Hepatocellular carcinoma (HCC) has one of the highest incidence rates among cancers worldwide and has become the third leading cause of death among all types of cancers (1, 2). Especially, in China, HCC is ranked as the second major cause of cancer-related death owing to the prevalence of hepatitis virus (3). It causes heavy burden on global health.

Despite the implementation of multiple treatment approaches such as ablation, liver transplantation, immune checkpoints inhibitors and CAR-T (chimeric antigen receptor T) immunotherapy for HCC in the clinic, hepatectomy remains the preferred option for patients with resectable HCC (4). Although hepatectomy effectively excises the primary tumor, it simultaneously causes unavoidable liver injury. Meanwhile, ischemia–reperfusion injury (IRI) induced by inflow occlusion during hepatectomy significantly activates local and systemic inflammatory responses, oxidative stress injury, and multiple organ injury, including the liver, kidney, and heart (4–6), which would even result in dangerous postoperative complications such as hepatic failure, renal dysfunction, and irreversible myocardial injury (4). Therefore, identifying the method to minimize liver injury and ameliorate liver function during hepatectomy will be highly clinically significant for patients with HCC.

As a highly selective α₂-receptor agonist, dexmedetomidine (DEX) is widely used in clinical anesthesia for satisfactory sedation and analgesia without causing respiratory depression and hemodynamic instability (7). Moreover, animal and human studies have reported that DEX is effective in preventing postoperative delirium, promoting liver regeneration, inhibiting sepsis-induced systemic inflammatory response and injury, and improving the functions of important organs such as the kidney, lung, intestinal tract, and heart postoperatively or in the intensive care unit (ICU) (8–11). Several fundamental experiments have proved the protective effects of DEX on liver function after surgery by demonstrating that perioperative DEX use significantly reduced inflammatory response and oxidative stress injury in hepatectomy or liver transplantation surgeries (12–14).

Nevertheless, the effects of DEX on liver function were primarily investigated in animal studies, and only a few clinical studies with small sample sizes have investigated this issue in patients undergoing hepatectomy (6, 15, 16). Therefore, we conducted this retrospective cohort study with a suitable sample size and using propensity score matching (PSM) to determine the effects of DEX on liver function in patients undergoing surgery due to HCC.

As depicted in Figure 1 , a total of 1069 patients who underwent hepatectomy from June 1, 2019, to July 31, 2020, were screened for the study. Then, 494 who fulfilled the criteria were finally enrolled and divided into the DEX group (n = 305) and DEX-free group (n = 189). In addition to DEX dosage, several other baseline characteristics of the patients, including the ASA score, hepatic inflow occlusion duration, volume of bleeding, and midazolam dosage, were significantly different between the two groups, as shown in Table 1 . To eliminate bias between the two groups, PSM was performed, and 107 pairs of patients were successfully matched finally. No significant differences were observed in the PSM score and baseline characteristics, except the dosage of DEX, between the two groups after PSM ( Table 2 ).

This retrospective cohort study suggests possible protective effects of DEX on liver function in patients with HCC who underwent hepatectomy. Perioperative DEX use may not only reduce liver injury but also improve the liver function of producing ALB during hepatectomy. Little effects of DEX on early postoperative inflammation were found between two groups.

With the development of surgical techniques and perioperative management, resection of hepatic tumors has been one of the most popular choices for patients with HCC (2018). The application of the occlusion of portal triad and total vascular exclusion minimizes intraoperative blood loss and the need for blood transfusion (4, 20). Nonetheless, both techniques cause inevitable IRI that may impair liver function and regeneration after hepatectomy. Furthermore, surgical trauma and stress response, excessive inflammatory response, and poor liver conditions with hepatitis or cirrhosis cause heavy burden on the liver (21). Therefore, perioperative protection of the liver is of significant concern for patients undergoing hepatectomy (22).

Numerous strategies have been designed for reducing liver injury and postoperative inflammatory response, and preserving liver function during hepatectomy (23, 24). For instance, studies have suggested that remote ischemia preconditioning (RIPC) could effectively reduce hepatic IRI after liver resection. In a randomized controlled trial (RCT) (23), our team investigated the effects of RIPC on hepatic IRI in patients undergoing liver resection (23). It was observed that the serum levels of ALT and AST were significantly decreased in the RIPC group compared to those in the control group. Second, some promising drugs such as ulinastatin and oxygen radical scavengers have been used for inhibiting inflammatory responses and oxidative stress (25, 26). However, their clinical application and validation are rarely reported and require more evidence.

DEX, a widely used sedative during surgery, was approved for sedation and analgesia by the United States Drug and Food Administration in 1999 (7). Owing to its excellent advantages of sedation, analgesia, antianxiety, inhibition of sympathetic nervous excitation, cardiovascular stabilization, and prevention of postoperative delirium, DEX has been widely used in clinical anesthesia and the ICU (8, 10, 27, 28). The contraindications of DEX mainly include 1) patients allergic to DEX, 2) pregnant, lactating women, and patients with severe heart block. Interestingly, numerous basic studies have also shown that DEX exerts strong multiorgan protective effects, including the liver, lung, heart, kidney, brain, and intestinal tract (5, 29, 30). These exciting findings prompt a series of clinical investigations. A meta-analysis discussed the effects of DEX on attenuating one-lung ventilation-associated lung injury by reviewing 20 clinical trials (31). The results suggested that perioperative administration of DEX could attenuate inflammation and ameliorate pulmonary oxygenation. Another meta-analysis reported that perioperative DEX infusion inhibited the release of epinephrine, norepinephrine, and cortisol and decreased the levels of blood glucose, interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and CRP (5). In addition, the immune function was improved (5, 28, 32). Li et al. (27) also systematically reviewed the anti-inflammatory effects of perioperative DEX administration as an adjunct to general anesthesia in 15 clinical trials and reported significant decreases in the serum levels of IL-6, IL-8, and TNF-α after DEX use.

Several clinical studies have also explored the effects of DEX on liver protection (15, 16, 29). In an RCT conducted by Wang et al., perioperative administration of DEX was found to attenuate intestinal and hepatic injury in patients undergoing elective liver resection with inflow occlusion with no potential risk (15). In another RCT conducted by Zhang et al., the concentrations of α-glutathione S-transferase, IL-6, TNF-α, ALT, and AST were found to be significantly lower in the DEX group than in the control group (6). Nevertheless, the sample sizes of these studies were relatively small (n = 22–29 per group). In our study, we included 494 patients for analysis in total. Protective effects of DEX on the liver along with a decrease in the serum levels of ALT and LDH in the DEX group were observed, compared to those in the DEX-free group. Interestingly, our results also suggested that the ALB level was significantly higher at 24h after surgery in the DEX group, which had not been reported previously in the case of hepatectomy. It appears that DEX could maintain the productive function of the liver as well. These findings support the use of DEX for reducing liver injury and maintaining ALB production in hepatectomy, which may bring significant improvement of liver function for patients. However, no differences in the levels of inflammation biomarkers such as serum CRP, WBC, and N% in peripheral blood between the two groups were found, indicating that DEX may exerted limited effects on early postoperative inflammatory responses.

The potential mechanism of action of DEX in alleviating liver injury involves multiple aspects such as anti-inflammatory and anti-IRI effects (33, 34), inhibition of hepatocyte apoptosis (35, 36), promotion of liver regeneration (9), regulation of immune function, and attenuation of oxidative stress (13, 35, 37). For instance, Zhang et al. reported that DEX could alleviate hepatic injury following intestinal IRI in vivo and vitro by upregulating β-catenin expression (34). Zhao et al. found that DEX alleviated hepatic injury by inhibiting oxidative stress and activating the Nrf2/HO-1 signaling pathway in vitro (13). Other potential signaling pathways that are regulated by DEX include TLR4/MyD88/NF-κB, GSK-3β/MKP-1/Nrf2, and PI3K/AKT (35, 38, 39). Studies have also shown that miRNA and LncRNA were regulated by DEX (36, 40, 41).

Regarding the effect of DEX on cancer biology, it still remains unclear and controversial (41–44). Basic and clinical studies have suggested that DEX could regulate the malignancy of cancer cells and influence the prognosis of patients, but the conclusions are conflicting (41, 44, 45). Though significant decrease in OS was found in the DEX group compared with the DEX-free group only before PSM, the difference disappeared after PSM. Therefore, it is hard to draw conclusions regarding the effects of DEX on the prognosis of patients with HCC based on the present findings, and therefore further well-designed, large sample size, prospective studies are required to explore the effects of DEX on the malignance of cancer cells. Considering the possible adverse effects of DEX on the long-term prognosis of patients with HCC, we should balance the benefits and harm of DEX for patients undergoing hepatectomy.

This study has several limitations. First, it is a single-center retrospective study, and a multicenter or a prospective cohort study with a larger sample size would elevate the reliability of our findings. Second, the duration of protective effects induced by DEX is unclear, and more investigative time points are necessary. Third, examination of more liver function and inflammation biomarkers may help us understand the effects of DEX on liver function and inflammatory response in a more comprehensive manner.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by This study was approved by the Eastern Hepatobiliary Surgery Hospital’s Institutional Review Board (Number: EHBHKY2021-K-011). The patients/participants provided their written informed consent to participate in this study.

Conceptualization, XW, YSu and JT. Methodology, XW, BQ and Y-RL. Software, XW and JL. Validation, YSh, ZP and YSu. Formal analysis, XW, ZP and FW. Investigation, JT. Resources, XW, XL and YL. Data curation, XW, YZ and XL. Writing—original draft preparation, XW and YSh; writing—review and editing, ZP and JT; supervision, JT. Funding acquisition, YSu, ZP, BQ and JT. All authors contributed to the article and approved the submitted version.