Impact of Dexmedetomidine on Analgesia and Inflammatory Response in Knee Surgery: A Study of IPACK and ACB Techniques

Introduction

Arthroscopic knee surgery (AKS) is a commonly performed orthopedic procedure known for its reduced tissue trauma and faster postoperative recovery. This minimally invasive technique encompasses a range of interventions, including joint examination, meniscal reshaping, and cruciate ligament reconstruction. However, despite its advantages, AKS is frequently associated with considerable postoperative pain due to factors such as surgical trauma, intraoperative tourniquet application, and inflammatory responses. Effective pain management is therefore essential to facilitate rapid patient recovery [1]. Recent evidence supports the use of ultrasound-guided adductor canal block (ACB) and interspace between the popliteal artery and posterior capsule of the knee (IPACK) block for controlling postoperative knee pain. These techniques selectively target sensory innervation of the anterior and posterior regions and preserving motor function, thereby reducing analgesic consumption and promoting quicker rehabilitation [2–4]. Our prior investigation evaluating the ACB-IPACK combination revealed significant reductions in 24-hour (h) postoperative Visual Analog Scale (VAS) scores and enhanced functional recovery. However, the inherent limitation of single-injection peripheral nerve blocks is their short analgesic duration. Nonetheless, the transient nature of single-shot peripheral nerve blocks necessitates strategies to prolong the effects of ACB and IPACK [5].

Dexmedetomidine (DEX), a highly selective alpha-2 adrenergic receptor (α2-AR) agonist, has sedative, analgesic, anxiolytic, and anti-inflammatory properties [6,7]. Preclinical and clinical studies suggest its ability to attenuate pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) implicated in postoperative pain pathogenesis. Notably, when used as a perineural adjuvant, DEX prolongs brachial plexus block duration and reduces rescue analgesia requirements [8–11]. However, the researchers suggested that the benefits and harms of prolonged nerve block duration should be weighed against adverse effects, and more studies are needed to confirm the safety of DEX as a local anesthetic adjuvant [12–14].

Meta-analyses suggested perineural DEX administration can extend postoperative analgesia duration compared to systemic delivery in peripheral nerve blocks; these conclusions are based on moderate-quality evidence with significant heterogeneity [15,16]. However, there have been no studies on the effects of perineural DEX to IPACK and intravenous DEX on postoperative analgesia and rehabilitation of patients with IPACK combined with ACB in AKS. Based on the above, we can assume that compared with intravenous DEX, perineural DEX has more advantages in prolongating IPACK and ACB block time and promoting postoperative rehabilitation. This study provides clinical evidence on the comparative effectiveness and safety of perineural versus intravenous DEX in enhancing and prolonging postoperative analgesia and functional recovery in AKS patients. Our findings can guide clinical practice by offering an efficient and safe analgesia regimen that can improve patient outcomes, reduce pain, and facilitate quicker rehabilitation. Improved pain management postoperatively can significantly enhance patient comfort, expedite recovery, and potentially reduce the length of hospital stays, thereby improving overall quality of life following AKS.

Material and Methods

RANDOMIZATION AND BLINDING:

Preliminary experimental data on postoperative analgesic effects across the 3 study groups revealed mean 24-hour VAS scores of 2.6, 2.2, and 1.8, with standard deviations of 0.8, 0.9, and 0.6, respectively. Using a 2-tailed test with an α level of 0.05 and a test power (1-β) of 90%, sample size calculations were performed using PASS 15 software. To account for a possible 10% attrition rate, the minimum required sample size per group was determined to be 34 participants. This resulted in a total sample size of 102 subjects, ensuring adequate power to detect statistically significant differences among the groups [17,18].

In this equation, n represents the sample size per group, g denotes the number of groups, and si and x represent the standard deviation and mean, respectively.

Patients were randomly allocated into 3 groups of 34 patients each. Using a computer to generate random serial numbers, the generated serial numbers were randomly divided into 3 groups: perineural DEX adjuvant+IPACK+ACB for Group E, intravenous DEX+IPACK+ACB for Group I, and IPACK+ACB was Group C (the control group). The randomized sequences were hidden in opaque envelopes that were opened by the anesthesiologist performing the procedure, who was not aware of the study protocol and was not involved in postoperative follow-up. The experimental drugs were dispensed by researchers who are completely unaware of the trials. The anesthesiologist who performed the procedure and the researchers who followed up and recorded the procedure were unaware of the drug configuration.

PARTICIPANTS:

A total of 102 eligible patients were enrolled in this study, all of whom were scheduled for unilateral knee arthroscopic elective surgery (these include knee arthroscopy, knee arthroscopic meniscus dressing, and knee arthroscopic anterior fork ligament reconstruction) in the Department of Osteoarthrosis. Participants were classified with ASA grades I to II, aged 19–69 years, and included males and females. Their BMI ranged from 18 to 30 kg/m². Patients were required to have no contraindications to anesthesia, no history of narcotic dependence or abuse, no known allergies to local anesthetics, and no history of poorly controlled hypertension, diabetes, or cardiovascular disease. Exclusion criteria were the inability to speak or comprehend Mandarin, contraindications to anesthesia, a history of alcohol or drug abuse, allergic to any medication, poorly controlled hypertension, diabetes, heart disease, sinus bradycardia, coagulation dysfunction, pregnancy, and long-term glucocorticoid use. General anesthesia was provided during excision as a backup measure and to identify patients for whom the ACB or IPACK block was ineffective. The anesthesia procedures were performed by a board-certified attending anesthesiologist (Researcher A) specializing in perioperative anesthesia management and ultrasound-guided regional nerve blocks. Researcher A independently screened and enrolled eligible participants according to the predefined inclusion/exclusion criteria to ensure methodological rigor.

PROCEDURES:

Prior to surgery, all patients followed a standardized preoperative protocol, abstaining from fluids for 4 h and food for 8 h. Upon arrival in the operating room, patient identification was verified, peripheral venous access was established, and continuous non-invasive monitoring of blood pressure, electrocardiogram, and blood oxygen saturation was initiated. For the administration of lumbar anesthesia, all patients underwent ultrasound-guided ACB and IPACK block, using 20 ml of 0.25% ropivacaine. In Group E, 0.5 μg/kg of DEX, totaling 1 μg/kg, was added to the local anesthetic mixtures for both blocks. Group I received a 1 μg/kg intravenous infusion of DEX over a 15-minute period, while Group C, serving as the control group, received no DEX administration.

ULTRASOUND-GUIDED IPACK AND ACB BLOCK:

The IPACK block was performed with the patient in the prone position. The ultrasound linear probe was placed transversely over the popliteal fossa, scanning parallel to identify the space between the high-echo line representing the femoral shaft and the popliteal artery. This identified the IPACK block target area, where the tibial nerve was located medially above the popliteal artery, and the common peroneal nerve was positioned laterally, both displaying a characteristic “honeycomb” appearance [5,19] (Figure 1).

Following the IPACK block, patients were repositioned supine for the ACB block, with the knee gently flexed and abducted. The ultrasound probe was positioned transversely over the inner thigh, targeting the middle and lower thirds of the line between the patella and inguinal region, identifying the femoral artery and femur. The ACB block area was characterized by a “triangular” hyperechoic shadow formed by the adductor magnus, sartorius, and vastus medialis muscles [5,20] (Figure 2).

Ten minutes after both blocks were administered, their anesthetic efficacy was evaluated. Upon confirmation of successful blocks, single-shot lumbar anesthesia was performed. The patient was positioned laterally with their arms folded over the knees and the head bent forward. The L3–4 interspace was identified, and a 2.5-ml dose of 0.5% ropivacaine was injected to achieve lumbar anesthesia, ensuring that the anesthetic level did not exceed the T8 dermatome.

POSTOPERATIVE ANALGESIA MANAGEMENT:

Postoperatively, all patients received a standard analgesic regimen of intravenous flurbiprofen ester at 1.0 mg/kg, administered twice daily. If patients reported a VAS score above 4, an additional intravenous dose of 30 mg of pentazocine was provided for supplementary pain relief. After discharge, patients were advised to manage any residual pain with 200 mg oral celecoxib once daily if the VAS score was above 4.

PRIMARY OUTCOME:

Patients were instructed to self-report their resting and active VAS scores, with particular attention to instances where the joint curvature exceeded 45°, at designated intervals of 6 h, 12 h, 24 h, 48 h, 54 h, and 60 h postoperatively, as well as 1 week after discharge. Additionally, changes in serum levels of IL-1β, IL-6, and TNF-α on the first postoperative day were compared to baseline levels obtained prior to anesthesia administration.

SECONDARY OUTCOMES:

The frequency of postoperative analgesic interventions in the ward and the amount of analgesics consumed during the week following discharge were meticulously recorded. Maximum ambulation distances at 24 h and 48 h after surgery were also assessed for the 3 patient groups, with family assistance provided for safety. Postoperative complication rates were carefully monitored and evaluated across all groups.

POSTOPERATIVE FOLLOW-UP:

Three data records were designed for this study:

:

Patient-reported outcomes were comprehensively logged by the postoperative follow-up personnel (Researcher B). Pain scores were measured according to VAS 0–10 (0 cm no pain and 10 cm worst pain). Data captured included resting and active VAS scores, particularly when the joint curvature exceeded 45°, as reported at 6, 12, 24, 48, 54, and 60 hours after surgery, and 1 week after discharge, adhering strictly to VAS scoring protocols. A measuring scale was installed at the entrance of adjacent wards to aid in data collection. With assistance from family members, patients recorded their maximum walking distances (in meters) at 24 and 48 hours after surgery. Analgesic consumption during the first week after discharge was also documented. After completing the records 1 week after discharge, patients were contacted by the data collector via WeChat to retrieve the completed forms.

:

Postoperative complications such as nausea, vomiting, urinary retention, nerve damage, and foot drop were systematically documented by the designated investigator (Researcher B). The frequency of postoperative pain relief interventions administered in the hospital was sourced from electronic medical records.

:

Intraoperative complications, including nausea, vomiting, hypertension, and sinus bradycardia, were recorded by the primary anesthesiologist (Researcher A).

Records Form 1 and 2 were supervised by the follow-up staff (Researcher B), who fully communicated with the experimenter before filling in the form and explained the content to be filled in after the operation. Patients completed Record Table 1. Venous blood samples were drawn by a visiting nurse prior to anesthesia and by the ward nurse on the first postoperative day. The blood samples were sent to the laboratory within 1 hour of collection to measure serum levels of IL-1β, IL-6, and TNF-α using a Rejing Bio-C2000 automatic chemiluminescence immunoanalyzer. Upon completion of the study, the laboratory consolidated the final dataset and provided it to the data collection team for analysis.

STATISTICAL ANALYSIS:

Data analysis was performed using SPSS version 29.0.1.0, whereas graphical representations were generated through GraphPad Prism 8.0, with statistical significance established at P values less than 0.05. Continuous variables were expressed as mean±standard deviation or median. Categorical variables were summarized using frequency and percentage. Continuous variables with normal distribution were analyzed utilizing one-way analysis of variance (ANOVA), followed by the Bonferroni correction for multiple tests. In cases of skewed continuous variables, the Kruskal-Wallis test was employed, accompanied by Bonferroni tests. Categorical variables were examined through chi-square or Fisher’s exact tests, as appropriate.

Results

SUMMARY OF PARTICIPATION:

Between March 27, 2024, and August 27, 2024, a total of 130 patients scheduled for unilateral AKS were screened. Of these, 28 patients were excluded based on predefined criteria: 9 did not meet 1 or more of the inclusion criteria, 8 met the exclusion criteria, 3 declined to participate, 5 had their surgeries canceled, and 3 underwent bilateral AKS. The remaining 102 patients were randomly allocated into 3 groups: Group E (n=34) received 1 μg/kg perineural DEX, Group I (n=34) received a 1 μg/kg intravenous DEX injection, and Group C (n=34) served as the blank control. Following allocation, 1 patient in Group I was excluded due to postoperative serum sample degradation, resulting in a final total of 33 participants in Group I. Group E and Group C retained all 34 participants (Figure 3). The treatment compliance rate was 100%, the adherence rate was 100%, and the drop-out rate was 0.02%. A total of 14 subjects had adverse reactions, and the incidence of adverse events was 13.7%.

The primary surgical procedures conducted among the 101 cases included joint cavity exploration, meniscal sculpting, and cruciate ligament reconstruction. Comparative analysis of baseline characteristics across the 3 groups showed no statistically significant differences in terms of sex, age, BMI, ASA grade, surgery duration, resting period 24 h before surgery, and preoperative VAS scores during physical activity (P>0.05) (Table 1).

POSTOPERATIVE RESTING AND ACTIVE VAS SCORES: Compared to Group C, Group E exhibited significantly lower resting VAS scores at 12 h (P=0.002, mean difference,−0.77; 95% CI, −1.30 to −0.23), 24 h (P<0.001, mean difference,−0.91; 95% CI, −1.42to −0.41), 48 h (P<0.001, mean difference −1.15; 95% CI, −1.65 to −0.65), and 54 h (P =0.015, mean difference −0.53; 95% CI, −0.98 to −0.08) after surgery, as well as lower active VAS scores at 12 h (P<0.001, mean difference 1.82; 95% CI, −2.30 to −1.35), 24 h (P=0.003, mean difference 0.71; 95% CI, −1.22 to −0.20), and 48 h (P<0.001, mean difference −0.91; 95% CI, −1.32 to −0.50). Group I demonstrated a significant reduction in active VAS scores at 12 h (P=0.007, mean difference −0.61; 95% CI, −1.09 to −0.13) after surgery. No significant differences were observed between the groups for resting and active VAS scores at other time points (P > 0.05). When comparing Group E to Group I, Group E showed significantly lower resting VAS scores at 12 h (P=0.029, mean difference −0.59; 95% CI, −1.13 to −0.05), 24 h (P=0.003, Mean difference −0.71; 95% CI, −1.22 to −0.20), and 48 h (P=0.005, Mean difference −0.67; 95% CI, −1.17 to −0.17), as well as lower active VAS scores at 12 h (P<0.001, mean difference −1.21; 95% CI, −1.69 to −0.73) and 24 h (P=0.035, mean difference −0.54; 95% CI, −1.06 to −0.03) (Figure 4A, 4B; Table 2).

DIFFERENCE IN INFLAMMATORY FACTORS BETWEEN THE FIRST DAY AFTER SURGERY AND BEFORE ANESTHESIA: In terms of inflammatory markers, Group E showed a significantly smaller difference in serum IL-1β levels on the first postoperative day and before anesthesia compared to Group I (P=0.04). Group I showed a significantly smaller difference in serum IL-1β levels on the first postoperative day and before anesthesia compared to Group C (P<0.001). However, no significant differences were observed in serum IL-6 levels across the groups at the same timepoint (P>0.05). Compared to Group C, Group I had a significant reduction in serum TNF-α levels on the first postoperative day and before anesthesia (P=0.005), while Group E showed no significant change in TNF-α levels (P>0.05) (Table 3).

POSTOPERATIVE ANALGESIC REMEDY TIMES AND CONSUMPTION: The number of analgesic interventions administered on the first postoperative day (PD1) did not show statistically significant differences among the 3 groups (P>0.05). However, a significant difference emerged in the number of analgesic interventions required on the second postoperative day (PD2), with Group E and Group I requiring fewer interventions compared to Group C (P<0.001). Among the cases, the distribution across groups was as follows: 2 (5.9%) in group E, 7 (21.2%) in group I, and 18 (52.6%) in group C. Regarding analgesic consumption 1 week after hospital discharge, no significant differences were noted among the groups (P>0.05) (Table 4).

MAXIMUM POSTOPERATIVE WALKING DISTANCE: Compared to Group C, Group E had significantly greater maximum walking distances at 24 h (P<0.001, mean difference 11.16; 95% CI, 6.44 to 15.88) and 48 h (P<0.001, mean difference 30.53; 95% CI, 17.52 to 43.54) after surgery, Group I had significantly greater maximum walking distances at 24 h (P=0.072, mean difference 4.48; 95% CI, −0.28 to 9.22) and 48 h (P=0.03, Mean difference,14.14; 95% CI, 1.03 to 27.24) after surgery. Additionally, Group I exhibited a significant increase in walking distance at 48 h postoperatively (P<0.05). Compared with Group I, Group E showed a statistically significant improvement in maximum walking distance at both 24 h (P=0.003, mean difference 6.69; 95% CI, 1.93 to 11.44) and 48 h (P=0.009, mean difference 16.39; 95% CI, 3.29 to 29.50) (Tables 5, 6).

INCIDENCE OF ADVERSE REACTIONS:

Regarding postoperative complications, there were significant differences in the incidence of sinus bradycardia among the 3 groups (P=0.019). The incidence was zero in Group E, 6 (18.2%) cases in Group I, and 2 (5.6%) cases in Group C. However, there were no significant differences in other complications between the 3 groups, including nausea, vomiting, urinary retention, nerve damage, foot drop, or hypertension (P>0.05). The incidence of nausea and vomiting in group E was the lowest (2.9%), but the incidence of postoperative nausea in group I and Group C was 15.2% and 17.6%, respectively, and the incidence of postoperative vomiting in group C was 15.2% (Table 7).

Discussion

STRENGTHS AND LIMITATIONS:

The study has 2 advantages:

However, the study has certain limitations. It was a single-center study with a relatively small sample size, which limits the generalizability of the findings. Future research involving larger sample sizes is necessary to corroborate these results. Additionally, single postoperative IL-1β/TNF-α measurements limit insight into longitudinal inflammatory trajectories. This should be addressed in future studies and further research is needed to explore the changes in serum inflammatory factors, which can eventually guide clinical diagnosis and treatment. In addition, the dose of DEX used in this study was 1 ug/kg. Although this dose was commonly used in previous studies, the dosage of perineural adjuvant DEX or intravenous injection could not guarantee that the dose of DEX was equivalent.

Conclusions

Perineural dexmedetomidine at 1 μg/kg optimally extends IPACK-ACB analgesia to 48 hours, facilitating earlier ambulation without motor compromise. While intravenous dexmedetomidine demonstrates anti-inflammatory advantages, its transient analgesic effects and bradycardia risk limit its utility as a standalone adjunct. These findings suggest the need for integration of route-specific dexmedetomidine within ERAS protocols for arthroscopic knee surgery.