The study evaluated the effects of intravenous esketamine infusion on the QoR and pain after LC from a multidimensional perspective reflecting the real clinical setting. Our findings demonstrated that intravenous esketamine can improve patient recovery and reduce pain after LC.
We analyzed the preoperative and postoperative global and dimensional data both horizontally and longitudinally. Our results showed that both lower (bolus 0.2 mg/kg, followed by 0.2 mg/kg/h) and higher (bolus 0.3 mg/kg, followed by 0.3 mg/kg/h) esketamine doses were superior to the control group in improving the QoR on POD-1. The postoperative discrepancies in the five dimensions were statistically different. The discrepancy in the postoperative global QoR-40 scores between the control and 0.2 mg groups was 6.77; and that between the control and 0.3 mg groups was 7.12. These values exceeded the MCID (6.3) [18], indicating that esketamine provided improved clinical efficacy. The postoperative global QoR-40 and dimensional scores were usually lower than the preoperative scores [19]. Our results are consistent with this view.
Our results verified the hypothesis and are consistent with previously reported data. Cheng Xiang [25] reported that esketamine (bolus 0.25 mg/kg, followed by 0.125 mg/kg/h) enhanced the QoR and reduced pain after video–assisted thoracic surgery (VATS). In contrast, ketamine did not improve the QoR in other previous similar studies. Moro [26] found that ketamine (0.2 mg/kg, or 0.4 mg/kg after anesthesia induction) did not improve the postoperative QoR after LC. Zhao Zijian [27] reported that ketamine (bolus 0.5 mg/kg, followed by 0.25 mg/kg/h) did not improve the overall QoR on POD-1 after breast cancer surgery. We speculated that the discrepancies were due to the heterogeneous of the studied population and the different prognoses resulting from different surgery types. Additionally, the research drugs were administered in different ways according to the drug metabolism.
Severe pain causes physical and psychological discomfort and affects prognosis. Adequate analgesia is a major goal and challenge in postoperative management, both for patients’ comfort and cure and for recovery and outcome [28, 29]. Recent studies have suggested the importance of patient-centered outcomes in assessing the effectiveness of anesthetic interventions [30]. Therefore, it is necessary to improve postoperative QoR by strengthening the analgesic effects and reducing the opioid-induced adverse events. Our results showed that intravenous esketamine infusion can reduce remifentanil consumption, 48-h NRS score, and the 48-h cumulative consumption of flurbiprofen axetil. Notably, esketamine, when used in combination with opioids during elective surgical anesthesia, has been shown to be an adjunct analgesic and to reduce postoperative pain [11–14, 31, 32]. A previous meta-analysis suggested that low-dose esketamine is comparable to morphine in terms of analgesic efficacy and safety, indicating that esketamine is an effective alternative analgesic for acute pain management [33]. Another meta-analysis [34] showed that esketamine serves as an auxiliary analgesic role for acute pain and decreases the postoperative pain. Our results are consistent with those of many previous clinical studies. Better initial pain management is vital to reduce the risk of a poor prognosis. Furthermore, we confirmed the hypothesis that, when used as part of a multimodal analgesic regimen, intravenous esketamine infusion can reduce pain intensity and the use of rescue analgesia, thereby ameliorating postoperative QoR.
Perioperative hemodynamic stability is crucial for patients. Esketamine has sympathomimetic interactions that trigger the release of catecholamines, inhibit the vagus nerves and reduce norepinephrine reuptake in neuronal and nonneuronal tissues [35]. Pharmacodynamic model studies have shown that esketamine increases cardiac output in a dose-dependent manner [15, 36]. Esketamine can maintain hemodynamic stability in elderly patients during anesthesia induction [37]. In our study, HR and MAP were relatively stable in the esketamine groups. Moreover, the incidence of hypotension was lower in the esketamine groups than in the control group. This was largely attributed to the circulatory–stabilizing effects of esketamine.
A 30% reduction in opioid consumption is considered clinically significant [38, 39]. However, we observed only an approximately 15% reduction. Owing to the different pharmacological mechanisms, it was not possible to estimate the equivalent doses of esketamine and sufentanil/remifentanil. Moreover, it was not possible to accurately assess the extent to which esketamine can reduce opioid consumption [40]. Eber [12] reported that perioperative esketamine administration reduced propofol consumption by approximately 20%. Our results showed that propofol consumption decreased by 12.5% and 20.8%, in the 0.2 mg and 0.3 mg groups, respectively, in accordance with previous data.
In our study, the extubation time was longer in the 0.3 mg group than in the other groups. In contrast, Eber [12] reported that esketamine did not affect the recovery time. An animal study [41] claimed that ketamine can accelerate recovery from isoflurane anesthesia by stimulating the arousal system. First, it may be related to the composite effects of drugs and to species differences. Second, prolonged recovery time may result from the dose-dependent sedative effect of esketamine[13].
In the esketamine groups, the incidence of postoperative SpO2 < 95% was significantly decreased, which was related to opioid reduction. Esketamine effectively antagonized the respiratory depression caused by opioids, which ascribed to an increase in opioids-reduced ventilatory CO2 chemosensitivity [42].
Neurological symptoms are the main adverse effects of esketamine[43]. In our study, the incidence of dizziness, nystagmus, and diplopia was significantly higher in the esketamine groups, with the higher esketamine dose resulting in a higher incidence of adverse effects.
The 48-h cumulative consumption of tropisetron hydrochloride decreased in the esketamine groups, which may be attributed to the decreased opioid consumption, thereby reducing postoperative nausea and vomiting (PONV). As is known to us, PONV are the most common side effects of opioids.
Notably, the original aim of this trial was to determine the optimal dose of esketamine for improving the postoperative QoR and pain. However, in the pilot trial, the postoperative extubation time was significantly prolonged in the 0.4 mg group (bolus 0.4 mg/kg, followed by 0.4 mg/kg/h), leading to a delayed recovery (> 1 h). Furthermore, the incidence of adverse events in the central nervous system was significantly higher in the 0.4 mg group than in the 0.2 mg and 0.3 mg groups, which increased the physical burden on patients. Therefore, the trial protocol was adjusted to consider patients’ safety and study feasibility.
Our study has some limitations. First, this was a single-center trial, which might limit the generalizability of the results. More powerful and authoritative trials are required to provide crucial evidence. Second, a subsequent study investigating changes in the neuroimmune microenvironment is required to objectively prove the effects of esketamine on postoperative QoR and pain. Third, the adverse effects of esketamine might have been inaccurately assessed considering the sample size. Larger studies are needed to assess the impact of our intervention on endpoints. Despite these limitations, our results suggested that esketamine (bolus 0.2 mg/kg, followed by 0.2 mg/kg/h) is beneficial and safe for improving postoperative QoR and pain.