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Neuromuscular blocking agents

Deep vs. moderate neuromuscular blockade during laparoscopic surgery

A systematic review and meta-analysis

Park, Sun-Kyung; Son, Young G.; Yoo, Seokha; Lim, Taeyoon; Kim, Won Ho; Kim, Jin-Tae

Author Information
European Journal of Anaesthesiology: November 2018 - Volume 35 - Issue 11 - p 867-875
doi: 10.1097/EJA.0000000000000884

Abstract

Introduction

Compared with open techniques, laparoscopic surgery has the advantages of less severe postoperative pain, shorter hospital stay, better cosmetic results and improved patient satisfaction.1 During laparoscopic surgery, the working and viewing space is created by insufflation of carbon dioxide (CO2) into the abdominal cavity to produce a pneumoperitoneum. It has been postulated that deep neuromuscular blockade (NMB) promotes better surgical conditions when pneumoperitoneum is created during laparoscopic surgery.2 However, the use of deep NMB may be associated with complications including longer reversal times, recurarisation or incomplete recovery of NMB compromising respiratory and upper airway function.3–5 The introduction of sugammadex has enabled rapid and effective reversal of deep NMB, even immediately after administration of high-dose rocuronium.6,7 In previous randomised trials, the use of sugammadex enabled the evaluation of deep NMB on surgical conditions without any consequences on postoperative patient conditions.

Recently, increasing evidence suggests that deep NMB contributes to improved surgical space conditions during laparoscopic surgery.8,9 Furthermore, deep NMB has been shown to reduce postoperative surgical wound and shoulder pain and shorten the duration of surgery.10–12 However, previous comparisons of surgical conditions between deep and shallow block were made using different rating scales at varying intervals and different abdominal pressures,12,13 with inconsistent results. A previous randomised trial found no difference in the surgical field score between deep and moderate block,14 another study reported no significant benefit of deep compared with moderate NMB during low-pressure laparoscopic cholecystectomy.15 Furthermore, although several studies reported that deep block was associated with less postoperative surgical wound and shoulder pain,9,10,16 postoperative analgesic consumption was not different between deep and moderate NMB.12,16,17 Hence, the benefit of deep NMB remains controversial and previous studies may have been biased by the surgical rating scales used and variable intra-abdominal pressures.

Therefore, to draw a comprehensive, evidence-based conclusion, we conducted a systematic review and meta-analysis on whether deep NMB improves surgical working conditions during laparoscopic surgery and prevents postoperative complications. To address the heterogeneity of previous studies, we attempted to evaluate the effect of different measurements of surgical field conditions and variable abdominal pressures on surgical rating scale.

Methods

The current systematic review with meta-analysis comparing deep with moderate NMB during laparoscopic surgery was performed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions18 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements.19 The research question was formulated according to the Participants, Interventions, Comparisons and Outcome model: P, adult patients undergoing any laparoscopic surgery; I, deep NMB; C, moderate NMB; O, the frequency of excellent or good surgical conditions on a rating scale as estimated by the surgeon. Our review protocol is available at https://doi.org/10.6084/m9.figshare.5649292.

We included only randomised controlled trials (RCTs) conducted in adult patients undergoing any kind of laparoscopic surgery that compared deep with moderate NMB as a variable that may influence surgical conditions. We reported surgical conditions on a rating scale regardless of the frequency of measurements. We also reported the incidence and severity of postoperative surgical wound and shoulder pain. Deep NMB was defined as a train-of-four (TOF) count of 0 with a posttetanic count (PTC) of 1 to 2; moderate NMB was defined as a TOF count of 1 to 3. One of the authors (S-KP) independently conducted searches of Medline via the PubMed interface, the EMBASE database and the Cochrane Central Register of Controlled Trials (Central, Issue 10 of 2017) from inception to October 2017. Two other authors (WHK, YGS) independently reviewed titles and abstracts of all studies found by the search to identify eligible trials. The search strategy is described in Supplemental Text S1, https://links.lww.com/EJA/A174. We also searched conference abstracts and reference lists of included articles for eligible studies.

Data were independently extracted from included studies by two authors (WHK, S-KP) using a uniform data extraction form developed by the authors. Discrepancies were resolved by discussion. We contacted principal investigators for further details of trial results. We extracted the following information from each trial: first author of the study, year of publication, number of enrolled patients, age distribution in both groups, inclusion and exclusion criteria, intervention in the deep NMB group, information regarding reversal of NMB, clinical setting, study design and outcome data.

Risk of bias of individual studies was assessed using domains described in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0.18 Two authors (WHK, S-KP) independently reviewed all included studies and assigned a ‘high’, ‘low’ or ‘unclear’ risk of bias, according to their judgement, across the following domains: allocation concealment, random sequence generation, blinding of participants and personnel, blinding of outcome assessment, selective reporting and incomplete outcome data. Disagreements were resolved by discussion between the two assessors and a third outside assessor, who provided arbitration.

The frequency of excellent or good rating on a surgical rating scale was the primary outcome of our meta-analysis, regardless of whether it was reported as a single or multiple scores in the same patient.8–10,12–15,20 Rating of surgical working conditions was estimated by the surgeon during the laparoscopic procedure. The frequencies of excellent or good ratings were extracted from studies reporting only one assessment9,12,14,20 or as a single representative value (e.g. worst during surgery) of multiple ratings,8,15 or calculated from the distribution of entire ratings measured repeatedly.10,13 A rating of excellent (or optimal) and good on a four or five-point scale was considered as the primary outcome. In the study by Rosenberg et al.,20 which used an 11-point score, scores of 8, 9 and 10 were considered as excellent or good on the surgical rating scale.

Secondary outcomes included the surgical rating scale as continuous variable,10,13,14,21 duration of surgery,8–10,12–17,21 analgesic consumption in the postanaesthesia care unit (PACU)9,10,12,17 and the incidence of postoperative nausea and vomiting (PONV) in the PACU.10,12,17 Analgesic consumption was defined as the postoperative consumption of morphine or equivalent doses of fentanyl and oxycodone.

Data were analysed using Review Manager 5.3 (RevMan; The Cochrane Collaboration, Oxford, United Kingdom). A random-effects model (Mantel–Haenszel method for a dichotomous outcome and inverse variance method for a continuous outcome) was used to estimate the effect size of outcome variables. The effect size was expressed as a pooled odds ratio (OR), mean difference or standardised mean difference (SMD) with 95% confidence interval (CI), and a forest plot. Heterogeneity between studies was evaluated using the I2 test.22,23 Statistically significant heterogeneity was considered to be present when I2 was more than 50%. Heterogeneity of the primary outcome was explored by the following subgroup analyses. First, subgroup analysis was performed according to the frequency of intra-operative surgical rating, on whether single9,12,14,20 vs. multiple assessments8,10,13,15 were carried out. We performed this analysis to evaluate the effect of the frequency of assessment of surgical conditions on the primary outcome. Second, subgroup analysis was performed according to abdominal pressures with the same, fixed abdominal pressures in both groups,8,10,14,20 with variable pressures, but across the same range in both groups.12,13,15

Trial sequential analysis was performed for our primary outcome variable using the TSA version 0.9.5.5 (Copenhagen: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, 2016).24,25 The required information size was estimated to be 840 using an incidence of excellent or good rating of 77.9% for deep NMB group and 62.3% for moderate NMB group with an 80% power and alpha error of 5%. Two-sided 5% symmetrical O′Brien–Fleming significance boundaries were depicted.

Publication bias could not be assessed adequately because only eight studies were included for assessment of the primary outcome. Inspection of funnel plots has limited value when the sample size is small and Egger's test is not recommended unless at least 10 studies are included in the analysis.26 A two-sided P value of 0.05 or less was considered statistically significant. ORs were considered statistically significant when the 95% CI did not include 1.0.

The sample size was not calculated prior to analysis, but study power was calculated with the sample size used in our analysis. With a sample size of 579 patients to compare surgical rating between groups, using the pooled frequency of excellent or good surgical rating in a moderate block of 62.3%, there was about 98% power to detect the observed difference of 15.6%. For the subgroup analysis according to the frequency of assessment of surgical conditions, 272 patients provided 99.9% power to detect the observed difference of 30.8%. For the subgroup analysis according to abdominal pressures, with a sample size of 260 patients, there was also 99% power to detect the observed difference of 30.0%.

Results

Supplemental Fig. S1, https://links.lww.com/EJA/A174 shows search results and reasons for exclusion from the study. After screening 3618 titles and abstracts, we excluded 640 duplicate studies and 2910 studies that did not meet the inclusion criteria. After carefully reviewing the full text of the remaining 68 studies, 57 were excluded due to the reasons shown. Finally, 11 RCTs comparing deep NMB with moderate (or shallow) NMB were included in the meta-analysis.8–10,12–17,20,21

Study characteristics are summarised in Table 1. All studies were published between 2014 and 2017. Overall, 844 patients who underwent laparoscopic procedures with 423 patients in deep NMB group and 421 in moderate NMB group were included (Supplemental Table S1, https://links.lww.com/EJA/A174). Of the nine studies reporting surgical rating, one study used an 11-point scale,20 five studies used a five-point scale9,10,13,14,21 and three studies used a four-point scale to assess surgical condition.8,12,15 The incidence of an excellent or good rating on the surgical rating scale was available in eight studies; one study reported surgical rating scale only as mean and SD.21 Two studies enrolled obese patients scheduled to undergo elective bariatric surgery.10,14

T1-9
Table 1:
Characteristics of included studies

Details of the assessment of the risk of bias are summarised in Supplemental Fig. S2, https://links.lww.com/EJA/A174. Six trials were judged to be at low risk in all the domains.8–10,12,14,21 Ten trials generated adequate randomised sequences8–10,12–16,20,21 and eight used appropriate allocation concealment.8–10,12,14–16,21 Nine RCTs were double-blinded8–10,12–14,17,20,21; outcome assessment was blinded in all studies.

Eight studies including 579 patients were available for analysis of the frequency of excellent or good surgical rating.8–10,12–15,20 Pooled analyses showed that the frequency of excellent or good surgical rating was significantly higher with deep compared with moderate NMB, with significant heterogeneity between studies (OR 2.83, 95% CI 1.34 to 5.99, P = 0.007, I2 = 59%). Subgroup analysis according to the reported frequency of assessment of surgical conditions revealed that the primary outcome was not significantly different when rating of surgical conditions from a single assessment was compared (OR 2.03, 95% CI 0.76 to 5.45, P = 0.16, I2 = 66%); however, it was significantly different when multiple assessments were compared (OR 4.29, 95% CI 1.62 to 11.35, P = 0.003, I2 = 26%) (Fig. 1). When we analysed the primary outcome at different abdominal pressures, the results were mixed. Subgroup analysis of studies performed under the same, fixed insufflation pressure revealed no significant difference between the two groups (OR 2.50, 95% CI 0.72 to 8.61, P = 0.15, I2 = 76%). However, subgroup analysis of studies under variable pressure, but across the same range, showed a significant difference (OR 3.13, 95% CI 1.45 to 6.76, P = 0.004, I2 = 0%) (Fig. 2).

F1-9
Fig. 1:
The frequency of rating as excellent or good on the surgical rating scale in all studies and subgroup analysis of single and multiple assessments on the surgical rating scale. CI, confidence interval; M–H, Mantel–Haenszel method.
F2-9
Fig. 2:
Subgroup analyses of the frequency of rating as excellent or good on the surgical rating scale according to different insufflation pressures.

The results of analysis of secondary variables are shown in Supplemental Fig. S3, https://links.lww.com/EJA/A174. Rating of surgical conditions as a continuous variable was significantly better (towards excellent) with deep compared with moderate block (mean difference 0.69, 95% CI 0.45 to 0.92, P < 0.00001, I2 = 52%). Postoperative analgesic consumption in the PACU was not different between groups with significant heterogeneity between studies (SMD 0.03, 95% CI −0.43 to 0.48, P = 0.91, I2 = 76%). Duration of surgery was significantly shorter with deep compared with shallow block (mean difference −3.36, 95% CI −6.14 to −0.58, P = 0.02, I2 = 12%). The incidence of PONV in the PACU was not different between groups, with no heterogeneity between studies (OR 0.92, 95% CI 0.49 to 1.72, P = 0.80, I2 = 0%).

Trial sequential analysis showed that the cumulative z-curve crossed the conventional boundary and the O′Brien–Fleming significance boundary for the outcome of excellent or good rating (Fig. 3). However, required information size was not achieved, showing that more studies are required and there is insufficient data to support the conclusions.

F3-9
Fig. 3:
Trial sequential analysis of deep vs. moderate block. The cumulative z-curve crossed the conventional boundary and the O’Brien–Fleming significance boundary for the outcome of excellent or good rating. However, required information size was not achieved, showing that further studies are required to support the conclusions.

Funnel plots analysis has limited value to assess publication bias, due to the small number of included studies (n<10).

Discussion

The meta-analysis compared rating of surgical conditions between deep and moderate NMB in patients who underwent laparoscopic procedures. Pooled analysis showed that deep NMB was associated with excellent or good surgical rating more often than moderate NMB, suggesting that deep NMB produces better surgical working conditions; however, there was significant heterogeneity between studies. The heterogeneity may be due to different frequencies of assessment of surgical conditions and variable intra-abdominal pressures, as suggested on subgroup analyses. Surgical rating was not significantly different on subgroup analysis of studies that used a single overall surgical assessment, whereas it was significantly different on pooling studies that used multiple assessments. This suggests that multiple assessments of surgical conditions increase the sensitivity to detect a difference. With the same, fixed intra-abdominal pressure, surgical rating was not significantly different suggesting that the benefit of deep NMB may be confounded by different abdominal pressures.

Pneumoperitoneum results in adverse physiological effects27 that may be worse at higher insufflation pressures. Therefore, it may be beneficial to maintain minimal intra-abdominal pressure during laparoscopy. Deep NMB may help perform laparoscopic surgery at lower CO2 insufflation pressures. In a previous study, the intra-abdominal pressure was adjusted by the surgeon with the use of deep or moderate NMB as the primary endpoint.9 As expected, the mean adjusted intra-abdominal pressure was lower in deep compared with moderate NMB.

Our meta-analysis corroborates these findings, with improved surgical conditions under deep NMB on assessment using the surgical rating scale. Optimal surgical condition may be achieved by improving surgical space volume by relaxation of abdominal muscles and preventing sudden muscle contractions. A previous study measured the volume of CO2 introduced and the skin to sacral promontory distance (SSPD) to compare deep and moderate NMB, with pneumoperitoneum at both 8 and 12 mmHg.28 Both volume and SSPD were significantly higher with deep compared with moderate NMB at both levels of pressures. Mean increase in SSPD was higher at an intra-abdominal pressure of 12 mmHg compared with 8 mmHg. However, the benefit of deep block on surgical field condition was NS when we performed subgroup analysis of procedures performed at the same, fixed intra-abdominal pressure. This suggests that previous studies may have been influenced by both the degree of NMB and the intra-abdominal pressure. Intra-abdominal pressure may be more important than the degree of NMB in determining surgical conditions.

Assessment using a surgical rating scale is a subjective measurement and may be subject to individual variability. Most studies did not define clear criteria to rate surgical conditions; they were reported on a four, five or 11-point scale from excellent to extremely poor. One of the studies addressed this issue and assessed surgical conditions according to predefined criteria.13 The study also evaluated the agreement of rating by the surgeons and the anaesthetist in urological procedures, but found little agreement. A recent study investigated intrarater and interrater reliability of the surgical rating scale during laparoscopy. They reported an intrarater correlation coefficient of 0.76 and an interrater correlation coefficient of 0.57 on a five-point rating scale.29 Therefore, our meta-analysis should be interpreted with caution as our primary outcome was pooled from subjective evaluations from different assessors. Also, we demonstrated that assessment of surgical conditions may differ according to the frequency of measurements during surgery. Some studies reported a single overall rating at the end of surgery,9,12,14,20 whereas others performed multiple intra-operative ratings.8,10,13,15 Subgroup analysis showed that only the comparison of surgical rating from multiple assessments was found to be significantly different. Future studies should include repeated assessments during surgery including the critical times of the procedure, to increase the sensitivity to detect any changes in surgical field conditions.

The type of surgery may play a role when we evaluate the effect of deep NMB on the surgical conditions. A recent study compared an overall surgeon rating in laparoscopic bariatric surgery and reported no difference between deep and moderate NMB.14 The authors attributed this to the specific type of surgery. The retroperitoneal approach used in nephrectomy or prostatectomy is more confined than intraperitoneal surgery and may benefit more from deep NMB. However, another study in bariatric surgery with multiple assessments of surgical conditions reported a significant benefit with deep NMB.10 This may also suggest the importance of multiple assessments.

Previous studies reported that the severity of postoperative wound pain and the incidence of shoulder pain were significantly lower with deep NMB.9,10,16,30 In two previous trials that compared shoulder pain,9,16 deep NMB was accompanied by lower CO2 pressures regardless of whether the pressure was the preplanned intervention or outcome. Therefore, it is unclear whether the lower incidence of pain is due to lower intra-abdominal pressure or deep NMB. A recent review suggested that the most effective intervention for reducing the incidence of shoulder pain was to lower the abdominal insufflation pressure.31 Deep NMB permitting low-pressure pneumoperitoneum in these studies may have resulted in a lower incidence of shoulder pain. Moreover, in our analysis, postoperative analgesic consumption was not different between groups, although there was significant heterogeneity between studies. Therefore, it is difficult to draw firm conclusions from the current evidence.

Deep NMB also has some drawbacks including the potential for postoperative residual paralysis. Although sugammadex decreased the incidence of residual NMB significantly, it is not universally available and still expensive. To achieve adequate recovery from a deep block of a PTC of 1 or 2, 4 mg kg−1 of sugammadex is required.32 There is no robust evidence to suggest that the advantages of the deep NMB significantly outweigh the drawbacks.

There are narrative reviews and a meta-analysis regarding the influence of deep NMB on surgical conditions.2,30,33 A previous review included studies on open abdominal and laparoscopic surgery and presented results favouring deep NMB.2 There was insufficient evidence to substantiate the performance of laparoscopic surgery at low intra-abdominal pressures.33 A low intra-abdominal pressure may only result in a less than optimal surgical field.34 According to the study by Staehr-Rye et al.,15 there was a failure rate as high as 40% to complete laparoscopic cholecystectomy at an intra-abdominal pressure of 8 mmHg although deep NMB was used. Recently, a meta-analysis on the influence of deep NMB during laparoscopic surgery was reported.30,35 They concluded that deep NMB improves surgical space conditions compared with moderate NMB. However, they included three studies comparing deep with no NMB2,36,37 and did not include two recent trials.14,20 By adding these studies and using a different primary outcome, we showed that significant heterogeneity exists regarding surgical rating. We demonstrated that variable abdominal insufflation pressures could explain heterogeneity; multiple assessments of surgical conditions may also be important.

Our meta-analysis has some limitations. First, as we discussed above, there was significant heterogeneity among included studies regarding the type of surgery, the frequency of assessment of surgical conditions and intra-abdominal pressures. The significant heterogeneity and results of subgroup analysis suggest that we cannot substantiate the benefit of deep NMB; well designed trials are still required to investigate this in greater detail. Second, more than half of the included studies had an unclear or high risk of bias. Some studies did not mention allocation concealment or blinding of personnel. Third, only eight studies were included for analysis of the primary endpoint, making it difficult to assess publication bias adequately with Egger's test or by inspection of the funnel plot.26 Fourth, although there is a continuous spectrum of the level of NMB, we only have the results that compared surgical conditions between just two levels: PTC of 1 or 2 and TOF of 1 or 2.

In conclusion, our meta-analysis suggests that deep NMB is associated with an excellent or good rating of surgical condition. However, there were significant heterogeneity between studies regarding the type of surgery, the frequency of outcome measurement and intra-abdominal pressure. Trial sequential analysis demonstrated there is insufficient information to support the benefit of deep NMB. Further studies are required to address the heterogeneity and shortage of power.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.

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