Laparoscopic cholecystectomy is a common surgical procedure. Although it is less invasive than open cholecystectomy, it may lead to moderate-to-severe postoperative pain (1). After laparoscopic cholecystectomy, the most severe and common pain occurred in abdominal wall incisions, which occurred in 41.1% of patients and required analgesics in 73.8% of patients (2). Opioids are commonly used postoperative analgesics, which can effectively relieve postoperative pain. However, opioids have many adverse reactions, such as respiratory depression, nausea and vomiting, gastrointestinal paralysis, and urinary retention, which may outweigh the benefits of analgesia (3).

Transversus abdominis plane (TAP) block was used for postoperative analgesia in patients undergoing cholecystectomy, radical gastrectomy, and hepatectomy (4). The TAP is similar to the intercostal region, which belongs to the high blood perfusion plane. However, a large volume of local anesthetics was usually required to achieve satisfactory analgesic effects, which could cause local anesthetic systemic toxicity (LAST) (5). When ropivacaine was administered at doses of 2.5 mg/kg or 3 mg/kg for the TAP block, the patient’s plasma ropivacaine concentration approached or exceeded the local anesthetic potential toxic concentration (2.2 μg/mL), up to 4 μg/mL (5–7). A patient with renal dysfunction was given 1.8 mg/kg ropivacaine during TAP block; the plasma ropivacaine concentration reached 2.5 μg/mL, and the patient experienced local anesthetic intoxication (8). The ED₅₀ (2.05 ~ 3.27 mg/kg) of ropivacaine in TAP blocks in reversal of ileostomy was close to the toxic threshold (3 mg/kg) (9). Therefore, it is necessary to reduce the dose of local anesthetics in TAP blocks to lower the risk of local anesthetic intoxication.

Adding adjuvants can improve the nerve-blocking effect of local anesthetics and reduce the dosage of local anesthetics (10). As a highly selective α₂ adrenergic receptor agonist, dexmedetomidine combined with local anesthetics has been shown to enhance the analgesic effect of nerve blocks, prolong the action time, and reduce the dosage of postoperative analgesics (11, 12). A meta-analysis also showed the safety and efficacy of dexmedetomidine in combination with local anesthetics for nerve blocks (13). In a previous study (14), Mostafa et al. found that levobupivacaine combined with dexmedetomidine during TAP block in pediatric laparoscopic orchiopexy could attenuate postoperative pain, prolong analgesic time, reduce the dosage of analgesics, and have the highest postoperative satisfaction and minimal sedation. In lumbo-sciatic nerve block and transversal plane block, dexmedetomidine, as a local anesthetic adjuvant, prolonged sensory and motor block time and decreased postoperative pain score in a dose-dependent manner. However, the incidence of adverse reactions such as bradycardia and excessive sedation increased significantly after the dose of dexmedetomidine reached 2 μg/kg (15, 16). Another study (17) suggested that 1 μg/kg dexmedetomidine was recommended as an adjuvant to ropivacaine for TAP block, compared to 0.5 μg/kg and 1.5 μg/kg. Therefore, we chose 1 μg/kg dexmedetomidine as an adjuvant to ropivacaine for TAP block in our study.

However, there has been no report on the effect of dexmedetomidine as an adjuvant on the local anesthetic dosage for postoperative analgesia in the TAP block. We hypothesized that the addition of dexmedetomidine as an adjuvant could reduce the local anesthetic dosage for postoperative analgesia in the TAP block. Therefore, we conducted this study to investigate the effect of 1 μg/kg of dexmedetomidine as a local anesthetic adjuvant on the EC₅₀ of ropivacaine for postoperative analgesia in the TAP block.

A total of 74 patients were recruited for the study; 9 patients did not meet the inclusion criteria, and 3 patients were excluded. In addition, two patients declined to participate. A total of 60 patients completed the study as shown in Figure 1.

There were no significant differences in age, gender, ASA, height, weight, anesthesia time and operation time between the two groups (p = 0.796, 0.793, 0.796, 0.385, 0.269, 0.953 and 0.726, respectively) as shown in Table 1.

The up-down sequential allocation results are shown in Figure 2. According to the probit regression, the EC₅₀ of ropivacaine was 0.207% (95% CI, 0.188% ~ 0.228%), and EC₉₅ was 0.255% (95% CI, 0.230% ~ 0.499%) in the R group. The EC₅₀ of ropivacaine was 0.165% (95% CI, 0.146% ~ 0.182%), and EC₉₅ was 0.209% (95% CI, 0.187% ~ 0.430%) in the RD group, as shown in Figure 3.

The physical comfort score, emotional state score, pain score, and total score of the QoR-40 score in the RD group were significantly higher than those in the R group (p = 0.036, 0.035, 0.027 and 0.020, respectively), as presented in Table 2. There were no differences between the two groups in the physical independence score and psychological support score of the QoR-40 score (p = 1.000 and 1.000), as presented in Table 2.

There were no differences in the incidence of hypotension, bradycardia, skin itching, hematoma formation and PONV between the two groups (p = 0.103, 0.299, 1.000, 1.000 and 0.434, respectively), as shown in Table 3.

In this up-down sequential allocation study, we found that dexmedetomidine as a local anesthetic adjuvant for TAP block can significantly reduce the EC₅₀ and EC₉₅ of ropivacaine while improving the quality of postoperative recovery in patients undergoing laparoscopic cholecystectomy.

Laparoscopic cholecystectomy can cause moderate to severe postoperative pain in patients. The TAP block can significantly reduce postoperative pain, lower opioid consumption, and decrease pain scores (27). However, TAP block usually requires a high-volume local anesthetic to dilate the plane and block the nerves that travel through this plane to achieve the analgesic effect. However, the analgesic time of low-concentration local anesthetics is limited for a single TAP block, while high-concentration local anesthetics are associated with the risk of local anesthetic intoxication. Therefore, adding adjuvants to local anesthetics, enhancing the analgesic effect of local anesthetics, and reducing the risk of local anesthetic poisoning have been the focus of research in recent years. Studies (28, 29) have shown that local anesthetic adjuvants fentanyl, sufentanil, clonidine, and dexamethasone can enhance the blocking effect of local anesthesia, but dexmedetomidine has a stronger analgesic effect, which shortens the blocking onset time, prolongs the analgesic time, and reduces postoperative adverse reactions.

In this study, we investigated the EC₅₀ and EC₉₅ of ropivacaine using the sequential method, which is a simple and scientific approach to assessing the dose–effect relationship of the drug. The EC₅₀ and EC_95, respectively, represent the concentration of the drug that is effective in 50 and 95% of individuals. In clinical practice, the EC₅₀ and EC₉₅ of the drug can be used to guide rational drug use. A previous study showed that the ED₅₀ (2.05 ~ 3.27 mg/kg) of ropivacaine in TAP blocks in reversal of ileostomy is close to the toxic threshold (3 mg/kg) (9). Therefore, local anesthetic intoxication can easily occur. Raof et al. (30) showed that the EC₅₀ of bupivacaine combined with dexmedetomidine was 0.055% for TAP block in children, while the EC₅₀ of bupivacaine alone was 0.0839%. In labor epidural analgesia, the EC₅₀ of ropivacaine alone was 0.083%, and when ropivacaine was combined with 0.5 ug/ml of dexmedetomidine, the EC₅₀ value decreased to 0.062% (31). In these studies, dexmedetomidine was used as an adjuvant for local anesthetics, reducing the EC₅₀ of local anesthetics by 34 and 25%, respectively. These are consistent with the results of our study. This study revealed that the EC₅₀ of ropivacaine combined with dexmedetomidine for TAP block in adults was 0.165%, whereas the EC₅₀ of ropivacaine alone was 0.207%. The combination of ropivacaine with dexmedetomidine resulted in a 20% reduction in EC₅₀ compared to ropivacaine alone. A recent study (32) found that the intranasal administration of 1 μg/kg and 2 μg/kg of dexmedetomidine decreased the EC50 of ropivacaine for the caudal block, and there was a specific dose-dependent effect. However, the incidence of hypotension and bradycardia was higher with 2 μg/kg dexmedetomidine as a local anesthetic adjuvant (13, 15, 16). This may be derived from the anti-sympathetic effects of dexmedetomidine, which may inhibit the sympathetic nerve terminal to release norepinephrine and enhance the activity of the vagus nerve (33). There was no difference in the incidence of hypotension or bradycardia between the two groups in our study. However, it is necessary to strengthen the monitoring of the patient’s cardiovascular system to actively prevent and treat complications in clinical applications.

The mechanism by which dexmedetomidine enhances the analgesic effect of local anesthetics has been poorly understood. Current studies have found that dexmedetomidine can inhibit neuronal excitability and A-α and C fibers that control pain perception by blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels or hyperpolarization-activated cation channel current (I_h current), delay rectifier K⁺ current (I_K(DR)) and Na⁺ current (I_Na) (34–37). The enhancement of sensory and motor blocks with intraneural dexmedetomidine may be related to the anti-inflammatory and neuroprotective properties of dexmedetomidine as a local anesthetic adjuvant. Kim et al. (38) revealed that interleukin (IL)-6 and IL-1β levels, scores of axon, myelinated fiber degeneration, and demyelinated fiber percentages were lower in the ropivacaine plus dexmedetomidine group than in the ropivacaine group. Huang et al. (39) found dexmedetomidine pretreatment elevated brain-derived neurotrophic factor (BDNF) expression by reducing miR-10b-5p expression, thereby alleviating ropivacaine-induced neurotoxicity. Dexmedetomidine can also prevent the absorption of the local anesthetic by vasoconstriction at the injection area and enforce the activity of the peripheral nerve to increase analgesia intensity and duration (40). Meanwhile, the release of peripheral norepinephrine is inhibited, which induces the hyperpolarization of cells and inhibits the transmission of pain signals to the brain center (41). Dexmedetomidine enhances the analgesic effect of anesthetics through these mechanisms. It has also been proven in clinical applications. In brachial plexus block, dexmedetomidine combined with ropivacaine can significantly shorten the onset time of ropivacaine block and extend its block time (42). A meta-analysis (43) showed that local anesthetics combined with dexmedetomidine significantly reduced postoperative pain intensity at 12 h, 24 h, and 48 h, and reduced opioid dosage in femoral nerve block.

The QoR-40 score was used to globally measure the quality of postoperative recovery from five dimensions involving emotional state, physical comfort, psychological support, physical independence, and pain in many clinical trials (44). The results of this study showed that the combination of dexmedetomidine and ropivacaine significantly increased the scores of physical comfort, emotional state, pain, and total score in the 24 h QoR-40 score of patients after surgery more than ropivacaine alone. This suggests that ropivacaine with dexmedetomidine (1 μg/kg) can meet superior pain relief in the early postoperative period, increase patient satisfaction, and improve the quality of postoperative recovery. Similar results were found in Yu Wu et al.’s study of dexmedetomidine combined with ropivacaine was used in deep serratus anterior plane block to improve postoperative recovery quality in patients undergoing modified radical mastectomy (45). Another study (46) discovered that 1 μg/kg (not 0.5 μg/kg) dexmedetomidine combined with ropivacaine in a deep serratus anterior plane block could provide superior postoperative analgesia for patients undergoing modified radical mastectomy. Although a study (47) showed that general anesthesia combined with spinal anesthesia, TAP block, or systemic administration of lidocaine, the quality of recovery on the first day after surgery did not differ from baseline. However, it is not known whether adding dexmedetomidine to the TAP block would have produced different results because clonidine was used in this study. In addition, although local anesthesia in the TAP block was confirmed by ultrasonography to spread at the correct level, the clinical effect could not be evaluated because the block was implemented after the induction of anesthesia.

There are several limitations to our study. First, the plasma concentration of ropivacaine was not detected. However, the concentration of ropivacaine used in this study was low and did not exceed the maximum dose. The median peak venous plasma ropivacaine concentrations were below the reported toxic threshold, even though the concentrations of ropivacaine were up to 0.25% (less than 0.25% in our study) in a previous study (48). Therefore, no patient experienced local anesthesia intoxication during the perioperative period. Second, the sample size of this study is small, and a larger sample study will be needed in the future to confirm the effect of dexmedetomidine on patients’ QoR-40 scores. Third, dexmedetomidine at different doses is used as a local anesthetic adjuvant for TAP block in the clinic, but this study only investigated the effect of 1 μg/kg of dexmedetomidine on the EC₅₀ of ropivacaine. We needed to explore whether different doses of dexmedetomidine would have the same effects. Finally, there is a potential bias due to the single-center design and the lack of long-term follow-up.

In the ultrasound-guided TAP block, the EC₅₀ of ropivacaine combined with dexmedetomidine was 0.165% (95% CI, 0.146% ~ 0.182%), and the EC₅₀ of ropivacaine alone was 0.207% (95% CI, 0.188% ~ 0.228%). Dexmedetomidine can significantly reduce the EC₅₀ of ropivacaine and improve the quality of postoperative recovery for patients undergoing laparoscopic cholecystectomy. Similar results may be achieved in other upper abdominal procedures, such as radical gastrectomy and hepatectomy. However, further research is needed.