Explanation for the choice of comparators

We aimed to examine the effects of different subanesthetic doses of esketamine administered during surgery on early postoperative quality of recovery in ARCR patients. Group S1 received a high dose of esketamine, group S2 received a low dose, and group C served as the control with an equal volume of normal saline solution.

Intervention description

Group S1 received an intravenous injection of 0.5 mg/kg esketamine diluted to 10 ml with normal saline before the surgical incision, followed by a continuous infusion of 0.25 (mg/kg.h) esketamine with normal saline up to 20 ml until the surgical incisions were closed. Group S2 received an intravenous injection of 0.25 mg/kg esketamine diluted with normal saline to 10 ml before the surgical incision, followed by a continuous infusion of 0.125 (mg/kg.h) esketamine with normal saline up to 20 ml until the surgical incisions were closed. Group C received the same volume of normal saline.

Management of anesthesia

Upon arrival in the operating room, standard monitors will be used, including pulse oximetry, invasive radial artery blood pressure monitoring, and electrocardiogram leads. Before the surgery, an INVOS 5100C device from Covidien is utilized to monitor regional cerebral oxygen saturation. The attending anesthesiologist administers general anesthesia intravenously using midazolam (0.05 mg/kg), dexamethasone (5 mg), penehyclidine hydrochloride (0.5 mg), sufentanil (0.4 μg/kg), propofol (2 mg/kg), and cisatracurium (2.0 mg/kg). The patient is intubated with a single-lumen tracheal tube and receives a lung-protective ventilation strategy with a tidal volume of 6–8 ml/kg predicted body weight, positive end-expiratory pressure (PEEP) of 5 cmH2O, and lung recruitment maneuvers. After being positioned laterally from the supine position, anesthesia is maintained through inhalation of sevoflurane and continuous infusion of remifentanil (0.1–0.2 μg/kg/min). To optimize visualization of the surgical field, a systolic blood pressure between 95 and 105 mmHg is aimed for by titrating the dosage of the anesthetic and administering a vasoactive agent such as nicardipine (0.1–0.3 mg per time) or ephedrine (3 mg per time). Neuromuscular blockade will be sustained by intermittent injections of cisatracurium as required, at a dose rate of 5 mg per injection. Approximately 30 min before the completion of surgery, sufentanil (0.1 μg/kg), flurbiprofen axetil (50 mg), and tropisetron (5 mg) are administered. If necessary for the purpose of reversal, neostigmine (0.02 mg/kg) and atropine (0.01 mg/kg) will be used. After the surgery is completed, all patients will be transferred to the postanesthesia care unit for recovery. For patients with a postoperative numeric rating scale (NRS) pain score ≥ 4, hydromorphone can be administered for additional analgesia at a dose equivalent to 10 μg/kg. In the ward, dezocine will be given to patients with an NRS-R score ≥ 4.

Criteria for discontinuing or modifying allocated interventions

The criteria for dropout are as follows: (1) patients who withdraw their consent, (2) patients who are lost to follow-up, (3) patients with a serious adverse event suspected to have been caused by the study drug and other anesthetics will be replaced, (4) patients for whom the entire clinical trial could not be completed due to other reasons. The detailed reasons for dropout will be recorded in the case report forms (CRFs).

Strategies to improve adherence to interventions

At the beginning of the study, the participants are once again informed about the course of the experiment. They can report their personal feelings at any time during the study, and we will provide appropriate feedback if necessary to improve compliance with the interventions.

Relevant concomitant care permitted or prohibited during the trial

The provision of additional care during the trial followed institutional protocols.

Provisions for post-trial care

This study does not increase the incidence of anesthesia-related risks and complications included in the anesthesia consent form signed by the patients, and the research unit has the conditions and ability to deal with the above anesthesia risks and complications. This study provides standard monitoring methods without additional physical harm.

Outcomes Primary outcomes

The primary outcome of our study is the quality of early recovery scores, which are assessed using the QoR-15 scale on POD1. The QoR-15 comprises 15 questions assessing physical comfort (5 items), emotional state (4 items), physical independence (2 items), psychological support (2 items), and pain (2 items) [13]. The higher the QoR-15 score was, the better the quality of recovery after surgery (range was 0 to 150 points).

Secondary outcomes (1)

The QoR-15 scale on POD3;

(2)

The consumption of remifentanil;

(3)

The use of vasoactive drugs during surgery;

(4)

Cerebral desaturation events (CDEs), CDEs were defined as rSO2 > 20% drop from baseline or < 55% absolute threshold lasting more than 15 s [25];

(5)

Rescue analgesia during PACU;

(6)

NRS pain scores on POD1 and POD2;

(7)

Postoperative delirium developed at 24, 48, and 72 h after surgery, as assessed using the 3-min Confusion Assessment Method (3D-CAM) [26];

(8)

Adverse events such as increase in heart rate and blood pressure by more than 20% of baseline during surgery; nausea, vomiting, dizziness, hallucinations, and skin rash from PACU to POD3.

The primary and secondary outcomes from POD1 to POD3 will be assessed in the ward between 09:00 and 10:00 am.

Participant timeline

The participant flow is shown in Fig. 1. A time schedule for enrolment, interventions, and assessments is presented in Table 1.

Fig. 1Table 1 Study schedule of assessments. NRS, Numeric Rating Scale; QoR-15, Quality of Recovery-15; 3D-CAM, 3-min Diagnostic Interview for the Confusion Assessment MethodSample size

The sample size for the primary outcome of this study was calculated based on a 2 to 1 ratio [27] between exposed patients (combined ketamine groups) and unexposed patients (control group), using the PASS 15.0 software. The minimal clinically important difference (MCID) in the QoR-15 scale was 6.0 [28]. The primary outcome of our study is based on the QoR-15 score of POD1 [29, 30], which serves as the basis for sample size calculation. According to the unpublished experimental data from the initial phase of the center, the total QoR-15 score on POD1 was 116 ± 14.6 in the esketamine group and 107 ± 15.3 in the control group. A sample size of 221 subjects was calculated using the preliminary study data, assuming SD = 15, type I error (α) = 0.05 and type II error (β) = 0.2. To account for a dropout rate of 5%, we anticipate enrolling 78 subjects in each group for this study.

Recruitment

Based on the operation volume of our center, we plan to enroll the first patient in February 2024 and complete recruitment by November 2024. The investigator conducted preoperative screening of eligible patients and obtained informed consent from patients or their relatives before or on the day of surgery. We ensure that all participants are fully informed and have a comprehensive understanding of the potential benefits and risks of the study before signing the informed consent form.