Efficacy of a Modified Cocktail for Periarticular Local Infiltration Analgesia in Unicompartmental Knee Arthroplasty: A prospective, double-blind, randomized controlled trial

doi:10.21203/rs.3.rs-5020018/v1

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Research Article

Efficacy of a Modified Cocktail for Periarticular Local Infiltration Analgesia in Unicompartmental Knee Arthroplasty: A prospective, double-blind, randomized controlled trial

https://doi.org/10.21203/rs.3.rs-5020018/v1

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Background: Periarticular local infiltration analgesia (LIA) has become a widely used method for postoperative pain management after unicompartmental knee arthroplasty (UKA). The present study aimed to evaluate the efficacy of a modified LIA cocktail.

Methods: 61 patients who underwent UKA were enrolled and randomly assigned to receive periarticular infiltration of a modified cocktail (comprising ropivacaine, epinephrine, dexamethasone, magnesium sulfate, and sodium bicarbonate ) or a conventional cocktail(comprising ropivacaine, epinephrine, dexamethasone, ketorolac, and morphine). The outcomes included the consumption of patient-controlled intravenous analgesia (PCIA) medication used for postoperative analgesia, pain score, early joint functional recovery, discharge time, and complication rates.

Results: In the initial 12 hours after surgery, the conventional cocktail showed no superiority over the modified cocktail in visual analog scale (VAS) scores. However, from the second postoperative day, the analgesic effect was significantly prolonged in the modified group, leading to lower VAS scores and better knee functional recovery. Additionally, patients in the modified group required less pain medication via PCIA, both within the first 24 hours and cumulatively up to 48 hours after surgery. Both groups had similar rates of complications.

Conclusions: The present modification of a conventional cocktail significantly prolonged the analgesic effect and reduced pain medication consumption after UKA surgeries, which was associated with better functional recovery on early postoperative days.

Trial registration: Chinese Clinical Trial Registry, ChiCTR2200060500. 21 March 2023

Periarticular local infiltration analgesia

Cocktail

Unicompartmental knee arthroplasty

Magnesium sulfate

Sodium bicarbonate

Analgesic drugs

Unicompartmental knee arthroplasty (UKA) is one of the surgical options for the treatment of end-stage osteoarthritis in a single compartment of the knee. This procedure involves only the surface replacement of the affected compartment, preserving the original tissue structure to the greatest extent. Following John Repicci's introduction of the minimally invasive surgical approach [1], the intraoperative invasion of the tissue was further reduced. Consequently, compared with total knee arthroplasty(TKA), UKA offers some advantages, including less postoperative pain, faster recovery, and fewer complications. Nevertheless, postoperative pain management is a crucial factor in ensuring patient satisfaction [2] and becomes even more important in view of the ongoing debate on performing knee arthroplasty in outpatient facilities. The analgesic mode of periarticular local infiltration analgesia (LIA) cocktail during the operation was proposed by Bianconi and used in total knee arthroplasty [3]. This technique is easy to operate and has a significant analgesic effect[4]. Given that the quantity, together with the composition of drugs available for analgesic cocktails, has not been fully standardized, orthopedic surgeons in various locations are adopting different cocktail formulations based on literature reports and their clinical experience[5, 6]. To improve the analgesic effects, numerous adjuvants have been added to the LIA cocktail, such as epinephrine, clonidine, morphine, nonsteroidal anti-inflammatory drugs, and corticosteroids[7–11]. A considerable number of surgeons will add morphine and ketorolac to an LIA cocktail for better pain relief effects[12, 13]. However, studies have observed that the advantages of doing so are not obvious and may lead to some side effects[14, 15]. Moreover, conventional cocktails generally last 10 to 24 hours[16, 17], which seems too short for the natural process of pain relief. We noticed that some literature reported modified LIA cocktail formulations that can maintain longer durations of pain relief[18, 19]. Based on a foundational LIA cocktail consisting of ropivacaine, adrenaline, and dexamethasone, we hypothesized that the addition of magnesium sulfate and sodium bicarbonate to the base LIA cocktail could prolong the duration of pain relief and achieve analgesic effects comparable to those of cocktails containing conventional analgesics (morphine & ketorolac).

Research Design

The current study was a single-center, randomized, controlled, double-blind, prospective trial, which enrolled 61 UKA cases in the period between August 2023 to March 2024. This study was conducted in accordance with the Declaration of Helsinki and was approved by our Ethics Committee, with ethics approval number: 008-IH01. The study was registered in the Chinese Clinical Trials Registry with the registration number: ChiCTR2200060500. Written informed consent was obtained from all patients. All patients signed an informed consent form before participating in the study.

Patient Recruitment

The inclusion criteria were as follows: (1) medial osteoarthritis, (2) American Society of Anesthesiologists (ASA) functional status was I-III, (3) intact anterior and posterior cruciate ligament as well as medial and lateral collateral ligaments, (4) knee flexion contracture deformity ≤ 10°, (5) knee varus deformity ≤ 15°, and (6) body mass index (BMI) of 18–35 kg/m².

The exclusion criteria were as follows: (1) age under 40 or over 85 years, (2) pathological conditions other than osteoarthritis, (3) a history of open knee surgery, (4) knee infection, (5) relevant allergies (to local anesthetics or metal), (6) a neuromuscular disease, and (7) cognitive or verbal restrictions.

Randomization

Patients were divided into two groups using a computer-generated random number table (Excel, Microsoft Corporation). Investigator 1, who was unaware of the study design and grouping, prepared sealed opaque envelopes for all patients. On the day of the surgery, Investigator 2 assigned each patient to either the conventional cocktail or the modified cocktail group at random. Before the surgery, Investigator 2 ensured that the anesthetist (not involved in other parts of the study) prepared the appropriate LIA cocktail in the anesthesia pharmacy. After general anesthesia, each type of cocktail was brought into the operating room. Investigator 3, as the outcome evaluator, was blinded to the group assignment. Investigator 4, also blinded to the group assignment, conducted the data analysis.

Surgery

All surgeries were performed by the same senior surgeon, completed by the same orthopedic surgery team, through a medial parapatellar approach and all patients received the same implant (Oxford mobile-bearing Partial Knee, Zimmer Biomet, USA). All patients received 1 g of tranexamic acid intravenously 10 min before skin incision and 6 h postoperatively. In addition, all patients underwent surgery under general anesthesia with laryngeal mask and had the same intra- and postoperative setting. No drains or tourniquet were used.

All patients received the same postoperative treatment. Full weight bearing with crutches as needed was allowed as well as flexion according to pain. Physiotherapy was started later after surgery and continued for several weeks if necessary.

Analgesic Protocol

Celecoxib (200 mg) was administered twice daily as a prophylactic analgesic the day before surgery. The anesthesiologist provided the intraoperative LIA cocktail, which was performed by the same surgeon.

The conventional cocktail group was administered ropivacaine (0.2%), epinephrine (2.0µg/mL), dexamethasone (0.1 mg/mL), ketorolac tromethamine (30mg), and morphine (10mg). While the modified cocktail group received ropivacaine (0.2%), epinephrine (2.0µg /mL), dexamethasone (0.1 mg/mL), magnesium sulfate (2.5 mg/mL), and sodium bicarbonate (15 mg/mL). The two groups were treated with the same methods except for the LIA cocktail composition. Before prosthesis implantation, 20 mL of cocktail was injected into the posterior aspect of the capsule, 20 mL of cocktail was utilized as infiltration analgesia for the medial collateral ligaments, 20 mL of the cocktail was utilized as infiltration analgesia for the quadricep and retinacular tissues, and the fat and subcutaneous tissues were infiltrated with the remaining 40 mL of the cocktail (Fig. 1, periarticular local cocktail injection). No systemic corticosteroids were administered.

Postoperatively, all patients received a patient-controlled intravenous analgesia (PCIA) pump within 48 hours post-surgery with a dosage of 3 mg per hour. And the bolus dose was 3 mg, with a lockout interval of 30 minutes, when the analgesia was insufficient[20]. ( sufentanil citrate injection 100µg, flurbiprofen axetil 100mg, and 0.9% normal saline diluted to 200mL)

Figure 1, periarticular local cocktail injection

Outcomes and follow‑up

The primary outcomes included the postsurgical pain score, and the total consumption of PCIA medication used for postoperative analgesia. Secondary outcomes included the time to the initial rescue analgesia (via self-control switch device of the PCIA), joint functional recovery, discharge time, and the incidence of complications.

Postsurgical pain was measured using a visual analog scale (VAS) from 0 to 10, assessed at rest or during motion (when the patient was asked to bend the knee to the extent possible). The measurements were performed at 3, 6, 12, 24, 36, 48, and 72 hours postoperatively. Joint functional recovery was evaluated by the range of motion (ROM) and daily ambulation distance. A goniometer was used three times daily at six-hour intervals to measure the ROM, with the best value of the day used for analysis. Patients began ambulating on the morning of the first postoperative day. During hospitalization, patients were encouraged to walk as far as possible with a walking aid, and the distance was recorded. The length of postoperative hospital stay was also recorded. Discharge criteria included acceptable pain control with oral celecoxib and walking up to 60 meters. Postoperative complications recorded included nausea, vomiting, nerve damage, a significant reduction in quadriceps strength, venous thrombosis events, wound complications, and falls.

Statistical Analysis

All data underwent descriptive analysis. Continuous variables were tested for normal distribution using the Shapiro-Wilk test. Normally distributed continuous variables were expressed as mean (standard deviation), and those not normally distributed were presented as median (interquartile range). Independent samples t-tests were used for normally distributed continuous variables, and repeated measures ANOVA was employed for outcomes measured at multiple time points, with Bonferroni correction used for multiple comparisons. Skewed continuous variables were analyzed using the Mann-Whitney U test. Categorical variables were displayed as frequencies (%) and analyzed using Pearson's chi-square test or Fisher's exact test. Statistical analysis was conducted using IBM SPSS Statistics ver. 23 (SPSS, Chicago, IL, USA), with a P-value < 0.05 considered statistically significant.

Baseline Characteristics

Of the 72 patients enrolled, 9 did not meet the inclusion criteria, and 2 did not sign the informed consent. The remaining 61 patients were randomly divided into conventional and modified cocktail groups. No patients withdrew during the postoperative follow-up period (Fig. 2, flow diagram of patient selection). Both groups had comparable clinical and demographic characteristics preoperatively (Table 1).

Figure 2, flow diagram of patient selection

Table 1

Baseline Patient Characteristics
Characteristic		Conventional Cocktail Group(n = 31)		P Value
Age(year.)	64.50 ± 6.38	62.72 ± 6.70	1.048	0.299
Sex(M/F)	13/17	17/14	0.368	0.446
Height(m)	1.69 ± 0.83	1.66 ± 0.71	0.955	0.343
Weight (kg)	63.1 ± 7.70	63.32 ± 8.33	0.108	0.914
Body mass index (kg/m²)	22.35 ± 3.64	22.88 ± 3.69	0.563	0.576
Surgery side, right/left	11/19	13/18	0.674	0.795
Preop. measures
Rest VAS pain score	2.57 ± 1.13	2.61 ± 1.25	0.151	0.881
Motion VAS pain score	5.40 ± 1.32	5.42 ± 1.46	0.054	0.957
Range of knee motion (deg)	99.1 ± 12.6	97.58 ± 10.86	0.527	0.600
ASA status, I/II/III	11/18/1	15/15/1	0.872	0.647
Duration of surgery (min)	68.37 ± 7.51	66.52 ± 8.90	0.874	0.386

Outcomes

The 24-hour PCIA consumption and total PCIA consumption in the modified cocktail group were significantly reduced compared with the conventional cocktail group. Moreover, the time to initial rescue analgesia via self-control PCIA was later in the modified cocktail group (Table 2). At 3, 6, and 12 hours postoperatively, there were no significant differences in the VAS pain scores during rest and motion between the two groups. At 24 hours, the VAS pain scores for both rest and motion were lower in the modified cocktail group compared with the control group, with statistically significant differences (rest 3.70 vs. 4.38, P = 0.007; motion 4.23 vs. 5.68, P < 0.001). At 36 hours postoperatively, the modified cocktail group had lower rest and motion VAS pain scores than the control group, with significant differences (rest 3.47 vs. 3.93, P = 0.015; motion 4.26 vs. 5.38, P < 0.001). At 48 and 72 hours, there were no significant differences between the two groups. (Fig. 3A and 3B)

On days 2 and 3 postoperatively, the modified cocktail group showed a higher ROM compared with the control group, with statistically significant differences. In terms of ambulation distance post-surgery, on days 2 and 3, the modified cocktail group was superior to the control group, and the difference was also statistically significant. However, the difference between the two groups was not significant on the first day after surgery. Additionally, the average length of postoperative hospital stay was shorter in the modified cocktail group (Table 3).

In the modified cocktail group, 6 patients experienced nausea and 4 experienced vomiting, compared with 8 patients with nausea and 7 with vomiting in the control group, with no significant difference between the groups. No other complications were observed in either group (Table 4).

Table 2

Postoperative PCIA medication consumption
Outcome	Modified Cocktail Group (n = 30)	Conventional Cocktail Group(n = 31)	t/x²	P Value
PCIA medication consumption within first 24h (ml)	79.8 ± 4.1	86.4 ± 7.9	4.112	< 0.001
Total PCIA medication consumption (ml)	159.9 ± 4.8	169.5 ± 9.0	5.208	< 0.001
Time to first rescue analgesia (h)	22.7 ± 4.4	13.5 ± 5.3	4.843	< 0.001

Fig.3 Postoperative VAS pain scores at rest (Fig. 3A) and during motion (Fig. 3B) in both groups.

* indicates a statistical difference (p < 0.05) between the two groups.

Table 3

Postoperative Functional Recovery
Outcome	Modified Cocktail Group (n = 30)	Conventional Cocktail Group(n = 31)	t/x²	P Value
Range of knee motion(deg)
Postop. day 1	96.9 ± 8.9	95.2 ± 9.3	0.717	0.476
Postop. day 2	107.6 ± 7.9	101.3 ± 9.8	2.772	0.007
Postop. day 3	109.63 ± 8.3	103.1 ± 10.1	2.734	0.008
Ambulation distance (m)
Postop. day 1	30.2 ± 8.9	25.8 ± 8.9	1.901	0.062
Postop. day 2	48.3 ± 4.3	38.1 ± 4.8	8.642	< 0.001
Postop. day 3	52.1 ± 5.0	41.9 ± 4.3	8.569	< 0.001
Time to discharge (h)	75.9 ± 15.8	90.8 ± 15.9	0.876	0.001

Table 4

Postoperative Complications
Complication	Modified Cocktail Group (n = 30)	Conventional Cocktail Group(n = 31)	x²	P Value
Nausea	6(20.0%)	8(25.8%)	0.762	0.408
Vomiting	4(13.3%)	7(22.6%)	0.802	0.273
Wound complication	0(0%)	0(0%)
Nerve damage	0(0%)	0(0%)
Venous thrombotic event	0(0%)	0(0%)
Fall	0(0%)	0(0%)
Substantial decrease in quadriceps strength	0(0%)	0(0%)

Due to less tissue invasion and smaller osteotomy volume, unicompartmental knee arthroplasty (UKA) typically results in less postoperative pain compared with total knee arthroplasty (TKA)[21]. However, postoperative pain in patients remains a common issue. Studies indicate that postoperative pain can affect joint function recovery, decrease surgical satisfaction, and even lead to anxiety and depression[22]. Multimodal pain management, often involving periarticular local infiltration analgesia (LIA), has become a widely used method due to its simplicity and effective pain relief[23]. However, a direct transfer of the positive results of the TKA study to UKA is not appropriate. Since UKA is less invasive, this procedure may not require as much analgesics as TKA. With more studies publishing modified LIA cocktail formulas[7–13, 18, 19], we were considering whether it is possible to alter the drugs in LIA to prolong the duration of pain relief while achieving similar clinical outcomes in analgesic effects.

In this study, we found that the VAS score of the conventional group was lower in the initial 12 hours after surgery, but this difference was not statistically significant. However, from the second postoperative day, the advantage of a modified LIA cocktail to prolong pain relief became apparent and lasted for the following 24–48 hours. Which brought patients in the modified group better knee ROM and ambulation distance from the second postoperative day. We used a PCIA instead of other forms of opioids for rescue analgesia because this method was efficient, and the consumption could be easily recorded. Administration of the modified cocktail to patients was associated with markedly reduced postsurgical PCIA medication use. In addition, the hospitalization time of the modified group was shorter. These results suggest that the modified LIA cocktail achieved analgesic effects comparable to the conventional LIA cocktail and provided longer-lasting pain relief. The rationality and safety of the magnesium sulfate and sodium bicarbonate in the modified LIA cocktail have been illustrated by Wang et al.[19] And another study also reaches similar conclusions[18]. These randomized controlled trials have indicated that the modified LIA cocktail is superior to a foundational LIA cocktail (consisting of ropivacaine, adrenaline, and dexamethasone). However, it is still unknown whether this superiority exists when compared with cocktails containing analgesics such as morphine and ketorolac. In fact, it is quite common to add analgesics to cocktails[12, 13]. And the current study has shown a comparison between the two formulations.

Magnesium sulfate has been found to improve ropivacaine action time[24]. N-methyl-d-aspartate (NMDA) receptors play a crucial in transmitting information about central pain and modulating acute hyperalgesia[25, 26]. NMDA receptors are highly permeable to calcium ions. Activation of NMDA receptors leads to calcium ions influx into the cell, increasing the excitability of spinal dorsal horn neurons, which results in the development of central sensitization and reduces the pain threshold after injury. Magnesium sulfate may prevent the activation of NMDA receptors due to the similar chemical properties of magnesium ions and calcium ions[27, 28]. For the excitation threshold of the nerve fiber membrane potential and the inflow of calcium ions, magnesium ions have a significant increasing and blocking effect, respectively, thereby enhancing the nerve-blocking effect of ropivacaine and prolonging its duration[29, 30]. Moreover, magnesium sulfate can promote the release of nitric oxide from vascular endothelial cells, preventing endothelial dysfunction secondary to ischemia-reperfusion, thereby alleviating pain[31]. The basic sodium bicarbonate can convert the non-ionized form of ropivacaine into an ionized form[32], whose affinity for the sodium canals is greater than that existing between the sodium channels and the nonionized fraction of ropivacaine[33]. In this way, an anesthetic block of extended duration is established.

It is noteworthy that mixing the modified LIA cocktail drugs directly will result in the formation of white precipitates within a few minutes due to the alkalinization of ropivacaine[34]. As a result, the appearance of the LIA cocktails of the two groups will be distinguishable (Fig. 4, the appearance of groups of cocktails), which could potentially affect the accuracy of the randomized trial. To address this issue, one simple approach could be to keep the ropivacaine separate and have a surgical technologist (not involved in the study) add it just before injection. This way, the cocktail will be nearly transparent at the time of injection, maintaining a consistent appearance with the LIA cocktail of the two groups. The white precipitate of the local anesthetic has been proven to be absorbable and safe[32, 35].

The limitations of this study arise from its short-term follow-up. We couldn't draw any conclusions about mid-term or long-term outcomes. However, it's important to note that immediate postoperative pain management is typically the most severe and crucial, as it may impede early joint function recovery. We only evaluated joint function up to 3 days after surgery. Future studies could investigate whether the two groups have differences in long-term results, but the authors of the present study do not expect this to be the case. Another limitation is that the doses of LIA cocktails were chosen based on the recommendations of previous studies. Future studies could investigate the optimal dosage of drugs. Moreover, other multimodal analgesia modalities, such as peripheral nerve blocks, general corticosteroids, and intraoperative ketamine, were not involved. These multimodal methods may bring better outcomes. However, despite the above limitations, the results of this study are consistent. We will continue to use the modified LIA cocktail in subsequent UKA surgeries and observe its long-term clinical outcomes.

Figure 4, the appearance of groups of cocktails

The present modification of a conventional cocktail significantly prolonged the analgesic effect and reduced pain medication consumption after UKA surgeries, which was associated with better functional recovery on early postoperative days. This modified, long-lasting LIA cocktail may improve postoperative pain management of the UKA. However, it requires further confirmation in future studies.

UKA: unicompartmental knee arthroplasty

TKA: total knee arthroplasty

LIA: local infiltration analgesia

ASA: American Society of Anesthesiologists

BMI: body mass index

PCIA: patient-controlled intravenous analgesia

VAS: visual analog scale

ROM: range of motion

Ethics approval and consent to participate

This study has obtained ethics approval of the ethics committee in our hospital and informed consent of all participants. Approval number: 008-IH01. And the study was registered in the Chinese Clinical Trials Registry with the registration number: ChiCTR2200060500. 21 March 2023.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the Research and Development Program for ‘Pioneer’ and ‘Leading Goose’ of Zhejiang Province (2024C03213).

Authors' contributions

BBZ and LGW conceived and designed the study. YCZ, SNS and LKC collected the data. YCZ and SNS analyzed and interpreted the data. YCZ and SNS wrote the paper. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Authors' information

¹Department of Orthopaedics, Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, P.R. China.

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Efficacy of a Modified Cocktail for Periarticular Local Infiltration Analgesia in Unicompartmental Knee Arthroplasty: A prospective, double-blind, randomized controlled trial

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Abstract

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Background

Methods

Research Design

Patient Recruitment

Randomization

Surgery

Analgesic Protocol

Outcomes and follow‑up

Statistical Analysis

Results

Baseline Characteristics

Outcomes

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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