Opioid-free anesthesia with quadratus lumborum block and Esketamine enhances postoperative recovery in laparoscopic colon cancer surgery: A randomized controlled trial.

Materials and methods

Study design and participants
This randomized controlled trial was conducted between March 2023 and January 2024 at the Anesthesiology Department of the First People’s Hospital of Yichang. The study was approved by the Ethics Committee of the First People’s Hospital of Yichang (Approval No: PJ-KY2022-45) and registered at the Chinese Clinical Trial Registry (ChiCTR2300068815, date of registration: 01/03/2023) before enrolment of the first patient.
Patients with American Society of Anesthesiologists (ASA) physical status Ⅱ–Ⅲ, aged 45 to 75 years, and body mass index (BMI) 18–25 kg·m−2 who were scheduled for laparoscopic radical resection of colon cancer were enrolled. The exclusion criteria were as follows: (1) presence of severe liver (Child-Pugh grade C) and kidney (serum creatinine > 442 umol·L−1 or requiring renal replacement therapy) dysfunction; (2) presence of glaucoma or cerebrovascular disease, increased intraocular pressure, or increased intracranial pressure; (3) presence of severe pulmonary hypertension, arrhythmia, or heart failure; (4) difficulty communicating; (5) BMI below 18 kg·m−2 or over 25 kg·m−2; (6) presence of drug abuse or with neurological or psychiatric diseases; (7) contraindications or allergy to any of the drugs used in this study. Dropout criteria include the following: (1) Discontinuation of the trial will occur if serious adverse events arise, based on the physician’s assessment; (2) Modifications to the surgical technique or the need for additional surgical procedures; (3) Significant violations of inclusion or exclusion criteria are identified after randomization.

Randomization and blinding
One researcher (M-Z) who was blinded to group assignment obtained written informed consent and collected data from participants in the wards one day before surgery. After enrollment, a computer-generated random number table was created by an independent member of our research department (X-Y) using SPSS software, version 22.0 (IBM Corp), with an unstratified block size of 4, to randomly assign the subjects at a 1:1 ratio to group A or group B. The random results were concealed in sequentially numbered sealed opaque envelopes. Shortly after the patients were brought into the operating room, a researcher (SJ-Y), who was blinded to the randomization procedure, opened the envelopes and prepared the study drugs and equipment according to group assignment. Two anesthesiologists (CX-C and K-W), who were informed about the study medications and the anesthesia protocol, performed anesthesia according to the assigned protocol. Regardless of medications and QLB block, all patients received a standardized intraoperative management and monitoring. Subjects, clinicians—aside from the anesthesiologists (CX-C and K-W)—including the surgeons, other health care team members, and the investigators responsible for patient recruitment (M-Z) and data collection (YX-J and W-Z) were fully blinded to group assignment.

Anesthesia management
After the patients were brought into the operating room, an 18-gauge peripheral venous catheter was placed in the peripheral vein and lactated Ringer’s solution was infused. Routine monitoring, including measurement of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), temperature, and end-tidal CO2 pressure (PetCO2); peripheral pulse oximetry (SpO2), electrocardiography (ECG); and bispectral index (BIS) monitoring were performed in the operating room.
After monitoring, patients in Group B were positioned in a lateral decubitus posture with flexed knees and an arched back. Patients subsequently underwent a QLB using an ultrasound-guided supra-lateral arcuate ligament approach. In accordance with published protocols19, the low-frequency convex array probe was positioned 6–8 cm lateral to the spine midline for a long-axis scan, with the marking point of the probe facing cephalad to locate the quadratus lumborum’s attachment at the T12 rib. Then, the probe was moved medially towards the spine and craniocaudally to image the area between the T12 rib and the L1 transverse process tip. A thin diaphragm that moved with respiration is visible deep in the quadratus lumborum on the ultrasound, with its lower border being the lateral arcuate ligament. We employed the in-plane puncture technique, using the probe to locate the T12 rib, L1 transverse process tip, quadratus lumborum, and diaphragm. The needle was then advanced through the erector spinae and quadratus lumborum to the apposition zone between the diaphragm and quadratus lumborum. To confirm correct placement, 3 mL of 0.9% saline was injected, resulting in downward movement of the diaphragm. After confirming spread of the fluid to the diaphragm-quadratus lumborum zone above the lateral arcuate ligament, 20 ml of 0.375% ropivacaine was administered. The contralateral QLB was performed using the same method, and its success was tested with acupuncture after 20 min. Following a successful block, anesthesia was induced with midazolam (0.05 mg·kg−1), lidocaine (1.5 mg·kg−1), propofol (2.0 mg·kg−1), esketamine (0.5 mg·kg−1), and cisatracurium (0.15 mg·kg−1). Three minutes later, the patient was intubated and placed on mechanical ventilation. Anesthesia was maintained with propofol (4–6 mg·kg−1·h−1), esketamine (0.25–0.5 mg·kg−1·h−1), lidocaine (1 mg·kg−1·h−1), and cisatracurium (0.1 mg·kg−1·h−1).
In group A, after ECG monitoring, anesthesia induction involved intravenous administration of midazolam (0.05 mg·kg−1), propofol (2.0 mg·kg−1), sufentanil (0.5 µg·kg−1), and cisatracurium (0.15 mg·kg−1). Post-induction, anesthesia was maintained with propofol (4–6 mg·kg−1), remifentanil (0.15–0.3 µg·kg−1·min−1), and cisatracurium (0.1 mg·kg−1·h−1).
After tracheal intubation, mechanical ventilation was performed with tidal volumes of 6–8 ml·kg−1, respiratory rate of 12–18 bpm, and inspiration and expiration ratio of 1:2 to maintain PetCO2 at 35–45 mmHg. The infusion rates of propofol, remifentanil, cisatracurium, and esketamine were adjusted based on BP, HR, and BIS values to maintain BP and HR within ± 20% of baseline and BIS between 40 and 60. During the operation, if MAP < 65 mmHg or SBP < 90 mmHg, 40 µg of phenylephrine was administered intravenously. If SBP ≥ 140 mmHg or DBP ≥ 90mmHg, anesthesia was deepened or 10 mg of urapidil was given intravenously. For HR < 50 bpm, 0.3 mg of atropine was administered intravenously. If HR > 100 bpm, anesthesia was deepened or 10 mg of esmolol was given intravenously. Fifteen minutes before surgery ended, group B received 30 mg of intravenous ketorolac tromethamine, while group A received 0.1 µg·kg−1 of sufentanil and 30 mg of ketorolac tromethamine. Drug infusion was then stopped and PCIA was used for 48 h post-surgery. The analgesic pump contained 240 mg of ketorolac tromethamine, 15 mg of tropisetron, and normal saline up to 100 ml, with no background infusion, a PCA dose of 3 ml, and a 10-minute lockout interval. Post-extubation, patients were monitored in the PACU and transferred to the ward once stable. If the resting NRS score exceeded 4 and the analgesic pump was ineffective, a 5 mg dezocine injection was administered intravenously, as needed, for pain relief.

Date collection and outcomes
Baseline data included age, sex, BMI, ASA grade, surgery, and anesthesia duration. Patients were followed up at one day before surgery and 2 h, 6 h, 12 h, 24 h, 48 h, 72 h, and 7 d after surgery at bedside and 30 d through telephone.
The primary outcome was the postoperative QoR-15 score at 1 day after surgery (24 ± 1 h postoperatively). The secondary outcomes included: (1) QoR-15 score 1 day before surgery, 3 d (72 ± 1 h postoperatively), 7 d (168 ± 1 h postoperatively), and 30 d (30 ± 1 d postoperatively) after surgery; (2) pain NRS score at 2 h, 6 h,12 h, 24 h, 48 h, on movement (defined as three deep breaths and cough once20) and at rest; (3) the number of times the patient pressed the postoperative PCIA pump within 48 h; (4) the proportion of requests for rescue analgesia within 48 h; (5) length of hospital and PACU stay, anesthesia recovery time (stop the drug infusion until the tracheal tube is removed), first anal exhaust times. Additionally the proportion of complications and adverse events at 30 days after surgery were also recorded (using the Clavien-Dindo classification21. An anesthesiologist (YX-J) who did not participate in this study evaluated the total postoperative recovery quality scores based on the QoR-15 scale before surgery, 1 d, 3 d, 7 d, and 30 d after surgery. The QoR-15 questionnaire comprised 15 questions, addressing physical comfort (5 items), emotional state (4 items), physical independence (2 items), psychological support (2 items), and pain (2 items)18. The higher the QoR-15 scores, the better the quality of recovery after surgery (range is 0 to 150 points).

Statistical analysis
According to our preliminary pilot study, the QoR-15 scores at 24 h postoperatively were equivalent to 98 ± 16 in A group. Assuming a difference of at least 8 points in the score to determine the clinical significance,22 with a type I error risk of 0.05, in a two-sided test and a power of 0.8, the estimated number of patients needed was 128 (64 patients in both groups). Accounting for 20% dropout rate, we planned to include 160 patients. The sample size was calculated using PASS15 (PASS Software by NCSS, LLC, USA).
Statistical analysis was performed using IBM SPSS Statistics 22.0 (IBM, Armonk, New York, USA). All indices were subjected to normality test, and those conforming to normal distribution were expressed as the mean ± standard deviation. Repeated measures ANOVA was used for the repeated-measures data (QoR-15), and the LSD test was used for pairwise comparisons between groups. Other normally distributed measurement data analyzed with Student’s t-test. Nonnormally distributed data (NRS pain score) are presented as the median (interquartile range [IQR]) and were analyzed with the Mann–Whitney U test. Categorical data (such as complications) are presented as the number (%) and were analyzed using the chi-square or Fisher’s exact tests. Values of P < 0.05 were considered to indicate statistical significance.

Results
A total of 160 patients were recruited from March 1, 2023 to January 1, 2024. After assessment for eligibility, 140 subjects were enrolled in the study and randomized to Group A and Group B. Ultimately, 136 patients (68 in each group) were included in the analysis. The Consolidated Standards of Reporting Trials (CONSORT) recruitment diagram is shown in Fig. 1. Baseline characteristics and surgery and anesthesia information were comparable among the two groups, and are summarized in Table 1. No significant differences were observed between the two groups.

As shown in Table 2, there were significant differences in QoR-15 at different time points (F = 929.823, P < 0.001) and differences between the two groups (F = 65.910, P < 0.001) after repeated measures ANOVA. LSD pairwise comparison found that: patients in group B had significantly higher QoR-15 scores than those in group A on day 1 (mean difference − 8.56, 95% CI − 10.11 to − 7.00; P < 0.001), day 3 (mean difference − 7.59, 95% CI − 9.30 to − 5.88; P < 0.001), and day 7 (mean difference − 4.46, 95% CI − 6.08 to − 2.83; P < 0.001) after surgery. No significant difference in QoR-15 scores was observed between the groups before the operation and on day 30 after surgery (Fig. 2; Table 2).

Among secondary outcomes, pain intensity at rest was lower in group B than in group A at 2 h (median difference 1, 95% CI 0 to 1; P < 0.001), 6 h (median difference 1, 95% CI 1 to 1; P < 0.001), 12 h (median difference 1, 95% CI 1 to 1; P < 0.001), and 24 h (median difference 1, 95% CI 1 to 1; P < 0.001) after surgery (Fig. 3; Table 2). Pain intensity with movement was also lower in group B at 2 h (median difference 1, 95% CI 1 to 1; P < 0.001), 6 h (median difference 2, 95% CI 1 to 2; P < 0.001), 12 h (median difference 1, 95% CI 1 to 1; P < 0.001), and 24 h (median difference 1, 95% CI 1 to 1; P < 0.001) after surgery (Fig. 4; Table 2). However, there was no significant difference between the groups at 48 h. Compared with Group A, Group B had longer anesthesia recovery (mean difference − 4.29, 95% CI − 6.67 to − 1.93; P < 0.001) and PACU stay times (mean difference − 6.07, 95% CI, − 8.83 to − 3.32; P < 0.001), but fewer PCIA compressions (mean difference 5.41, 95% CI 3.78 to 7.05; P < 0.001) and fewer requests for rescue analgesia (odds ratio 2.96, 95% CI 1.37 to 6.42; P = 0.005) within 48 h post-surgery. Additionally, group B experienced shorter postoperative hospital stays (mean difference 0.91, 95% CI 0.20 to 1.62; P = 0.012) and quicker first anal exhaust times (mean difference 0.65, 95% CI 0.26 to 1.03; P = 0.001) (Table 2).

The incidence of PONV (odds ratio 2.50, 95% CI 1.00 to 6.27; P = 0.046) was lower in Group B than in Group A. Additionally, no significant differences were observed between the groups with regard to the incidence of other postoperative adverse reactions and complications (Table 3).

Discussion
This randomized controlled study compared the impact of OFA (using QLB and esketamine) versus traditional opioid-based anesthesia on postoperative recovery in patients undergoing laparoscopic surgery for colon cancer. Our study indicates that the use of ultrasound-guided QLB with esketamine-based OFA enhances short-term recovery after laparoscopic colon cancer surgery. It effectively reduces pain and the need for additional painkillers within the first 24 h, shortens hospital stays, and lowers the incidence of PONV. However, we also found that OFA delayed recovery and extended PACU stay without enhancing 30-day recovery quality or significantly reducing complications, with the exception of PONV.
The QoR-15 is a widely adopted tool for assessing postoperative recovery quality and serves as a key benchmark for comparing the effects of different anesthesia methods during the perioperative period23–25. This study assessed the impact of OFA using a QLB and esketamine versus traditional opioid-based anesthesia on postoperative recovery with the QoR-15 score. The average differences in scores between the two groups were 8.56, 7.59, and 4.46 on the 1 st, 3rd, and 7th days post-surgery, respectively, showing statistical significance. In the sample size estimation, a minimum difference of 8 points in the QoR-15 score was initially deemed clinically significant22. However, this threshold was subsequently revised to 6 points26. Based on the above criteria, we conclude that the OFA enhances recovery quality in the first 3 postoperative days. Although a statistically significant difference in QoR-15 scores was observed between patients on the 7th postoperative day, this difference was not clinically significant. Furthermore, no statistically or clinically significant differences in QoR-15 scores were detected at 30 days post-surgery. The observed phenomenon may be attributed to the duration of effective analgesia provided by the QLB and the amelioration of postoperative negative emotions through the administration of esketamine.
Patients undergoing surgery for colon cancer experience significant physical and psychological effects postoperatively. Physically, pain and postoperative complications, such as PONV, restrict patients’ physical activity and impair their ability to perform self-care27–29. Psychologically, these patients often experience tension, anxiety, insomnia, and other adverse emotional states, which can severely hinder their postoperative recovery27,28,30,31. Consequently, this study employed QLB to alleviate postoperative pain and esketamine to mitigate negative emotional states following surgery.
The primary goal of perioperative opioid use is to alleviate surgical and trauma-induced pain, while OFA aims to achieve pain relief using non-opioid drugs and techniques. In this study, we employed ultrasound-guided QLB with esketamine and lidocaine administered via intravenous pump during surgery. The quadratus lumborum suprarcuate ligament block injects local anesthetics into the quadratus lumborum muscle near the arcuate ligament and thoracolumbar fascia. The anesthetic then spreads through these fasciae into the thoracic paravertebral space and thoracolumbar fascia, blocking the spinal nerve roots and their branches19. The QLB, when administered at the arcuate ligament, can achieve a blockade of the thoracolumbar nerve roots, their branches, and the sympathetic trunk, thereby extending the block plane to encompass the T7-L1 segment17,32. As a result, this technique is extensively employed for both intraoperative and postoperative analgesia in abdominal and pelvic surgeries33–36. It has been shown that a single dose of QLB provides effective postoperative analgesia up to 48 h in patients undergoing gastrointestinal surgery, improves QoR-15 scores, and reduces opioid use and opioid adverse effects such as PONV29,37,38. Our study found that the OFA group had lower NRS scores, fewer PCIA compressions, and fewer rescue analgesic administrations within 24 h post-surgery compared to the conventional opioid-based anesthesia group. This indicates that QLB may significantly enhance perioperative analgesia, contributing to the higher QoR-15 scores observed in the OFA group. This outcome is in partial agreement with the findings reported by Dai et al.17
Esketamine exhibits anesthetic, analgesic, sedative, and anxiolytic properties, and is among the most extensively utilized narcotic agents in the domain of OFA. Research indicates that esketamine-based anesthesia is commonly used in thoracoscopic surgery, gynecological laparoscopy, and radical mastectomy, which reduces the consumption of perioperative opioids, PONV, as well as the occurrence of postoperative chronic pain13–15,17. Leger et al. demonstrated that OFA utilizing esketamine enhanced postoperative QoR-15 scores in patients undergoing plastic, abdominal, otolaryngological, and urological surgeries10. Conversely, Luo et al. reported that a single perioperative administration of esketamine mitigated anxiety, depression, and pain during the first one to three days post-surgery31. In a separate study focusing on patients undergoing radical surgery for colorectal cancer, a continuous infusion of esketamine significantly decreased fatigue and negative mood scores during the first seven days postoperatively39. In our study, we observed that patients in the OFA group exhibited a significantly higher QoR-15 score postoperatively. This finding may be attributable to the administration of esketamine, which was utilized to mitigate postoperative anxiety and other adverse emotional states, thereby facilitating an enhancement in the patients’ emotional well-being following surgery.
Lidocaine is the most commonly used local anesthetic. In breast cancer surgery, liver lobectomy, abdominal and retroperitoneal surgery, intravenous infusion of lidocaine has been proven to effectively manage intraoperative pain, decrease postoperative pain scores, and reduce opioid consumption40,41. Additionally, it has been shown to lower the incidence of postoperative intestinal obstruction and PONV, facilitating the early recovery of intestinal function42. This study determined that the postoperative intestinal ventilation time in the OFA group was significantly reduced. This reduction may be attributed to the facilitation of intestinal function recovery by lidocaine, as well as the optimal analgesia provided by the OFA group, which supports early ambulation.
Intestinal surgery, laparoscopic surgery, and opioid administration during the perioperative period are recognized as significant risk factors for PONV43,44. In this study, we observed the occurrence of PONV in both patient cohorts; however, the incidence was significantly lower in OFA group. Although esketamine administration during the perioperative period can also contribute to PONV, its incidence is comparatively lower than that associated with opioid use. In this study, we employed an OFA protocol that primarily utilized QLB in conjunction with intravenous esketamine and lidocaine. This approach not only provides effective analgesia but also significantly reduces opioid consumption during the perioperative period, consequently decreasing the incidence of PONV. These findings are consistent with those reported by Feng et al.14 Furthermore, patients in the OFA group experienced shorter postoperative hospital stays. This outcome may be attributed to the superior analgesic efficacy of the OFA protocol and the enhancement of postoperative emotional well-being by esketamine, thereby facilitating patient recovery.
In this study, it was observed that patients in the OFA group experienced a significantly extended duration of anesthesia recovery and prolonged stays in PACU. This phenomenon may be attributed to the metabolism and retention characteristics of esketamine and its metabolites within the body45. As the D-isomer of ketamine, esketamine possesses a half-life ranging from 4 to 6 h when administered at a continuous infusion rate exceeding 0.5 mg·kg−1·h−1. It is prone to accumulation in adipose tissue, muscle, and other bodily tissues. Upon a reduction in blood concentration, esketamine is gradually released from these tissues back into the bloodstream, resulting in a “secondary distribution” that extends its central nervous system effects. Additionally, its metabolite, desesketamine, retains pharmacological activity, exerting sedative and analgesic effects through competitive antagonism of NMDA receptors and inhibition of glutamatergic neurotransmission. Even when blood concentrations of the drug decrease to sub-anesthetic levels, the continued antagonism of NMDA receptors may persistently influence the recovery of consciousness, thereby manifesting as prolonged emergence time. While Duan et al.46 proposed that esketamine could expedite recovery from isoflurane anesthesia in animal studies, subsequent investigations by Feng et al.14 and Massoth et al.47 indicated that esketamine may actually extend the recovery duration from anesthesia. These findings align with the results of our study.
This study has certain limitations. In this study, the administration of analgesic drugs such as esketamine and remifentanil during the operation was adjusted empirically based on intraoperative changes in blood pressure and heart rate. This approach lacked objective evidence as a basis to guide dosage adjustments, raising the possibility that the administered doses of analgesic drugs may have been either excessive or insufficient. Currently, various devices such as the Analgesia Nociception Index, Surgical Pleth Index, Pupillometry (AlgiScan/Neurolight), and the Nociception Level index are used to monitor noxious stimulation and analgesia during surgery48. However, owing to limitations and insufficient clinical evidence, they are not widely adopted49,50.

Conclusions
This study concluded that the opioid-free anesthesia approach, utilizing ultrasound-guided QLB in conjunction with intravenous esketamine infusion, may enhance the quality of early postoperative recovery in patients undergoing laparoscopic radical resection for colon cancer by alleviating postoperative pain and minimizing perioperative opioid-related adverse effects. Nevertheless, this strategy is associated with an extension of postoperative recovery duration and prolonged stay in PACU, and its effects on long-term postoperative recovery remain unclear.