Administration of neuromuscular blockade (NMB) improves surgical conditions and is thus essential for laparoscopic surgeries. Moreover, the use of deep NMB [posttetanic count (PTC) 1 to 2] during laparoscopic surgery results in a further improvement in the quality of surgical conditions compared with moderate NMB [train-of-four (TOF) 1 to 2].1–3 Previous studies, including a meta-analysis, showed that the use of deep NMB during laparoscopic surgery readily facilitates low-pressure pneumoperitoneum, the most important benefit of which is lower postoperative pain scores.4,5
A recent randomised controlled trial evaluated the effect of deep NMB and low-pressure pneumoperitoneum in laparoscopic hysterectomy and reported that deep NMB and low-pressure pneumoperitoneum reduced the incidence of postoperative shoulder pain compared with standard-pressure pneumoperitoneum with standard NMB6; however, the study design did not enable a distinction between the effects of deep NMB and low-pressure pneumoperitoneum, or whether the combination of the two had a synergistic effect. Theoretically, deep NMB may have an analgesic effect because it facilitates maximum stretching of abdominal wall muscle fibres, which leads to increased abdominal wall compliance during laparoscopic surgery and that may reduce pressure-related postoperative pain.7 Yet, there is a lack of interpretable and applicable data on whether deep NMB per se has analgesic effects on patients who underwent laparoscopic surgery.
Importantly, studies on the analgesic effect of deep NMB have shown conflicting results. One study showed that deep NMB resulted in less postoperative pain compared with moderate NMB in patients undergoing bariatric surgery.8 In contrast, Rosenberg et al.1 showed that deep NMB did not reduce the intensity of pain after laparoscopic cholecystectomy in comparison with moderate NMB. Taking these studies together,1,8 the question of whether the use of deep NMB affects postoperative pain scores after laparoscopic surgery remains unanswered. We evaluated the effect of depth of NMB during laparoscopic gastrectomy on postoperative pain in surgical patients by randomly allocating them to either deep or moderate NMB with a standard-pressure pneumoperitoneum.
Materials and methods
The current study is an investigator-initiated, randomised, double blind clinical trial. The study protocol was approved by the institutional review board of Asan Medical Centre (2017-0966, Seoul, Republic of Korea), and registered before patient enrolment at ClinicalTrials.gov (NCT03266419, principal investigator: C-BM, date of registration: 30 August 2017). Patients eligible for inclusion were scheduled for laparoscopic gastrectomy, aged 20 to 65 years, and American Society of Anesthesiologists Physical Status 1 to 3. Patient exclusion criteria included known hypersensitivity to rocuronium or sugammadex, clinically significant laboratory findings, evidence of pregnancy, pre-operative visual analogue scale (VAS) score at least 1, history of abdominal surgery and neuromuscular disease that may interfere with neuromuscular data, and BMI at least 35 kg m−2. Written informed consent was obtained from all patients. Patients were randomly assigned to deep or moderate NMB group in a ratio of 1 : 1. Computer-generated random allocations sequence by simple randomisation was performed. Patient randomisation was undertaken by a coordinator who was not involved in this study. One investigator, who was blinded to the group allocation, assessed the variables related to postoperative pain in all patients. The five surgeons who rated the surgical condition scores were also blinded to the group allocation.
All patients were fasted from midnight, and received no premedication. In the operating theatre, the patients were monitored using electrocardiography and pulse oximetry, and their end-tidal carbon dioxide partial pressure, noninvasive blood pressure and bispectral index (BIS monitor; Covidien, Boulder, Colorado, USA) were measured. Neuromuscular transmission was monitored using the M-NMT module at the adductor pollicis muscle (Carescape B850; GE Healthcare, Milwaukee, Wisconsin, USA). Throughout surgery, all these data were continuously downloaded to personal computers using RS232C cables. Following pre-oxygenation with 100% O2, anaesthesia was induced with propofol and remifentanil, which were administered using an effect-site concentration target-controlled infusion pump (Perfusor Space; B. Braun Melsungen, Melsungen, Germany).9,10 Tracheal intubation was facilitated with rocuronium (0.6 mg kg−1), and the patients’ lungs were ventilated with oxygen in air (1 : 1). The ventilation rate was adjusted to maintain the end-tidal carbon dioxide partial pressure between 4.7 and 6.0 kPa. For the deep NMB group an intravenous bolus of rocuronium (0.7 mg kg−1) was given 2 min after intubation, followed by a continuous rocuronium infusion at 0.8 to 1.2 mg kg−1 h−1 to maintain deep NMB (PTC 1 to 2) during surgery. The PTC was measured every 5 min. In case of deviation from the target PTC, the pump speed was adjusted or a bolus dose (10 mg) was given. For the moderate NMB group no further loading dose of rocuronium was given. An intravenous infusion of rocuronium (0.2 to 0.6 mg kg−1 h−1) was started at a TOF count of 1 to maintain a moderate NMB (TOF 1 to 2) during surgery. TOF was measured every 5 min. In case of deviation from the target TOF, the pump speed was adjusted or a bolus dose (10 mg) was given. The target effect-site concentration of propofol was adjusted within a range of 2.5 to 3 μg ml−1 to maintain the BIS values at less than 60 during the induction and maintenance of anaesthesia. The target effect-site concentrations of remifentanil was titrated within a range of 2 to 20 ng ml−1 to maintain stable haemodynamic parameters [SBP > 80 mmHg, heart rate (HR) > 45 bpm]. If necessary, ephedrine or atropine was administered to maintain SBP above 80 mmHg and HR above 45 bpm during anaesthesia. Abdominal pressure was maintained at 13 mmHg during the laparoscopic surgery. When surgeons asked for muscle relaxation to obtain a visible laparoscopic field, an additional bolus dose of rocuronium (10 mg) was given.
All patients received a bolus dose of oxycodone (0.05 mg kg−1) at the end of pneumoperitoneum. Intravenous patient-controlled analgesia (IV PCA) with oxycodone was started after the administration of a loading dose. A semi-electronic pump (AutoMed 3200; Ace Medical, Seoul, Republic of Korea) was used for PCA with a demand bolus of 1 ml, background infusion of 1 ml h−1 and lock-out time of 15 min. The concentration of oxycodone in IV PCA bag was 1 mg ml−1, and the volume of oxycodone-normal saline mixture delivered to patients for approximately 4 days was 200 ml. Rocuronium infusions were discontinued after deflation of the CO2 pneumoperitoneum. The duration of pneumoperitoneum was recorded. After the end of surgery, a single intravenous bolus dose of sugammadex 2 or 4 mg kg−1 was administered for reversal of moderate or deep NMB, respectively. Tracheal extubation was performed when the TOF ratio was greater than 0.9 and the BIS value was greater than 80. After the end of surgery, patients were taken to the postanaesthesia care unit (PACU) and assessed for pain every 10 min using the VAS (0 = no pain; 10 = most severe pain). Pain was measured at rest and when the wound areas were compressed with a force of 20 N (i.e. 2 kg of pressure imposed by three fingers on a 10 cm2 area). The wound compression was performed by an investigator blinded to group allocation who was trained with an algometer (Commander Algometer, J Tech Medical Industries, Midvale, Utah, USA) for consistent application of force. The patients were given intravenous oxycodone 2 mg (body weight <80 kg) or 3 mg (≥80 kg) every 10 min until the pain intensity had decreased to a VAS score of less than 3 at rest and less than 5 on wound compression, at which point the minimum effective analgesia dose (MEAD) of oxycodone was determined.11 The VAS scores for wound and shoulder pain were also assessed at 6 and 24 h after the end of surgery. Postoperative nausea and vomiting were evaluated using the Rhodes index of nausea vomiting and retching at 6 and 24 h after the end of surgery.12 After the end of surgery, surgeons scored the surgical working conditions according to a five-point surgical rating scale ranging from 1 (extremely poor conditions) to 5 (optimal conditions).13 Good to optimal ratings (scores of 4 to 5) in the surgical condition scores were regarded as acceptable.2 Postoperative pain management in the general wards was conducted by general surgeons according to the usual clinical practice in the Department of Surgery: patients received 50 mg tramadol when the numerical rating scale (NRS) for pain was at least 4. The research process is summarised in Fig. 1.
The primary endpoint was the MEAD of oxycodone in the PACU. A preliminary study to determine the appropriate sample size was conducted by measuring the MEAD of oxycodone in 13 patients. The mean ± SD values were 9.0 ± 3.96 for the deep NMB group and 13.3 ± 7.97 for the moderate NMB group. On the basis of this observation, a sample size of 50 patients per treatment arm was calculated to be sufficient to allow the detection of a 4-mg difference in the MEAD of oxycodone, with 90% power at an alpha of 0.05. All statistical analyses were conducted using R (version 3.5.1; R Foundation for Statistical Computing, Vienna, Austria) or SigmaStat 3.5 for Windows (Systat Software, Chicago, Illinois, USA). Normally distributed continuous variables are expressed as mean ± SD, nonnormally distributed variables as median [25 to 75th centile], and categorical variables as counts (%). Outcome variables between the two groups were compared using the two-sample t test, Mann–Whitney rank sum test or χ2 test as appropriate. The area under the curve (AUC) of VAS for wound pain was calculated by noncompartmental methods (WinNonlin Professional 6.3; Pharsight, St. Louis, Missouri, USA). P values less than 0.05 were considered as statistically significant.
A consort diagram of the study is shown in Fig. 2. A total of 122 surgical patients scheduled for elective laparoscopic gastrectomy were enrolled in this study and the data from 100 were analysed. There was no statistically significant difference between the two groups in terms of baseline patient characteristics (Table 1). The median value of the MEAD of oxycodone was 8 mg in both groups. Likewise, variables associated with postoperative pain including mean VAS in the PACU and frequency of rescue analgesics in the ward did not differ significantly between the groups (Table 2). VAS changes while resting and during wound compression in the PACU are presented in Supplementary Fig. 1S, https://links.lww.com/EJA/A222. AUCs of VAS over time were similar in both groups (Table 2). The surgical rating scores evaluated by surgeons are shown in Fig. 3. The number of patients attaining the acceptable surgical score was not significantly different between the two groups. However, the proportion of cases that required additional muscle relaxants was significantly higher in the moderate group (Table 2). Of the moderate group, 18 patients received one (n = 12), two (n = 5) or three (n = 1) additional 10 mg doses of muscle relaxant during anaesthesia. Deep NMB was not observed in the moderate group after the administration of the additional muscle relaxant. The relationship between the duration of pneumoperitoneum and the MEAD of oxycodone is shown in Fig. 4; although the two variables were not highly correlated (Pearson correlation coefficient r = 0.226), a statistically significant positive correlation was observed (P = 0.024), indicating that longer duration of pneumoperitoneum was associated with greater postoperative pain.
To the best of our knowledge, this is the first study to evaluate the effect of depth of NMB on postoperative pain using the minimum effective analgesic dose (MEAD), which is a relatively objective variable. Compared with moderate NMB, deep NMB did not significantly reduce the MEAD of oxycodone administered in the PACU but the duration of pneumoperitoneum was positively correlated with MEAD.
The results of this study indicate that deep NMB during surgery does not affect postoperative pain significantly, which is in agreement with the results of a previous study by Madsen et al.,6 who reported that incisional pain and lower abdominal pain over 4 days were not significantly different between patients who received deep NMB and low-pressure pneumoperitoneum and those who received moderate NMB and standard-pressure pneumoperitoneum6; the authors, however, reported that the incidence of shoulder pain after laparoscopic hysterectomy was lower in the deep NMB/low-pressure pneumoperitoneum group, which may be due to the operating position (steep Trendelenburg) used during laparoscopic hysterectomy. In the steep Trendelenburg position, shoulder supports are frequently used to prevent patients from slipping, and consequently, the weight of the entire body is concentrated on the shoulders, leading to pain after surgery. On the other hand, laparoscopic gastrectomy is performed in the reverse-Trendelenburg position with no weight on the shoulders during surgery. Accordingly, our patient cohorts reported little postoperative shoulder pain (Table 2). Subcutaneous emphysema caused by pneumomediastinum may be related to shoulder pain.14 However, in our current study, we did not observe any changes related to subcutaneous emphysema (crepitus, insufflation problem or intra-operative increase in partial pressure of end-tidal CO2 > 5.3 kPa). Another study showed that deep compared with moderate NMB did not result in a significant difference in postoperative pain in patients undergoing laparoscopic cholecystectomy, albeit that postoperative pain assessment was not the primary endpoint of the study and the study had an inadequate sample size for drawing a firm conclusion on this matter.1 In addition, in our current study, the muscle relaxation was reversed immediately by administration of sugammadex at the end of surgery, thereby possibly masking the effect of deep NMB on pain immediately after surgery. Collectively speaking, increased abdominal wall compliance induced by deep NMB does not seem to reduce postoperative pain.
A number of previous studies showed that deep NMB improved the quality of surgical conditions compared with moderate NMB.1–3,13 However, in our current study, there was no significant difference in the five-point surgical rating scale between the two groups. This could be explained by the fact that the moderate NMB group had a significantly higher proportion of cases requiring additional muscle relaxants. As a whole, our results are not in contradiction with those of previous studies. The fact that there was no significant difference in the five-point surgical rating scale between the two groups may be influenced by the surgical proficiency of our surgeons. Stomach cancer is the most prevalent type of cancer in the Republic of Korea,15 and laparoscopic surgery is carried out frequently in patients with stomach cancer.16 In our hospital, about 1300 cases of laparoscopic gastric cancer surgery are performed annually, which enables our surgeons to be highly skilled in laparoscopic surgery. The depth of muscle relaxation does not have significant effects on the course of the surgery, provided that a certain degree of surgical condition is secured for the surgeons. Even in the case of laparoscopic cholecystectomy, in which the operation is relatively easy, better surgical space conditions were marginally associated with deep NMB than with moderate muscle relaxation (P = 0.05).17
It is not difficult to accept that a longer duration of pneumoperitoneum will be associated with a higher MEAD. A longer duration of pneumoperitoneum would lead to more pressure-related postoperative pain although its contribution to MEAD was only 7%, which means that the influence of the duration of pressure maintenance was not large. Multiple factors, including patient characteristics as well as type and extent of surgery, contribute to postoperative pain,18 and it seems reasonable that the power of the contribution to MEAD from the duration of pneumoperitoneum was low.
The current study is limited in the following aspects. First, pain assessment was performed only until 24 h after the end of surgery. It is possible that pain on the 2nd or 3rd day after surgery may differ between the two groups. However, because the effect of muscle relaxation is completely reversed by sugammadex,19 the effect of deep NMB on postoperative pain can be expected to occur mainly in the PACU. It is also difficult to expect the effect of muscle relaxation on postoperative pain to last for more than a day. For these reasons, we assessed pain only up to 1 day after the end of surgery. We also retrospectively reviewed the medical records of the study patients and found that postoperative pain assessed by the NRS until the 4th postoperative day was similar between the two groups (Supplementary Fig. 2S, https://links.lww.com/EJA/A222). It is well known that acute pain after surgery can be converted to chronic pain.20 In this study, we could not determine whether the depth of NMB affects chronic postsurgical pain (CPSP), which is defined as the persistence of pain for at least 3 months after a surgical procedure.21 There are multiple risk factors for the development of CPSP.21 A previous study showed that the incidence of CPSP was higher in patients undergoing open cholecystectomy than in those undergoing laparoscopic cholecystectomy,22 another study showed that early postoperative pain was the only factor that was significantly associated with CPSP,23 as patients who later developed CPSP had had significantly greater pain intensity on the first postoperative day than did those who did not develop CPSP.23 Taken together, it is unlikely that deep block will significantly reduce the incidence of CPSP. Further targeted studies are needed to clarify this. Third, it may be difficult to generalise the results of this study to other laparoscopic procedures. For example, in patients receiving bariatric surgery, deep NMB resulted in significantly lower pain score than did moderate NMB, as assessed by NRS in PACU. Therefore, the effect of deep NMB in postoperative pain compared with moderate NMB should be evaluated specifically in other laparoscopic procedures.
In conclusion, in patients who underwent elective laparoscopic gastrectomy, compared with moderate NMB, deep NMB did not significantly reduce the MEAD of oxycodone administered in the PACU. Although the explanatory power was low, our results also showed that the duration of pneumoperitoneum may affect the determination of the MEAD.
Acknowledgements relating to this article
Assistance with the study: the authors are grateful to H-K Jin, MPH, and J-S Yang, MPH (Research Associates, Department of Anesthesiology and Pain Medicine, Asan Medical Center), for supporting the clinical trial progress and preparing the data used in this study. We thank Dr Joon Seo Lim, from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this article.
Financial support and sponsorship: this work was supported in part by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this article are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.
Conflicts of interest: none.
1. Rosenberg J, Herring WJ, Blobner M, et al. Deep neuromuscular blockade improves laparoscopic surgical conditions: a randomized, controlled study. Adv Ther
2. Koo BW, Oh AY, Na HS, et al. Effects of depth of neuromuscular block on surgical conditions during laparoscopic colorectal surgery: a randomised controlled trial. Anaesthesia
3. Park SK, Son YG, Yoo S, et al. Deep vs. moderate neuromuscular blockade during laparoscopic surgery: a systematic review and meta-analysis. Eur J Anaesthesiol
4. Ozdemir-van Brunschot DM, van Laarhoven KC, Scheffer GJ, et al. What is the evidence for the use of low-pressure pneumoperitoneum? A systematic review. Surg Endosc
5. Hua J, Gong J, Yao L, et al. Low-pressure versus standard-pressure pneumoperitoneum for laparoscopic cholecystectomy: a systematic review and meta-analysis. Am J Surg
6. Madsen MV, Istre O, Staehr-Rye AK, et al. Postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum: a randomised controlled trial. Eur J Anaesthesiol
7. Warle MC, Dahan A. Does deep neuromuscular block affect pain after laparoscopic surgery? Eur J Anaesthesiol
8. Torensma B, Martini CH, Boon M, et al. Deep neuromuscular block improves surgical conditions during bariatric surgery and reduces postoperative pain: a randomized double blind controlled trial. PLoS One
9. Schnider TW, Minto CF, Gambus PL, et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology
10. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology
11. Choi BM, Lee YH, An SM, et al. Population pharmacokinetics and analgesic potency of oxycodone. Br J Clin Pharmacol
12. Lee YH, Seo JH, Min KT, et al. Population pharmacokinetics and prophylactic antiemetic efficacy of ramosetron in surgical patients. Br J Clin Pharmacol
13. Martini CH, Boon M, Bevers RF, et al. Evaluation of surgical conditions during laparoscopic surgery in patients with moderate vs deep neuromuscular block. Br J Anaesth
14. Suzuki K, Ushiyama T, Ihara H, et al. Complications of laparoscopic adrenalectomy in 75 patients treated by the same surgeon. Eur Urol
15. Park DJ, Han SU, Hyung WJ, et al. Long-term outcomes after laparoscopy-assisted gastrectomy for advanced gastric cancer: a large-scale multicenter retrospective study. Surg Endosc
16. Honda M, Hiki N, Kinoshita T, et al. Long-term outcomes of laparoscopic versus open surgery for clinical stage I gastric cancer: the LOC-1 study. Ann Surg
17. Staehr-Rye AK, Rasmussen LS, Rosenberg J, et al. Surgical space conditions during low-pressure laparoscopic cholecystectomy with deep versus moderate neuromuscular blockade: a randomized clinical study. Anesth Analg
18. Gerbershagen HJ, Pogatzki-Zahn E, Aduckathil S, et al. Procedure-specific risk factor analysis for the development of severe postoperative pain. Anesthesiology
19. Fuchs-Buder T, Meistelman C, Raft J. Sugammadex: clinical development and practical use. Korean J Anesthesiol
20. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet
21. Pozek JP, Beausang D, Baratta JL, et al. The acute to chronic pain transition: can chronic pain be prevented? Med Clin North Am
22. Stiff G, Rhodes M, Kelly A, et al. Long-term pain: less common after laparoscopic than open cholecystectomy. Br J Surg
23. Katz J, Jackson M, Kavanagh BP, et al. Acute pain after thoracic surgery predicts long-term postthoracotomy pain. Clin J Pain