FormalPara Key Summary Points

Why carry out this study?

Chronic postsurgical pain (CPSP) is hard to treat and is increasingly recognized as a public health problem.

Deep neuromuscular blockade (DNMB) can reduce acute postsurgical pain. However, there is still a lack of studies examining the effects of DNMB on CPSP.

The most recent peri-operative management guidelines for neuromuscular blockade recommend that more well-designed studies are needed to investigate if deep neuromuscular blockade (DNMB) is superior to moderate neuromuscular blockade (MNMB).

What was learned from this study?

DNMB significantly reduced the occurrence of CPSP in patients undergoing spinal surgery.

DNMB may relieve acute postsurgical pain and reduce postoperative opioid consumption.

DNMB improved long-term recovery quality in patients who have undergone spinal surgery.

Introduction

Lumbar degenerative disease, which causes pain and disability, is very common in the elderly population [1]. Currently, spinal surgery is performed to treat degenerative conditions of the lumbar spine [2]. The annual number of spinal surgeries is increasing [3], as are complex procedures and the age of patients [4]. Major spinal surgeries may cause significant postoperative pain [5]. An increased risk of chronic postsurgical pain (CPSP) is associated with high-intensity and persistent postoperative pain [6]. Pain lasting more than 3 months is defined as chronic pain [7], which is difficult to treat and is sometimes permanent [8]. Thus, an effective perioperative pain control strategy is essential to improving patient recovery after surgery and reducing the chronic pain risk [9].

Neuromuscular blocking agents are integral in general anesthesia [10]. Studies have shown that profound neuromuscular blockade during anesthesia can reduce postoperative pain scores [11,12,13,14] and improve conditions of surgical space [11, 12, 14,15,16]. Deep neuromuscular block (DNMB) in spinal surgery is associated with various advantages, such as lower airway pressure, lower pain and rescue opioid consumption [17], as well as less bleeding [18, 19].

However, the effects of DNMB on CPSP and long-term recovery quality have not been fully established. Therefore, we assessed whether DNMB can reduce the incidence of CPSP after spinal surgery. Further, the impact of DNMB on the quality of long-term recovery in patients undergoing spinal surgery was investigated.

Methods

Study Design and Patients

This randomized, double-blind study was registered on https://www.chictr.org.cn/ (ChiCTR2200058454) and approved by the ethics committee of the Affiliated Hospital of Xuzhou Medical University. This study was conducted between May 2022 and November 2022 at the Affiliated Hospital of Xuzhou Medical University. Written informed consent was obtained from all participants prior to their inclusion in the study.

A total of 220 patients aged > 18 years old who underwent spinal surgery under general anesthesia and scored between I and III on the American Society of Anesthesiologists (ASA) physical status scale were recruited. The exclusion criteria were: (i) Known rocuronium allergies; (ii) Known allergies to cisatracurium or neostigmine; (iii) Contraindications to the use of neostigmine, such as bronchial asthma, glaucoma, myocardial ischemia and epilepsy; (iv) Preoperative hyperalgesia; (v) History of spinal surgery or neuromuscular disease that may interfere with data collection; (vi) Communication disability; (vii) Peripheral neuropathy caused by diabetes; (viii) History of chronic analgesics treatment; (ix) History of drug or alcohol abuse and (x) body mass index (BMI) ≥ 35 kg/m2.

Patients were randomly assigned (1:1 ratio) to the DNMB group (D group) or the moderate NMB (MNMB) group (M group) using an online randomization system (https://www.randomizer.org) to generate a random number table. Two unblinded personnel that were not otherwise involved in the study packed 220 opaque envelopes based on a computer-generated randomization protocol. The participants were screened and included by blinded researchers. Each participant was randomly assigned an envelope on-site at the end of the screening process. All participants were blinded. Each randomization envelope was opened by an unblinded individual who ensured that the NMB level was appropriate according to allocation of treatments.

Perioperative Management

Before surgery, all participants fasted for 8 h. After entering the operating room, they were monitored using basic monitors such as electrocardiograms, pulse oximeters, and invasive blood pressure (IBP). A general anesthetic with endotracheal intubation was used for all surgical procedures. Anesthesia was induced using midazolam (0.05–0.10 mg/kg), etomidate (0.2–0.3 mg/kg), sufentanil (0.5 µg/kg), and rocuronium (1.0 mg/kg). The bispectral index (BIS) monitor (BIS VISTATM, Aspect Medical System, USA) was used to measure the depth of anesthesia during surgery. Neuromuscular functions were monitored using the Philips IntelliVue neuromuscular transmission (NMT) module (connected to Philips IntelliVue MP70/MX800 patient monitor, J. 10. 52; Philips, Amsterdam, The Netherlands) or a train-of-four (TOF)-Cuff NMT monitor (RGB Medical Devices S.A., Madrid, Spain).

Propofol (3–6 mg/kg h), remifentanil (0.1–0.3 µg/kg min), and sevoflurane (0–1 vol%) were utilized for anesthesia maintenance. Pum** rates of propofol and remifentanil were continuously adjusted to maintain the hemodynamic stability and reach a BIS value of 40–60. Cisatracurium was continuously infused at a rate of 0.06–0.12 mg/kg h to maintain muscle relaxation within the target range. The volume control mode was used to ventilate the patients, with a tidal volume of 6–8 ml/kg. A 35–45 mmHg end-tidal CO2 pressure was maintained by controlling the respiratory rate. Core temperatures were maintained above 36 °C and continuously monitored. Pump delivery of cisatracurium in the M group was started when the TOF count returned to 2. The TOF count was maintained between 1 and 3 by adjusting the pump rate. In the D group, after tracheal intubation for 15 min, a cisatracurium pump was started, and its rate was adjusted to maintain a post-tetanic count (PTC) in the 1–2 range. Cisatracurium infusion was temporarily stopped when muscle relaxation deepened in both groups until they returned to predefined levels. Muscle relaxation monitoring was on standby during transition from the supine-to-prone position and prone-to-supine position. Monitoring resumed when positional change was completed. Pump delivery of cisatracurium was stopped approximately 30 min before the end of surgery.

After surgery, the muscle relaxant monitoring mode was adjusted to a TOF mode in all patients. Then, they were administered with neostigmine 1 mg and atropine 0.5 mg when the TOF count returned to 2 or TOF exceeded 70%. The endotracheal tube was removed when the TOF returned to 90% and the patient completed movements, such as eye-opening and handshaking, as instructed by the anesthesiologist. After extubation, a mask of high-flow oxygen was administered. When blood oxygen saturation stabilized above 95%, patients were transferred to a post-anesthesia recovery unit (PACU) where routine monitoring was performed. Sufentanil (2 µg/kg) and tropisetron (6 mg) were used for patient-controlled analgesia (PCA). Moderate pain (VAS score 4–6) was treated with fentanyl 0.05 mg, and severe pain (VAS score 7–10) with fentanyl 0.1 mg, with an aim to reduce pain scores to less than or equal to 3. All patients were discharged to the ward after fulfilling the PACU discharge criteria.

Outcomes

Patients’ baseline characteristics and intraoperative data were carefully documented. The primary outcome was the incidence of CPSP, which was defined as pain with VAS ≥ 4 and lasting more than 3 months [20]. At the third month after surgery, patients were followed up over the telephone, and VAS scores were used to measure the current and past three months’ pain status. Secondary outcomes included VAS scores in PACU, at 12, 24, 48 h and 3 months after surgery; postoperative opioid consumption expressed in cumulative oral morphine equivalents; quality of recovery-15 (QoR-15) scores [21] on the second postoperative day, before discharge, and 3 months after surgery; consumption of propofol and remifentanil; time to extubation; hypoxemia incidences after extubation and readmission incidences due to pain.

Sample Size

The primary objective of this study was to determine whether DNMB can prevent CPSP after spinal surgery. In the pre-experiment, the incidence of CPSP in the MNMB group was about 35%. To detect a 50% difference in CPSP incidence, 97 patients in each arm were required at a two-sided level of significance of 0.05 and a power of 80%. Therefore, assuming a 10% dropout rate, we included 110 patients in each group.

Statistical Analysis

All statistical analyses were conducted using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov tests were used to assess the normality of continuous variables. Normally distributed variables were expressed as mean ± standard deviation (mean ± SD) while non-normally distributed variables were expressed as medians (interquartile range [IQR]). Continuous variables were compared between groups using the two-sample t test and Mann–Whitney U test, where appropriate. Categorical variables were expressed as numbers (percentages). Fisher’s exact test or chi-square test, where appropriate, were used to compare categorical variables. Analysis of continuous variables for intra-group comparisons over time was performed using repeated measures ANOVA followed by Bonferroni’s post hoc test. Repeated measures ANOVA models were sphericity tested using the Mauchly test and corrected for Greenhouse–Geisser sphericity as necessary. P values less than 0. 05 were considered statistically significant.

Results

Patient Selection

A total of 308 patients were assessed for eligibility, of which 220 patients were included and randomized. Among the 308 patients, 39 declined participation, seven had a history of spinal surgery, 28 had a history of chronic analgesic treatment and 14 had BMI ≥ 35 kg/m2. Then, 220 patients were randomized into two groups. Five patients in the M group and six in the D group were lost to follow-up. Therefore, 104 patients in the DNMB group and 105 patients in the MNMB group were finally analyzed (Fig. 1).

Fig. 1
figure 1

Flowchart of the patient selection procedure

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Patient Characteristics

Differences in demographic characteristics, including age, sex, height, weight, Charlson Comorbidity Index (CCI), and analgesic treatment between the groups were insignificant. Moreover, differences in surgical duration, type of surgery, and number of lumbar segments between the groups were insignificant. The total amount of rocuronium was similar between the two groups (p = 0.281), while the cisatracurium consumption was significantly more in the D group than M group (p < 0.001) (Table 1).

Table 1 Baseline characteristics and surgical data for the overall study population
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Primary Outcomes

There was CPSP in 45 of 105 patients (42.86%) in the M group, a significantly higher rate than in the D group (30/104, 28.85%, p = 0.035) (Table 2).

Table 2 Primary and secondary outcomes
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Secondary Outcomes

As shown in Table 2, lower VAS scores were observed at the third month (p = 0.016) in the D group. Regarding acute postoperative pain, there were significant interactions between the groups over time in terms of VAS scores (all p < 0.05). Pairwise comparisons in the PACU and 12 h after surgery revealed significantly higher VAS scores in the M group than in the D group (p < 0.001, p = 0.004, respectively) (Fig. 2). The total amount of opioid consumption postoperatively was more in the M group, than in the D group (p = 0.027) (Table 2). In Fig. 3, at 3 months after surgery, the D group had significantly higher quality of recovery-15 (QoR-15) scores than the M group (p = 0.003).

Fig. 2
figure 2

Comparisons of VAS scores at different time points after surgery between the two groups. *p < 0.05, compared with the M group

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Fig. 3
figure 3

Comparisons of QoR-15 scores after surgery between the groups. *p < 0.05, compared with the M group

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Differences between the groups in terms of total amount of propofol and remifentanil used during surgery were insignificant (p = 0.103, p = 0. 079, respectively). The D group had a significantly longer time to extubation (p < 0.001). Incidences of hypoxemia after extubation and readmission due to pain were comparable between the groups (p = 0.070, p = 0.277, respectively) (Table 2).

Discussion

Compared with MNMB, DNMB significantly reduced the incidence of CPSP and improved the long-term quality of recovery.

Physiologically, CPSP is pain (VAS score ≥ 4) that persists longer than 3 months after surgery and limits social activities [22]. It worsens the quality of life for patients, causing distress and impairment of functions [23]. Thus, there is an urgent need to develop better options for prevention and management of chronic pain [24]. There is a positive relationship between chronic pain and severe postoperative pain. Moreover, it is risky for chronic pain to develop after surgery when severe postoperative pain still exists [25, 26]. Reduced postoperative pain hastens functional recovery and hospital discharge, decreases acute morbidity, and may prevent chronic pain [27].

During anesthesia, DNMB reduces postoperative pain scores [11,12,13,14]. Moreover, DNMB confers several advantages in spinal surgery, such as lower airway pressure, lower pain and rescue opioid consumption [17], as well as less bleeding [18, 19]. However, a limited number of studies have assessed the effects of DNMB on CPSP and long-term recovery after spinal surgery. In this study, we found significantly reduced incidences of CPSP in DNMB patients. The incidence of CPSP was 28.85% in the D group and 42.86% in the M group. It was also found that DNMB reduced postoperative pain in the PACU and 12 h after surgery, and reduced postoperative opioid consumption. We speculate that the possible mechanism is that deep neuromuscular block can improve the surgical condition, reduce muscle traction, and decrease injury to muscle caused by surgery. In terms of QoR, patients in the DNMB group scored higher at 3 months after surgery. Nevertheless, the VAS scores at 24, 48 h after surgery and QoR-15 scores 2 days after surgery, before discharge were not significantly different between the two groups.

The extubation time was significantly earlier in the M group (p < 0.001) because longer time was needed for TOF count to return to 2 or for TOF% to exceed 70% in the D group. To reverse the blockade of neuromuscular functions, all participants were administered with neostigmine. Thus, deep NMB did not increase the incidence of hypoxemia after extubation.

The mechanisms by which acute pain becomes chronic pain have not been fully established [28]. The exact mechanisms that sustain chronic pain and underlie the transition between acute and chronic pain are unknown. Since postoperative pain can be a marker of chronic pain, reducing acute pain may reduce the transition from acute to chronic pain [29, 30]. We found that maintaining DNMB intraoperatively alleviated acute postoperative pain, which may be the key reason of low CPSP incidence in the D group.

Unlike previous studies, we investigated not only the effect of DNMB on postoperative pain, but also on CPSP and long-term QoR, which is a strength of this study. To the best of our knowledge, this is the first study to investigate the effects of DNMB on CPSP and long-term QoR. This study has several limitations. First, our study population only included patients who underwent lumbar surgery, while those who underwent cervical or thoracic surgery were excluded. Therefore, future studies should explore the effect of DNMB on cervical or thoracic surgery patients, which may be informative. Second, the mechanism and mediators of the interventions were not the focus of this study and need further research. Third, for simplicity, we chose a relatively simple QoR-15 scale rather than the QoR-40 scale. Fourth, a follow-up period longer than 3 months is required to evaluate the QoR. Finally, we did not record the surgeons’ scores for surgical working conditions.

Conclusions

In conclusion, compared with MNMB, DNMB significantly reduced CPSP and postoperative opioid consumption in spinal surgery patients. Moreover, DNMB improved the long-term recovery of patients.