Ultrasound-Guided Femoral Nerve Block with Esketamine Adjuvant for Postoperative Analgesia in Total Knee Arthroplasty–A Randomized, Double-Blind, Controlled Trial

Abstract

Objective

To evaluate the analgesic effect and complication profile of ultrasound-guided femoral nerve block (FNB) with esketamine as an adjuvant to ropivacaine in patients undergoing total knee arthroplasty (TKA).

Methods

This was a prospective, randomized, double-blind, controlled clinical trial. Sixty patients undergoing elective TKA were randomized 1:1 into Group A (n=30) and Group B (n=30). Group A received 20 mL of 0.25% ropivacaine for ultrasound-guided FNB, whereas Group B received 20 mL of 0.25% ropivacaine combined with 0.5 mg/kg esketamine for identical FNB. All patients received combined general anesthesia and FNB. Postoperative visual analogue scale (VAS) pain scores at 2, 4, 6, 8, 10, and 12 h, 24-hour sufentanil consumption, incidence of postoperative nausea and vomiting (PONV), and other adverse events were documented.

Results

Baseline characteristics including age, height, weight, ASA physical status, gender composition, and operation duration were comparable between the two groups (all P>0.05). The VAS score at 10 h postoperatively was significantly lower in Group B than in Group A (P=0.026), while no significant differences were detected at other time points (all P>0.05). Total 24-hour sufentanil consumption was significantly reduced in Group B compared with Group A (P<0.001). The incidence of PONV did not differ significantly between the two groups (P=0.467).

Conclusion

Ultrasound-guided femoral nerve block (FNB) combined with esketamine and ropivacaine relieved postoperative pain at 10 hours and reduced opioid consumption in patients undergoing total knee arthroplasty (TKA), with no increase in adverse events. This regimen can serve as a safe analgesic option for TKA patients.

Introduction

Total knee arthroplasty (TKA) is a well-established surgical intervention indicated for end-stage knee osteoarthritis, rheumatoid arthritis, and post-traumatic joint deformities.1 While it effectively restores joint function and alleviates refractory pain, the procedure is frequently associated with moderate to severe postoperative pain, which remains a major obstacle to early functional rehabilitation and the implementation of enhanced recovery after surgery (ERAS) protocols in orthopedics.2 Inadequate pain control not only diminishes patient adherence to postoperative rehabilitation but also delays the recovery of knee range of motion and increases the risk of chronic postsurgical pain (CPSP), ultimately compromising long-term functional outcomes and quality of life.3

Postoperative pain following knee surgery substantially delays functional rehabilitation, prolongs overall recovery, and extends hospital length of stay.4 Current analgesic strategies for total knee arthroplasty (TKA) include non-opioid analgesics, opioids, and local anesthetics, administered via intravenous, epidural, or peripheral nerve block approaches.5 Systemic opioids are associated with well-documented adverse effects, including nausea, vomiting, urinary retention, hypotension, and respiratory depression.6 Although epidural analgesia offers effective pain relief, it carries inherent risks such as hypotension, urinary retention, and delayed ambulation—complications that are inconsistent with early mobilization protocols.7

In recent years, ultrasound-guided peripheral nerve blocks have gained widespread acceptance for postoperative analgesia in lower extremity surgery, owing to advantages such as real-time visualization, high success rates, minimal invasiveness, and preserved hemodynamic stability.8 Among these, femoral nerve block (FNB) has emerged as the most utilized regional analgesic technique for total knee arthroplasty (TKA). It provides selective blockade of the sensory innervation to the knee, thereby enhancing postoperative pain control while avoiding systemic opioid-related side effects.9

A study confirmed that peripheral nerve block reduces pain scores in the postanesthesia care unit, decreases postoperative analgesic requirements, lowers PONV incidence, shortens postanesthesia care unit length of stay, and improves patient satisfaction in ambulatory settings. Nevertheless, single-shot FNB with conventional local anesthetics provides limited analgesic duration, which often fails to cover the postoperative pain peak and meet ERAS requirements.9 Therefore, identifying safe and effective local anesthetic adjuvants to prolong analgesia and enhance analgesic efficacy has become a research focus in TKA regional anesthesia.

Local anesthetic adjuvants are pharmacological agents coadministered intravenously or perineurally to modulate block characteristics via diverse mechanisms. A wide range of agents have been investigated as perineural adjuvants, including dexamethasone, clonidine, dexmedetomidine, epinephrine, buprenorphine, and magnesium.10

Esketamine, the highly pure S-enantiomer of ketamine, is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It produces peripheral and central analgesia by blocking NMDA receptors, inhibiting central sensitization and hyperalgesia, with rapid onset and stable efficacy. In contrast to conventional perineural adjuvants, esketamine demonstrates a superior safety profile with fewer adverse events and produces synergistic analgesic effects when coadministered with local anesthetics.11 Currently, evidence regarding perineural esketamine as an adjuvant to ultrasound-guided FNB in TKA remains insufficient, and its clinical efficacy and safety require further validation.

This study aimed to explore the efficacy and complications of esketamine combined with ultrasound-guided FNB in TKA, to provide evidence for optimizing postoperative analgesic protocols in TKA patients.

Methods

Study Design

This prospective, randomized, double-blind, controlled trial was performed in accordance with standard clinical research protocols. This prospective randomized study was approved by the Ethics Committee of the First People’s Hospital of Lianyungang (approval No. KY-20220507001-01) and registered with the Chinese Clinical Trial Registry (ChiCTR2200065065) on October 27, 2022. The study was reported in strict accordance with the CONSORT 2010 guidelines, and all study procedures were conducted in compliance with the Declaration of Helsinki. Eligible patients aged 55–75 years with American Society of Anesthesiologists (ASA) physical status I–II who were scheduled for elective total knee arthroplasty (TKA) under general anesthesia were enrolled. Written informed consent was obtained from all participants prior to study initiation. Patients were excluded if they had a history of hypersensitivity to any of the study medications, skin lesions or local infection at the ultrasound scanning site, severe cardiovascular or respiratory disorders, renal or hepatic failure, or impaired communication ability. In the operating room, all patients underwent continuous monitoring with electrocardiography (ECG), pulse oximetry, and non-invasive blood pressure, with secure venous access established. All patients received ultrasound-guided FNB combined with general anesthesia (Figure 1).

Figure 1.

Consolidated standards of reporting trials flow diagram showing the progress of patients through the study.

Eligible consenting patients were randomized 1:1 using a computer-generated random number sequence with variable block sizes. Randomization was performed using Random Allocation Software 2.0, and allocation results were sealed in opaque envelopes. The research coordinator assigned one envelope per patient to the anesthesiologist performing the FNB. The outcome assessor was blinded to group allocation throughout the study.

Anesthesia Management

All patients received standard general anesthesia (GA) with ASA-standard monitoring. Anesthesia was maintained with sevoflurane in oxygen, titrated to a minimum alveolar concentration (MAC) of 0.8–1.0. Mechanical ventilation was delivered with a tidal volume of 6–8 mL/kg, and respiratory rate was adjusted to maintain end-tidal carbon dioxide (EtCO₂) at 30–40 mm Hg. Mean arterial pressure (MAP) was maintained within 20% of baseline using 10 mg ephedrine or 15 mg urapidil as needed. For heart rate <50 bpm or >120 bpm, 0.5 mg atropine or 10–30 mg esmolol was administered intravenously, respectively.

Study Drug Preparation

All study solutions were prepared by a dedicated nurse. For Group A, 20 mL of 0.25% ropivacaine was prepared by diluting 50 mg/5 mL ropivacaine (Naropin^®; AstraZeneca AB, Södertälje, Sweden) with 15 mL of 0.9% normal saline (Baxter Healthcare). For Group B, 50 mg/2 mL esketamine (Hengrui Pharmaceutical, Lianyungang, China) was diluted with 8 mL of 0.9% normal saline to a total volume of 10 mL. The diluted esketamine volume was weight-adjusted; for a 50-kg patient, 5 mL of esketamine solution was mixed with 5 mL of Naropin and 10 mL of 0.9% normal saline to yield 20 mL of 0.25% ropivacaine plus 0.5 mg/kg esketamine.

Ultrasound-Guided FNB Procedure

FNB was performed under ultrasound guidance (Philips CX50, Philips Ultrasound, Inc., Bothell, WA, USA). A 6–13 MHz high-frequency linear transducer was placed at the inguinal crease to identify the femoral nerve lateral to the femoral artery. The probe was adjusted until the femoral nerve was clearly visualized. A 21G×100 mm insulated needle (UniPlex NanoLine, Pajunk, Geisingen, Germany) was advanced via the long-axis in-plane technique (Figure 2), followed by injection of 20 mL of the study solution (0.25% ropivacaine for Group A; 0.25% ropivacaine plus 0.5 mg/kg esketamine for Group B). Effective block was defined as reduced sensation over the anterior, medial, and lateral thigh at 20 min post-injection; patients with failed FNB were excluded from the study.

Figure 2.

Ultrasound imaging of FNB (Femoral Nerve Block). The significance of the Abbreviated words (e.g. FA, FN) provided within Figure 2 Ultrasound imaging of FNB (Femoral Nerve Block).jpg.

Abbreviations: FA, Femoral Artery; FN, Femoral Nerve.

Postoperative Analgesia Protocol

Intravenous patient-controlled analgesia (PCA) was used for postoperative pain management. The PCA device was set to deliver a background infusion of sufentanil at 0.04 μg/kg/h (total regimen 2 μg/kg/100 mL). A bolus dose of sufentanil 0.05 μg/kg was available on demand, with a 15-minute lockout interval, if VAS >3 or requested by the patient. Rescue intravenous sufentanil 3 μg was administered if VAS remained >3 despite PCA use. Intravenous paracetamol 1 g was given over 5 min as rescue analgesia to maintain numerical rating scale (NRS) <4 during movement.

Time to first analgesic request was defined as the interval from extubation to the first PCA bolus activation, representing the FNB-provided analgesic duration. PCA bolus usage was recorded at 0–2, 2–4, 4–6, 6–8, 8–12, and 12–24 h postoperatively, and total 24-hour sufentanil consumption was calculated. Intraoperative and postoperative data were collected using a standardized case report form.

Outcome Measurements

VAS pain scores were recorded at 2, 4, 6, 8, 12, and 24 h after FNB. Postoperative analgesic consumption, and adverse events (hypotension, hypertension, respiratory depression, nausea, vomiting, urinary retention) were documented.

Statistical Analysis

Statistical analysis was performed using SPSS 22.0 software. Normally distributed quantitative data are presented as mean ± standard deviation (SD), and non-normally distributed data as median (interquartile range, IQR). Independent-samples t-test and one-way analysis of variance (ANOVA) were used for between-group comparisons of normally distributed data. Enumeration data were analyzed using the chi-square (χ²) test, and non-normally distributed continuous data using the Mann–Whitney U-test. A P-value <0.05 was considered statistically significant.

Results

Baseline Characteristics and Operation Duration

Sixty patients were enrolled, with 30 patients in each group. Baseline characteristics including age, height, weight, ASA physical status, gender distribution, and operation duration were comparable between Group A and Group B (all P>0.05; Table 1).

Table 1.

Patient Demographics and Duration of Operation

Demographics	Group A (n=30)	Group B (n=30)	P value
Age (yr)	66.53 ± 4.08	65.07 ± 4.59	0.386
Height (cm)	159.17 ± 6.29	160.60 ± 7.52	0.528
Weight (kg)	68.37 ± 7.43	67.10 ± 7.44	0.517
ASA physical status, n			0.439
I	14	17
II	16	13
Gender, n			0.579
Male	11	8
Female	19	22
Duration of operation (min)	88.83 ± 3.85	88.77 ± 4.42	0.951

Postoperative VAS Pain Scores

VAS pain scores were assessed at 2, 4, 6, 8, 10, and 12 h after FNB. No significant intergroup differences were found at 2, 4, 6, 8, or 12 h (all P>0.05). The VAS score at 10 h was significantly lower in Group B than in Group A (P=0.026). Data are presented as median (IQR; Table 2).

Table 2.

Postoperative VAS Pain Scores

VAS	Group A (n=30)	Group B (n=30)	P value
2h	2.0 (1.0–2.0)	2.0 (1.0–2.0)	0.650
4h	2.0 (2.0–3.0)	2.0 (1.0–2.0)	0.408
6h	2.0 (2.0–3.0)	2.0 (2.0–2.0)	0.272
8h	3.0 (2.0–3.0)	2.0 (2.0–3.0)	0.172
10h	3.0 (2.0–3.0) *	2.0 (2.0–3.0) *	0.026
12h	2.0 (1.0–2.0)	2.0 (1.0–2.0)	0.525

Notes: Data are expressed as median (interquartile range). *p<0.05.

Postoperative Outcomes within 24 Hours

Total 24-hour sufentanil consumption was significantly lower in Group B than in Group A (P<0.001). The incidence of PONV did not differ significantly between groups (P=0.467; Table 3).

Table 3.

Postoperative Variables During the First 24 hours Postoperatively

Postoperative Variables	Group A (n=30)	Group B (n=30)	P value
PONV, n (%)	7 (23.33)	5 (16.3)	0.467
Total 24h sufentanil consumption (μg)	108.52 ± 10.71	96.30 ± 12.85	<0.001

Note: Data is expressed as mean ± SD or n (%).

Abbreviation: PONV, postoperative nausea and vomiting.

Total opioid use was significantly lower in the esketamine group than in the ropivacaine-alone group, and the 10-hour VAS score was significantly lower in the esketamine group.

Discussion

Total knee arthroplasty is one of the most performed orthopedic procedures, indicated for knee joint dysfunction, deformity, and severe knee pain. General anesthesia is the mainstream anesthetic approach for TKA but is limited by insufficient postoperative analgesia. Ultrasound-guided nerve block addresses this limitation and improves anesthetic efficacy.4 Previous studies have demonstrated that the combination of esketamine and ultrasound-guided nerve block reduces complication rates in pediatric lower extremity fracture surgery, offering superior analgesic efficacy compared to either modality alone.12

Emerging evidence suggests that the addition of esketamine as an adjuvant reduces postoperative VAS scores and analgesic consumption in surgical patients.13 In this context, local anesthetic adjuvants have emerged as a promising strategy to extend the analgesic benefits of single-shot peripheral nerve blocks, offering a potential alternative to continuous catheter-based techniques.9 As a chiral cyclohexanone derivative, esketamine exerts its analgesic effects primarily through NMDA receptor antagonism and has also been shown to possess local anesthetic properties on spinal and peripheral nerves.3 The present study demonstrates that while ultrasound-guided FNB with esketamine combined with ropivacaine does not significantly prolong the duration of the sensory block, it effectively reduces postoperative sufentanil consumption and shows a trend toward a lower incidence of PONV.

Ropivacaine, a long-acting amide local anesthetic, was selected for this study due to its favorable sensory-motor differential block profile, as well as its low cardiotoxicity and neurotoxicity, making it a preferred agent for postoperative analgesia in lower limb surgery.14 Its sensory-selective blocking property largely preserves motor function, which is essential for early ambulation and rehabilitation following total knee arthroplasty.15 When combined with esketamine, the two agents act on distinct targets along the nociceptive pathway, resulting in a complementary analgesic mechanism that optimizes pain control without significant motor impairment.

Esketamine exerts peripheral and central analgesic effects primarily through selective non-competitive antagonism of NMDA receptors, thereby inhibiting nociceptive signal transmission and attenuating central sensitization—mechanisms that are particularly effective against postoperative inflammatory pain and hyperalgesia.16 Unlike systemic administration, perineural esketamine acts locally on peripheral nerve endings to potentiate the analgesic effect of ropivacaine, while minimizing central adverse effects (eg, hallucinations, dizziness) associated with high plasma concentrations.13 Additionally, esketamine exhibits mild inhibitory activity on peripheral voltage-gated sodium channels, which may further enhance the local anesthetic effect of ropivacaine at the nerve trunk level.3 The significantly lower VAS scores at 10 hours postoperatively in the esketamine group confirm the synergistic analgesic effect of the combination during the intermediate postoperative period. Notably, this analgesic benefit emerged at a time point coinciding with the gradual decline of single-shot local anesthetic action, suggesting that esketamine effectively bridges the “analgesic gap” and stabilizes pain control without prolonging the duration of sensory blockade.

Ultrasound-guided FNB is a preferred technique for lower extremity surgery due to its clear visualization, high puncture accuracy, and low risk of vascular or nerve injury.17 In the present study, all blocks were performed under high-frequency linear ultrasound guidance, which ensured accurate local anesthetic spread and contributed to a high block success rate, thereby providing a reliable foundation for intergroup comparisons of analgesic efficacy. Compared with continuous FNB, the single-shot FNB with esketamine as an adjuvant offers several practical advantages: it avoids catheter-related complications such as infection, displacement, or dislodgement;18 simplifies clinical workflow; and aligns more effectively with the goals of accelerated postoperative rehabilitation. While continuous nerve blocks require prolonged catheter maintenance and impose additional nursing burden, the single-shot adjuvant strategy employed in this study achieves reliable analgesia with a simpler procedure and greater patient acceptance.

Reduced opioid consumption holds particular clinical significance for patients undergoing TKA. Sufentanil, a potent opioid analgesic, is associated with dose-dependent adverse effects including PONV, urinary retention, and respiratory depression—complications that can impede early mobilization and functional rehabilitation.19 In the present study, the significant reduction in 24-hour sufentanil consumption observed in the esketamine group not only mitigates opioid-related adverse events but also aligns with ERAS principles, potentially contributing to shorter hospital stays and improved rehabilitation outcomes. Effective postoperative analgesia facilitated early initiation of knee flexion and straight leg raise exercises, which in turn accelerated recovery of knee joint range of motion and reduced the risk of joint stiffness. Although the between-group difference in PONV incidence did not reach statistical significance, the lower rate observed in the esketamine group suggests a potential protective effect on gastrointestinal function mediated through opioid sparing—a finding that warrants confirmation in larger-scale studies. Furthermore, reduced opioid demand may also lower the risk of CPSP by attenuating central sensitization,3 a hypothesis that merits long-term observation in future research.

Compared with conventional perineural adjuvants such as dexamethasone, clonidine, and dexmedetomidine, esketamine offers distinct pharmacological advantages. Dexamethasone may affect glucose metabolism and is relatively contraindicated in diabetic patients;20 clonidine and dexmedetomidine can induce hypotension and bradycardia, potentially compromising hemodynamic stability in elderly individuals.21 In contrast, esketamine maintains cardiovascular stability and does not interfere with metabolic function,22 rendering it particularly suitable for the elderly TKA population, which often presents with a high burden of comorbidities. Additionally, esketamine is metabolized independently of hepatic function—a characteristic well-aligned with the physiological status of elderly patients who may exhibit mild to moderate organ function decline—thereby further enhancing its clinical safety profile.

In the present study, no severe adverse events (eg, respiratory depression, severe hypotension, or neurological complications) were observed in either group, and the incidence of mild adverse events was low. These findings support the safety of perineural esketamine administration at a dose of 0.5 mg/kg. The combination of low dosage and local perineural administration results in low plasma concentrations, which substantially reduces the risk of central nervous system side effects such as dysphoria, hallucinations, and dizziness. This favorable safety profile is particularly important for elderly patients, who are generally more sensitive to anesthetic and analgesic agents.

This study has several limitations that should be acknowledged. First, as a single-center trial with a relatively small sample size (n = 60), the findings may be subject to selection bias and have limited generalizability. Second, the observation period was restricted to 24 hours postoperatively, precluding assessment of long-term analgesic efficacy, knee functional recovery, or the development of CPSP). Third, the optimal perineural dose of esketamine was not investigated; the efficacy and safety of different dose gradients require further validation. Fourth, the potential impact of the combined regimen on motor blockade—a key safety parameter for peripheral nerve blocks—was not evaluated.

In conclusion, the addition of esketamine as a local anesthetic adjuvant to ropivacaine for ultrasound-guided femoral nerve block provides superior intermediate-term postoperative analgesia, significantly reduces opioid consumption, and demonstrates a favorable safety profile in patients undergoing TKA. This regimen is straightforward to administer and clinically feasible, positioning it as a preferred option for postoperative analgesia in TKA. Future multicenter studies with larger sample sizes and extended follow-up periods are warranted to optimize esketamine dosing and further elucidate its role in promoting postoperative rehabilitation following total knee arthroplasty.

Conclusion

Ultrasound-guided femoral nerve block (FNB) combined with esketamine and ropivacaine relieved postoperative pain at 10 hours and reduced opioid consumption in patients undergoing total knee arthroplasty (TKA), with no increase in adverse events. This regimen can serve as a safe analgesic option for TKA patients.

Funding Statement

Lianyungang First People’s Hospital Youth Talent Fund.

Data Sharing Statement

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. All data are fully anonymized to protect the privacy of the study participants, and no identifiable personal information is included in the shared datasets.

The data sharing scope includes: (1) the complete raw clinical data of all enrolled participants, including baseline characteristics, intraoperative and postoperative outcome indicators, and safety data; (2) the complete statistical analysis code and scripts used in this study; (3) the original study protocol, case report form (CRF), and ethical approval documents.

All data sharing activities will strictly comply with the ethical requirements approved by the Institutional Review Board (IRB) of our hospital, the Declaration of Helsinki, and relevant national and international regulations on clinical research data management. The requester will be required to sign a data use agreement to ensure that the shared data are only used for non-commercial academic research purposes, and will not be used for any other purposes or disclosed to any third party without authorization.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that there is no conflicts of interest in this work.