INTRODUCTION
Carotid endarterectomy (CEA) is an effective intervention for patients with carotid artery stenosis who are at high risk of ischemic stroke [1]. However, the procedure requires temporary carotid artery clamping and reperfusion via a shunt, which can abruptly alter cerebral blood flow and cause postoperative hypertension in up to 66% of patients [2]. These hemodynamic fluctuations increase the risk of cerebral hyperperfusion syndrome, which is closely associated with neurological deficits and higher mortality [3]. Ensuring stable intraoperative hemodynamics and effective postoperative pain control is critical to improve patient outcomes.
Opioids remain a standard component of pain management in vascular surgeries, such as CEA, which is performed under general anesthesia [4]. However, excessive opioid use can lead to adverse effects, such as respiratory depression and postoperative nausea and vomiting [5], potentially delaying postoperative recovery. To minimize these risks, local infiltration analgesia is commonly performed by surgeons during CEA and has been shown to reduce early postoperative morphine requirements [6]. However, this technique primarily provides analgesia limited to the superficial tissues and may not sufficiently anesthetize deeper structures, such as the carotid sheath [6].
Multimodal analgesia has emerged as a promising strategy for reducing postoperative opioid use, with regional anesthesia playing a central role [7]. Cervical plexus block (CPB) has been widely used as a regional anesthesia technique for intraoperative anesthesia and postoperative analgesia in CEA [8]. Depending on the injection depth, CPB is classified as superficial, intermediate, or deep [8]. Intermediate CPB involves injecting beneath the investing fascia and superficial to the prevertebral fascia, which enables the effective spread of local anesthetic within the cervical fascial layers while reducing the risk of complications from deeper injections near major neurovascular structures [8,9]. A previous randomized trial in awake patients who underwent CEA under regional anesthesia demonstrated that superficial or intermediate CPB provided superior analgesia compared to surgical infiltration [10]. However, evidence supporting intermediate CPB as part of a multimodal analgesic strategy under general anesthesia, particularly for optimizing postoperative pain control and minimizing opioid consumption, remains limited.
Therefore, in this randomized clinical trial, we evaluated the efficacy of multimodal analgesia using intermediate CPB in patients who underwent CEA. The primary aim was to assess whether this approach significantly reduces postoperative opioid consumption within the first 24 h, compared to conventional opioid-based analgesia with local infiltration.
MATERIALS AND METHODS
Study design and ethics
This study protocol was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Republic of Korea (approval number: 2023-04-004) and was prospectively registered with the Clinical Research Information Service (registration number: KCT0008461) on May 23, 2023, before the first patient was enrolled on May 24, 2023. Detailed registration information is available at: https://cris.nih.go.kr/cris/search/detailSearch.do?seq=29667.
Study participants
This study was conducted between May 2023 and December 2024 at Samsung Medical Center. We targeted adult patients aged 20-80 years who underwent elective CEA under general anesthesia and had an American Society of Anesthesiologists physical status classification of I to III. Patients were excluded if they refused CPB, had neurological deficits or bleeding disorders, or had a contraindication for nerve block due to infection. Additional exclusion criteria included long-term opioid use, severe opioid-related adverse effects, allergies to local anesthetics, history of CEA surgery, or CPB failure. Forty patients were enrolled, and written informed consent was obtained from all registered participants one day before surgery.
Randomization
A random allocation sequence with a block size of 4 was generated using an online tool (www.sealedenvelope.com), and participants were assigned in a 1:1 ratio to either the multimodal group (multimodal analgesia with intermediate CPB, n = 20) or the control group (local infiltration, n = 20), and all participants were blinded to the type of analgesic technique administered. An anesthesiologist or nurse who is not participating in the study opened the sealed envelopes to determine group allocation and prepared the block formulations. In the multimodal group, a single investigator (RAK) performed the intermediate CPB before surgery, whereas in the control group, two vascular surgeons (YJP and SSY) performed local anesthetic infiltration before suturing the surgical wound. The clinicians who performed the procedures did not participate in outcome evaluation or patient management, and all assessments were conducted by an investigator (JC) who was blinded to the group allocation and study procedures.
Study procedure
All patients received a detailed explanation of the study’s objectives and methods one day before surgery and provided voluntary informed consent. General anesthesia was induced using intravenous (IV) propofol (1.5-2 mg/kg) with rocuronium (0.8 mg/kg), followed by endotracheal intubation. Radial arterial cannulation was performed to monitor blood pressure. Anesthesia was maintained using sevoflurane and remifentanil infusion (0.01-0.05 µg/kg/min) as required. Sevoflurane concentration and remifentanil dosage were adjusted to maintain a bispectral index of 40-60, and mean arterial pressure and heart rate within 20% of their baseline values. Throughout anesthesia, intraoperative nociception was monitored using the Analgesia Nociception Index (ANI) system (MDoloris Medical Systems).
Table 1 shows the study protocols of the two groups. In the multimodal group, ultrasound-guided intermediate CPB was performed following the induction of general anesthesia to ensure patient comfort and facilitate accurate ultrasound-guided injection without patient movement. Patients were placed in the backup position with the head slightly turned to the contralateral side. A high-frequency (6-13 MHz) linear ultrasound probe was placed transversely at the level of the C4 vertebra, and the probe was positioned posterior to the sternocleidomastoid (SCM) muscle to identify the posterior border of the SCM and underlying cervical plexus structures. A 22-gauge, 50 mm echogenic needle (UniPlex NanoLine, PAJUNK) was inserted in-plane from the posterior border of the SCM, using a lateral-to-medial approach. The needle was advanced toward the deep fascia of the SCM, targeting the intermediate cervical plexus region, which lies between the investing fascia of the neck (superficial layer) and prevertebral fascia (deep layer). After confirming proper positioning, 10 ml of 0.5% ropivacaine was injected. The block success was assessed using real-time ultrasonography. A successful block was defined as an adequate spread of local anesthetic between the investing fascia of the SCM and the prevertebral fascia (Fig. 1). CPB failure was defined as the inadequate spread of the local anesthetic that precluded the confirmation of an effective block. For postoperative analgesia, 50 μg of IV fentanyl, 1 g of IV acetaminophen, and 30 mg of IV ketorolac were administered 30 min before the end of surgery. Palonosetron (0.075 mg) and dexamethasone (5 mg) were administered intravenously to prevent postoperative nausea and vomiting. IV ketorolac was omitted if preoperative creatinine was 1.2 mg/dl or higher, and acetaminophen was withheld if aspartate aminotransferase or alanine aminotransferase exceeded 40 U/L and 41 U/L, respectively.
In the control group, the same general anesthesia protocol was applied without CPB after inducing general anesthesia. At the time of wound closure, 10 ml of 0.75% ropivacaine was injected under direct vision into the subcutaneous tissue overlying the investing layer of the deep cervical fascia at the posterior border of the SCM muscle and along the surgical incision, without ultrasound guidance. The local anesthetic was distributed along the entire incision line through multiple injection points, and aspiration was repeatedly performed to prevent inadvertent intravascular injection. Deep needle placement and excessive injection pressure were avoided to minimize the risk of inadvertent spread into deeper tissue planes. For postoperative analgesia, 50 μg of IV fentanyl was administered 30 min before the end of surgery, without additional non-opioid multimodal analgesics. No prophylactic antiemetic medications were administered to the control group.
After extubation of the endotracheal tube, all patients were transferred to the intensive care unit (ICU), where postoperative management followed the standardized protocol of the vascular surgery department. Patients were discharged to the general ward 24 h post-surgery if they were hemodynamically stable and exhibited no neurological symptoms. All patients received 2 L/min of oxygen via a nasal cannula and were continuously monitored using electrocardiography, pulse oximetry, and arterial blood pressure until transfer to the general ward. The pain intensity was assessed using an 11-point numerical rating scale (NRS, 0-10; 0 = no pain, 10 = worst pain). Patients with moderate-to-severe pain (NRS > 4/10) received IV hydromorphone (1 mg every 4 h) as needed. Administration was guided by NRS assessment and reassessment after dosing, but repeated titration to a specific target score was not routinely performed. IV ramosetron (0.3 mg) was administered to treat the postoperative nausea and vomiting. If systolic blood pressure (SBP) was 140 mmHg or higher, blood pressure was managed with IV nicardipine (1-2 mg), hydralazine (10-20 mg), or labetalol (10 mg) as a bolus.
Outcomes
The primary outcome was the total IV opioid consumption during the first 24 h post-surgery. If opioids were administered after the patient was transferred from the operating room to the ICU, the dose was converted to IV morphine equivalents (IME) and recorded accordingly. The IME dose was determined based on the assumption that 1.5 mg of IV hydromorphone corresponds to 10 mg of IV morphine [11].
The secondary outcomes were resting pain score upon ICU arrival (NRS, 0-10); pain score during motion upon ICU arrival (NRS, 0-10); time to first opioid administration after surgery; incidence of hypertension within 24 h postoperatively, defined as SBP ≥ 140 mmHg [3]; total usage of antihypertensive agents within 24 h postoperatively; incidence of nausea or vomiting within 24 h postoperatively (0 = none, 1 = symptoms without the need for antiemetics, 2 = antiemetic administration); patient satisfaction with pain management and sleep quality on the first postoperative night, assessed using a Likert scale (1 = very dissatisfied, 2 = dissatisfied, 3 = neutral, 4 = satisfied, 5 = very satisfied); quality of recovery score at 24 h postoperatively, assessed using the Korean version of the Quality of Recovery-15 (QoR-15K) questionnaire [12]; incidence of postoperative complications, including vocal cord palsy and respiratory depression; incidence of cerebral hyperperfusion syndrome including headache, seizure, and focal neurological deficit [3]; and the average value of the ANI scores assessed at 5-min intervals during surgery (0-100, 0 = minimum parasympathetic activity, high pain, 100 = maximum parasympathetic activity, low pain).
Statistical analysis
A preliminary institutional analysis (unpublished data) indicated that the mean IME consumption within 24 h for patients who underwent CEA with opioid-based pain management was 19.5 mg (standard deviation [SD] = 8 mg) at our institution. The sample size was determined using this value. If multimodal analgesia, including intermediate CPB, would reduce opioid consumption by 40%, the required sample size was determined using a 5% significance level (α = 0.05) and 80% power (β = 0.20), resulting in 17 patients per group (34 in total). To account for potential dropouts, the final sample size was set at 20 patients per group (40 patients in total).
Continuous variables were presented as mean (SD) or median (1Q, 3Q) and compared using either the independent t-test or Mann-Whitney U test, while categorical variables were reported as counts (%) and analyzed using the chi-squared test or Fisher’s exact test. Group comparisons were performed using two-sided tests, and statistical significance was defined as P < 0.05. The Bonferroni correction was used to adjust for multiple comparisons of postoperative pain scores assessed at rest and during motion upon ICU arrival, and for the five QoR-15K dimension scores.
The primary outcome was analyzed based on the intention-to-treat (ITT) principle. For sensitivity analysis, a per-protocol (PP) analysis was performed, excluding patients with block failure, those who did not receive protocol-specified analgesics, and those who were administered additional analgesics beyond the study protocol. All secondary outcomes were analyzed using the ITT approach. All statistical analyses were conducted with IBM SPSS Statistics 29.0 (IBM Co.).
RESULTS
Study participants
Between May 2023 and December 2024, 58 patients were screened for eligibility, and 18 patients who did not meet the inclusion criteria were excluded (Fig. 2). All 40 patients were included in the ITT analysis. Five patients were excluded from the PP analysis. In the multimodal group, two patients with CPB failure and one who did not receive the allocated intervention were excluded from the analysis. The latter case involved the omission of protocol-specified analgesics 30 min before the end of surgery. In the control group, two patients who received additional analgesics beyond the allocated intervention 30 min before the end of surgery were excluded.
Patient characteristics were comparable between the two groups, except for body weight, which was significantly lower in the control group than in the multimodal group (median [1Q, 3Q]: 61 [56, 67] kg vs. 68 [66, 73] kg; P = 0.033) (Table 2).
Primary outcome
Participants allocated to the control and multimodal groups consumed a median of 13.3 (6.7, 20.0) mg and 10.0 (6.7, 13.3) mg of IME, respectively, during the first 24 h post-surgery, with no statistically significant difference between the groups (P = 0.191). Similar results were observed in the PP analysis (13.3 [6.7, 20.0] vs. 6.7 [6.7, 13.3] mg, respectively; P = 0.247).
Secondary outcomes
Immediately after surgery, pain at rest and during motion were significantly higher in the control group than in the multimodal group (rest: 5.0 [4.0, 7.0] vs. 0.0 [0.0, 2.0], P < 0.001; motion: 6.0 [4.0, 7.8] vs. 0.0 [0.0, 2.0], P < 0.001) (Table 3). The time to first opioid administration post-surgery was also significantly shorter in the control group than in the multimodal group (0.9 [0.6, 2.5] h vs. 3.9 [0.8, 15.9] h; P = 0.047) (Table 3). QoR-15K scores were significantly lower in the control group compared with the multimodal group (112.5 [100.0, 122.5] vs. 124.0 [120.3, 135.0]; P = 0.004) (Table 3). Additional analysis according to the five validated dimensions of the QoR-15K (Physical comfort, physical independence, pain, emotional state, and psychological support) is provided in Supplementary Table 1 [13]. Of these, the multimodal group showed significantly higher scores in the Pain (15.0 [10.5, 17.8] vs. 19.0 [18.0, 19.8]; P = 0.002) and Emotional State (32.5 [21.3, 37.8] vs. 37.5 [36.0, 40.0]; P = 0.040) dimensions. No significant differences were observed between the two groups in terms of the incidence of postoperative hypertension, use of antihypertensive medication, postoperative nausea and vomiting, satisfaction with pain management, satisfaction with first-night sleep quality, complications, occurrence of cerebral hyperperfusion syndrome, or intraoperative ANI scores (Table 3).
DISCUSSION
In this randomized, observer-blinded clinical trial, a multimodal analgesia strategy incorporating intermediate CPB did not significantly reduce opioid consumption within the first 24 h after CEA compared with conventional local infiltration. However, the multimodal group experienced significantly lower pain scores at rest and during motion immediately post-surgery, a longer time to first opioid administration, and higher QoR-15K scores. These secondary outcomes suggest meaningful clinical benefits in early postoperative pain control and enhanced recovery.
In this study, the primary goal was not achieved, but the observed improvements in early recovery parameters highlight the potential utility of multimodal analgesia in enhanced recovery protocols, particularly for older patients who underwent CEA, who are more vulnerable to opioid-related side effects, including postoperative nausea, vomiting, and respiratory depression [5,14,15]. Enhanced Recovery After Surgery (ERAS) guidelines recommend a multimodal analgesic approach incorporating regional anesthesia, nonsteroidal anti-inflammatory drugs, and acetaminophen to minimize opioid reliance and promote early recovery [16]. Despite its increasing use, multimodal analgesia remains insufficiently studied in vascular surgery. While some studies have addressed its use in lower limb vascular and open aortic surgery, its role in CEA has not been well established [17,18]. Therefore, identifying effective analgesic strategies in CEA is of great importance. Most patients experience moderate to severe pain after CEA, which may activate the sympathetic nervous system, elevate blood pressure, and increase the risk of cerebral hyperperfusion syndrome [19-21]. In this context, the reductions in pain, the delayed requirement for the first opioid administration, and the improvements in QoR-15K observed in our study may hold clinical relevance in the recovery process, even though the primary outcome was not statistically significant. Therefore, these secondary outcomes align with the principles of ERAS recommendations, suggesting that a multimodal analgesic strategy may contribute to facilitating early recovery in patients undergoing CEA.
However, the lack of statistical significance in the primary outcome may be related to limited statistical power. In the PP analysis, opioid consumption was reduced by over 40%, which exceeds the threshold for the minimal clinically important difference reported in previous literature [22]. This suggests that the observed reduction may be clinically meaningful; however, the limited sample size likely prevented the difference from reaching statistical significance. Our sample size was calculated based on a 5% significance level and 80% power. Nonetheless, adopting a more conservative design with a higher power of 90% or more to minimize the risk of type II error would have been preferable [23,24]. These methodological considerations indicate that larger-scale, adequately powered trials are warranted to confirm the clinical relevance of the findings observed in the present study.
To reflect real-world clinical practice, this trial compared a bundled multimodal strategy consisting of ultrasound-guided intermediate CPB performed immediately after induction of general anesthesia, combined with acetaminophen and ketorolac, with conventional local infiltration performed by the surgeon at wound closure. In this study, we prioritized the pragmatic applicability over isolating the independent effects of each component. Preventive antiemetics were included in the multimodal group in accordance with ERAS recommendations and were not used in the control group [16].
Intermediate CPB involves injecting the local anesthetic deep into the investing cervical fascia and superficial to the prevertebral fascia, thereby anesthetizing the four cutaneous branches and the sensory and motor fibers innervating the SCM muscle, providing sensory blockade of the surgical field and analgesia for muscle manipulation during CEA [8]. In contrast, local infiltration targets primarily the skin and subcutaneous tissues, offering effective analgesia for superficial pain but limited coverage of deeper structures [25]. However, an anatomical study reported that local anesthetics can freely diffuse into deep spaces through the adipose tissue, indicating that effective sensory blockade may be achieved regardless of whether it is injected superficially or deep into the investing fascia [26]. This anatomical characteristic may have contributed to minimizing the differences between the two techniques, which is consistent with another clinical study reporting similar rates of completing CEA without supplemental local anesthetic in patients receiving superficial or intermediate CPB [27]. In this study, local infiltration was performed without ultrasound guidance, increasing the possibility of inadvertent deposition into deeper planes. Moreover, CPB success was assessed solely by ultrasound visualization of the spread, without sensory testing, leaving uncertainty regarding the true extent of blockade in both groups. These factors may have reduced the difference in opioid consumption between groups.
Notably, the difference in ropivacaine concentration between groups—0.5% for intermediate CPB and 0.75% for local infiltration—may have influenced block effectiveness and acted as a confounding factor [28]. Furthermore, CPB success was assessed solely via ultrasound spread without sensory confirmation. These factors, along with the possibility of inadvertent deep infiltration in the control group, may have reduced the observable differences in opioid consumption.
From a safety perspective, no significant between-group differences were observed in procedure-related complications, postoperative hypertension, cerebral hyperperfusion syndrome, or postoperative nausea and vomiting, in contrast to a previous report on awake patients who underwent CEA that showed higher complication rates with intermediate CPB [10]. These findings suggest that intermediate CPB does not appear to confer a safety disadvantage compared with local infiltration anesthesia.
The intermediate CPB was adopted as part of a multimodal analgesia strategy, with consideration given to the balance between efficacy and safety. This approach offers potential safety advantages over the deep technique, as it can provide a wider sensory blockade while reducing the risk of phrenic nerve palsy or local anesthetic systemic toxicity associated with deeper injections [8,29]. These complications were not systematically evaluated; however, the absence of severe adverse events suggests the potential relative safety of the intermediate technique.
This study has some limitations. First, the relatively small sample size and lower-than-expected opioid use in the control group may have limited the statistical power to detect significant differences in the primary outcome. A larger trial might have demonstrated clinically meaningful differences, although secondary outcomes such as early pain scores, time to first opioid request, and QoR-15K showed clear benefits of multimodal analgesia. Second, there was an average time difference of approximately 1.8 h between the two techniques, which may have introduced bias in early pain assessment. This reflects the real clinical workflow of CEA; however, it may have introduced potential bias due to the preemptive analgesic effect of CPB. Third, the difference in ropivacaine concentration between the groups may have influenced the analgesic effect and acted as a confounding factor, with the higher concentration in the control group potentially compensating for the shallower infiltration technique. Fourth, rescue analgesia in the ICU was guided by NRS assessment, but it was not titrated to a target score, which may have attenuated between-group differences in opioid consumption. Fifth, block success was confirmed only by ultrasound visualization of the local anesthetic spread, without sensory testing, leaving uncertainty regarding the true extent of blockade. Finally, the study was limited to the first 24 h post-surgery and therefore did not capture long-term outcomes. Previous research has suggested that intermediate CPB may reduce persistent postoperative pain and analgesic requirements compared with superficial CPB [29], underscoring the need for further investigation into its long-term effects.
The bundled multimodal analgesia strategy incorporating intermediate CPB did not significantly reduce 24 h postoperative opioid consumption; however, it was associated with improved early pain control and recovery scores. These findings suggest that the overall multimodal analgesic bundle contributed to enhanced early recovery while maintaining safety.
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