based upon orthopedic surgeons preferred infiltration technique. The intra-op medication was confirmed by automated drug cabinet reports. Patients who have contraindications or hypersensitivity to bupivacaine formulations, a history of opioid dependence, or disposition after surgery to a long term care facility/rehabilitation center were excluded. Other data collected included patients age, sex, height, weight, total postoperative opioid consumption, non-opioid analgesics, pain score (visual analogue scale), and hospital length of stay. It was pre-determined to document 0.5 days for a patient being discharged at or before 1200.

Pain Control Regimen

Patients undergoing TKA could have been prescribed any of following non-opioids based on surgeon preference: oral acetaminophen 650 mg, celecoxib 200 mg, gabapentin 300 mg, or ketorolac tromethamine 15 to 30 mg IV if renal function within normal limits. For opioid analgesics majority of patients were prescribed oral oxycodone HCl 2.5 mg every 4 hours for mild pain, 5 mg every 4 hours for moderate pain or prior to physical therapy, and 10 mg every 4 hours for severe pain. Other oral opioid options included oral hydromorphone 1 mg every 4 hours for mild pain, 2 mg every 4 hours for moderate pain or prior to physical therapy, and 3 mg every 4 hours for severe pain, oral tramadol 50 mg every 6 hours for mild pain, 100 mg every 6 hours for moderate pain or prior to physical therapy. For pain that could not be controlled by oral opiates, the patients were additionally offered intravenous (IV) morphine sulfate 2 to 4 mg or hydromorphone HCl 0.5 to 1 mg every 4 hours as needed. None of the patients included were offered morphine or hydromorphone patient controlled analgesia.

Outcome Measures

The primary outcome was to identify whether patients who received an infiltration with liposomal bupivacaine had a lower total opioid consumption (oral morphine equivalents) during their hospital stay. Secondary outcomes included average pain score postoperatively until discharge using visual analogue scale (VAS), and hospital length of stay.

Statistical Analysis

Continuous variables are reported as mean (SD) and analyzed using a 2-tailed t test. Categorical data was compared using Chi square. Differences in pain score, opioid consumption, and length of stay were tested using the Mann-Whitney U test. P < .05 was considered significant. Statistical analysis was performed using SPSS, Version 25 (IBM Corp).

Results

A total of 114 patients who had a DRG 470 code and were above the age of 65 years were studied. Analysis of the demographic data (Table 1) shows that the 2 groups were well matched. Analysis of non-opioid analgesics (Table 2) between the 2 groups shows no statistical significance, although the bupivacaine HCl group had a higher overall percentage of IV ketorolac use compared to the liposomal bupivacaine group respectively 45% versus 29%; P = .099. There was no statistically significant difference in mean total opioid consumption (oral morphine equivalents) between the bupivacaine HCl and liposomal groups respectively, 93.76 versus 83.72 mg; P = .569; Figure 1. In addition, patients in both groups had similar lengths of hospital stay, 2.5 versus 3 days; P = .529; Figure 2 and mean pain scores until discharge 3.7 versus 4.34 on VAS; P = .305; Figure 3.

Table 1.

Patient Characteristics.

	Bupivacaine HCl 0.25% + Epi 1:200 000(n = 29)	Liposomal bupivacaine 1.33% (n = 85)	P value
Gender, male (n [%])	10 [34]	37 [44]	.812
Mean age (years ± SD*)	71 ± 6.8	73 ± 5.8	.446
Mean height (m ± SD)	1.69 ± 0.09	1.66 ± 0.11	.133
Mean weight (kg ± SD)	93 ± 26	90 ± 19	.532
BMI (kg/m2 ± SD)	32 ± 7.4	33 ± 5.7	.812
Right TKA (n [%])	14 [48]	42 [49]	.544

Table 2.

Non-Opioid Analgesics.

	Bupivacaine HCl 0.25% + Epi 1:200 000 (n = 29)	Liposomal bupivacaine 1.33% (n = 85)	P value
Acetaminophen	29 [100]	82 [96]	1.00
Celecoxib	24 [83]	63 [74]	.893
Pre-op only	19 [66]	50 [59]	.341
Ketorolac IV	13 [45]	25 [29]	.099
Gabapentin	26 [90]	74 [87]	.500

Figure 1.

Total opioid consumption.

Figure 2.

Hospital length of stay.

Figure 3.

Mean pain score until discharge.

Discussion

There were no significant differences found in both the primary and secondary outcomes in patients who received bupivacaine HCl versus liposomal bupivacaine. The absolute difference of total opioid use was 10 mg of oral morphine equivalents between the bupivacaine HCl and liposomal bupivacaine group. The difference of 10 mg of morphine equivalents could be argued for clinical significance. Previous studies have use an a priori designation of at least 15% reduction of the reported outcome as clinically meaningful. ¹⁵ Our difference would be a 10.6% reduction and not meet clinical significance.

Similar average pain scores were observed between both groups for geriatric patients. This agrees with results from a study by Hyland et al ¹² who reported no significant clinical benefit of using liposomal bupivacaine over standard of care in TKA. In our review, both groups had similar use of non-opioid analgesics which addresses some of the potential confounders in regards to patient’s overall pain. This is even more critical in patients 65 and older who are often have multiple chronic medications.

It has been shown that older patients have longer lengths of stay when compared to younger patients. ¹⁴ Multiple studies have reported a decreased length of stay for patients who received liposomal bupivacaine.^16-18 Broome and Burnikel ¹⁷ noted 1 out of 8 patients in the received liposomal bupivacaine on average were discharged on postoperative day 1 versus none of the patients who received a femoral nerve block. Berend et al ¹⁸ reported more robust data with more than 98% of patients discharged on postoperative day 0 with a decreased time in PACU. Our review contrasts this data as the liposomal bupivacaine group had an average 3-day admission which was 0.5 days longer than the bupivacaine HCl group. Our review only included patients discharged to home and removed confounders of patients referred to rehabilitation facilities or other facilities which often have delays due to nonmedical issues such as availability of transportation and family to help in their care.

This study has several limitations, including retrospective design, which can lead to selection bias. Additionally, there was no standard postoperative adjunctive pain medication regimen for opioid and non-opioid analgesics, and a smaller than anticipated sample size due to exclusion of patients younger than 65 during the pre-determined time period. Our review also had an imbalance in the bupivacaine HCl group versus liposomal bupivacaine group. This may have contributed to the trends seen in the primary and secondary outcomes.

Conclusion

The results of this drug utilization evaluation did not find a statistically significant difference in mean total opioid consumption between the 2 groups. Albeit, the absolute difference of 10 mg of oral morphine equivalents may suggest a clinical advantage to the use of liposomal bupivacaine. In addition, the use of non-opioid analgesics, mean pain scores, and hospital lengths of stay were similar in both groups. Additional studies are needed to validate our conclusions.