The armamentarium of anaesthesiologists to manage neuromuscular blockade has been widened with the availability of sugammadex.1 Contrary to acetylcholine-esterase inhibitors such as neostigmine, no minimum degree of prereversal recovery is required when using sugammadex.2,3 Thus, a tailor-made approach to neuromuscular block management becomes possible, as any degree of neuromuscular block, including deep or intense levels, may now be reversed in less than 10 min.4 This has led to an increased interest in evaluating the potential clinical benefits of deep neuromuscular blockade, especially for laparoscopic surgery.5–11 Several studies have demonstrated an improvement in the surgical conditions.12,13 However, the clinical benefits of this deep block concept still remain controversial.14–17 Kopman and Naguib17 claimed that well designed studies investigating the question ‘is deep block superior to moderate block vis-a-vis surgical conditions’ were essentially nonexistent. Indeed, many of these patients had ongoing neuromuscular recovery at the time when the surgical conditions were evaluated rather than a moderate neuromuscular block. Moreover, surgical space conditions are not solely determined by the depth of neuromuscular block but also by nonrelaxation related factors such as depth or type of anaesthesia, that is volatile versus intravenous. Moreover, patient-related factors such as abdominal wall constitution, adhesions, organ size, age or sex may also have an impact in this context. Finally, the requirements for myorelaxation may not be constant during a procedure, at some stages more relaxation might be needed than at others. Therefore, timing of the assessment of the surgical conditions may be of importance, also. Thus, to determine the impact of depth of neuromuscular block on surgical conditions, all these nonrelaxation-related factors should be considered. This study aimed to evaluate specifically the impact of deep neuromuscular block on surgical conditions in patients undergoing laparoscopic gastric bypass surgery for morbid obesity.
Materials and methods
Ethical approval (No. 2014-000289-23) for this study (Ethical Committee CPP 14.03.04) was provided by the Ethical Committee ‘Comité de Protection des Personnes EST-III’ (Chairperson Dr P. Peton) on 7 April 2014. The research protocol was registered at clinicaltrial.gov (NCT02118844) before enrolment of the first patient. Patients were included between July 2014 and October 2015. All patients gave written informed consent and all the clinical data were obtained in our department. Exclusion criteria were hypersensitivity to any of the drugs used during this study, previous history of bariatric surgery or other complex abdominal surgery, refusal to participate and the absence of written informed consent. This study was reported according to the CONSORT statement.18
Monitoring established on arrival in the operating room included electrocardiography, noninvasive arterial pressure, pulse oximetry, capnography and bispectral index measurement. Neuromuscular block was monitored in the abducted left arm with a TOF Watch-SX acceleromyography device (Organon, Paris, France) at the adductor pollicis muscle as recommended.19 According to the Good Clinical Research Practice recommendation, a moderate level of block was defined as the time period from the reappearance of the first twitch of the train of four (TOF) until the reappearance of the forth twitch.19 Each time when the TOF Watch-SX starts displaying a TOF-ratio instead of a TOF count, additional bolus doses of 10 mg rocuronium were given until a TOF count of 4 or less was obtained. A deep neuromuscular blockade was defined as a posttetanic count (PTC) 1 to 3. Anaesthesia was induced in all patients with 1.5 to 2.5 mg kg−1 Propofol (B Braun Medical, Boulogne, France) and an effect-site target-controlled infusion (TCI) of 3.0 to 4.5 ng ml−1 remifentanil (B Braun Medical) according to the pharmacokinetic model by Minto et al.20 Neuromuscular block was induced with 1 mg kg−1 rocuronium (Hospira, Paris, France). Anaesthesia was maintained with 4.0 to 6.0 vol% desflurane (Baxter, Guyancourt, France) in oxygen – air (50%/50%), 2.0 to 3.0 ng ml−1 TCI of remifentanil and bolus doses of 10 mg rocuronium as required. Remifentanil doses were adjusted to lean body weight, rocuronium and sugammadex dosing was adjusted to ideal body weight and propofol doses were based on actual body weight.21,22 Neuromuscular blockade was routinely antagonised with 2 or 4 mg kg−1 sugammadex (Merck, Lyon, France), depending on the degree of neuromuscular block at the time. By using a warming blanket, the central body temperature was maintained over 35°C and the peripheral body temperature measured at the thenar eminence of the palm was maintained at 32°C or higher. End-tidal pressure of carbon dioxide was maintained between 32 and 36 mmHg.
Evaluation of surgical conditions
The surgical conditions were evaluated using the four-point King score with the following grades: 1 = excellent, 2 = good, 3 = acceptable and 4 = poor or unacceptable.23 Immediately before starting the gastrojejunal anastomosis, the procedure was temporarily stopped and the surgical conditions were evaluated twice within a 5 to 10-min interval by the surgeon; there was no staff communication between these two assessments. At the first evaluation (E1), all patients had a moderate neuromuscular block. At that stage, patients with excellent conditions, that is King score 1, were withdrawn from the primary outcome analysis, as their surgical conditions could not be further improved. The remaining patients were randomly assigned to deep neuromuscular block (group A) and moderate neuromuscular block (group B). Group A patients received one or several 10 mg rocuronium bolus until a PTC of 1 to 3 was obtained. Group B patients received a bolus dose of 0.9% saline to maintain the moderate block. Once the respective neuromuscular target was reached, the surgeon, blinded to the degree of neuromuscular block, performed the second rating. Thereafter, he continued the surgical procedure. Both evaluations were performed within 10 min by the same surgeon.
According to the study protocol, a rescue dose of rocuronium (15 mg) was given in case of persisting poor intra-operative surgical conditions after the second evaluation. If poor conditions still persisted after an additional rescue dose of rocuronium, the surgeon was allowed to convert to an open procedure.
The study had a double-blind design with the surgeons, patients and ward nurses blinded to treatment, whereas the attending anaesthesiologist and anaesthesia nurses were un-blinded. Participants were enrolled by anaesthesiologists during the pre-operative visit. The method used to generate the random allocation sequence was a computer-generated random list with a sealed envelope. Randomisation was performed after the first evaluation (E1). The full trial protocol can be assessed at the Clinical Research Support Facility (PARC, Nancy University Hospital).
The primary efficacy endpoint was an improvement of the surgical conditions of at least 1 point between E1 and E2. The secondary efficacy endpoints recorded were intra-abdominal pressure (mmHg) at E1 and E2, the time (min) needed to perform the gastrojejunal anastomosis and the incidence of peri-operative surgical complications. Intra-operative adverse events were classified using the iAEs classification as proposed by Kaafarani et al.24 Only relevant complications with the need for additional treatment or intervention (i.e. Grade II to V) were considered. Postoperative complications were evaluated and classified within 30 days using the Clavien-Dindo classification25 (Table 1). Only relevant postoperative complications needing pharmacological treatment or surgical, endoscopic or radiologic intervention (i.e. Grade II to V) were considered. The absolute risk increase of having at least one perioperative surgical complication in relation to a King score 4 (poor surgical conditions) at E1 and/or at E2 was estimated and the number needed to harm (NNH) was calculated.26 A positive NNH indicated how many patients had to be exposed to the intervention (i.e. moderate neuromuscular block) to produce a particular event (i.e. perioperative surgical complication) in one patient, who would not have had this event had she or he had a deep neuromuscular block.
Prior data indicated that the success rate among controls is about 20%.27 If the true success rate for experimental individuals was 80%, it was estimated that we would need to study 23 experimental individuals and 23 control individuals to be able to reject the null hypothesis that the failure rates for experimental and control individuals were equal with a power of 0.9 and a type I error of 0.05. As patients with an excellent rating (i.e. King-score 1) at E1 could not further improve their surgical operating conditions at E2, according to the study protocol, these patients were excluded from randomisation after the E1 evaluation. To compensate for these previewed exclusions, 30 patients per group were studied. To anticipate potential drop-outs, a total of 65 patients were included. A continuity-corrected Chi-squared statistic or Fisher's exact test was used to evaluate the null hypothesis. Patients’ characteristics and secondary outcomes were compared using Mann–Whitney U test, χ2 test or a Fisher exact test as appropriate. Intention-to-treat analysis included every individual who was randomised. In case of patients changing group, an ‘as-treated’ analysis was also planned. A P value of less than 0.05 was considered statistically significant.
Eighty-nine patients undergoing gastric bypass surgery under general anaesthesia were initially enrolled in this study. Four of these patients were excluded: three because of protocol violations and one because of missing data (Fig. 1). Data from 85 patients were included and analysed (Table 2).
Intra-operative surgical conditions: At the first evaluation (E1): all patients (n = 85) had a moderate level of neuromuscular block and the surgical conditions were as follows: excellent in 20 patients (24%), good in 35 (41%), acceptable in 18 (21%) and poor in 12 (14%). At this stage, the 20 patients with an excellent rating (King-score 1) were withdrawn from the study and the remaining 65 patients were randomly assigned to either deep block (group A, n = 34) or to moderate block (group B, n = 31). At the second evaluation (E2), 29 out of 34 (85.3%) patients in group A had an improvement of their surgical conditions of at least one point on the 4-point King scale compared with four out of 31 (12.9%) patients in group B. No change in surgical conditions was observed in five patients in group A and 26 patients in group B, with one patient in group B developing worse surgical conditions (P < 0.0001, Table 3). Seven patients in group A had poor surgical conditions at E1 and all of them improved at E2, whilst in group B, none of the five patients with poor surgical conditions at E1 improved at E2. According to the study protocol, these five patients received a supplemental dose of rocuronium after the E2 evaluation and an additional rating was performed as soon as they had a PTC of 3 or less. All five patients improved their surgical rating and no case required conversion to an open procedure.
Mean intra-abdominal pressure remained similar between E1 and E2 in all patients: 14.9 (0.39) versus 14.9 (0.43) mmHg (P = 0.657) respectively. Similarly, there was no difference in mean intraabdominal pressure between group A and group B: 14.9 (0.42) versus 14.9 (0.25) mmHg (P = 0.828), respectively. Mean time to perform the gastrojejunal anastomosis was 18.7 (7.3) min in all patients with no significant difference observed between group A and group B patients: 17.6 (6.8) versus 20.2 (7.9) min (P = 0.195), respectively. Among all patients included, 19 had at least one perioperative surgical complication (22.4%): nine had an intra-operative adverse event and 10 developed a postoperative complication (Table 4). Peri-operative surgical complications were significantly more frequent in patients with poor surgical conditions at either E1 or E2: eight of the 13 patients (61.5%) with poor surgical conditions had at least one peri-operative surgical complication compared with 11 of the 72 patients (15.3%) with better surgical conditions; odds ratio 7.12 [95% confidence interval (95% CI): 2.16 to 23.45], P < 0.001. This corresponded to a 46% absolute increase in the risk of a perioperative surgical complication (0.46, 95% CI 0.20 to 0.80) and a NNH of 2.2 (95% CI, 1.5 to 4.2).
The present study evaluated for the first time whether the transition from a moderate neuromuscular blockade to a deep neuromuscular block improves surgical conditions. The most important findings are firstly, even at a moderate level of neuromuscular blockade, surgical conditions were good to excellent in the majority of patients, but they were just acceptable or poor in one-third of them. Secondly, the transition from moderate to deep neuromuscular block reliably improved surgical conditions. Finally, preliminary evidence suggests that patients with poor surgical conditions had a higher incidence of intra and postoperative surgical complications than patients with a better surgical rating.
Two studies recently evaluated the role of the depth of neuromuscular block on surgical conditions in patients undergoing laparoscopic bariatric surgery.28,29 An improvement of surgical rating with a reduction in postoperative pain was reported with deep block in one study,28 whilst the other study could not confirm these findings.29 However, to explore specifically the impact of neuromuscular blockade on surgical conditions, nonrelaxation-related factors (e.g. anaesthesia-related factors or patient-related factors) should be controlled. Furthermore, the requirements for relaxation may vary during surgery, with parts of the procedure needing greater or lesser intensity neuromuscular block, and therefore, the evaluation of surgical conditions should be standardised too. Neither of these studies28,29 focused on these issues. In the present study, each patient was their own control and surgical rating was performed twice within a 10-min interval. At the first evaluation, all patients had moderate neuromuscular block. At this stage, the 20 patients with already excellent surgical rating were excluded, as they could not contribute to answer the question whether the transition to a deep neuromuscular block improves surgical conditions. The remaining patients were then randomly assigned to deep or moderate neuromuscular blockade and a second evaluation performed. To avoid any confounding contribution from ongoing surgery, it was discontinued between both ratings and the timing of both evaluations was standardised: it always took place immediately before the beginning of the gastro-jejuneal anastomosis, which is considered to be a key step in gastric-bypass surgery. Furthermore, surgical ratings were performed by the same surgeon. Contrary to the rather fair inter-rater reliability of the subjective rating scales for the assessment of surgical workspace, the intra-rater reliability of these scores has recently been proven to be excellent.30 Finally, the target neuromuscular blockade, that is deep or moderate neuromuscular blockade, respectively, was achieved in all patients at E1 and E2, see Table 2. However, there is some inconsistency in the literature about the definition of moderate block. Although the current recommendations define moderate neuromuscular block as the interval between reappearance of the first twitch and the reappearance of the fourth twitch of the TOF,19 some studies define it as the interval between the reappearance of first and the third twitch and others restrict it to the interval between the reappearance of the first and second twitch.12,13 In the present study, all patients in the moderate block group had at least one twitch after TOF stimulation and no more than just the reappearance of the fourth twitch response. Thus, when the surgical rating was performed, all patients with a moderate neuromuscular block were within the range defined by the current recommendations (Table 2) and none had ongoing neuromuscular recovery, that is a degree of neuromuscular recovery allowing the expression of a TOF ratio. Moreover, all patients in the deep block group had a PTC between 1 and 3. Hence, from a methodological point of view, the results from the present study should allow an answer to the question whether deep compared with moderate neuromuscular blockade improves surgical rating. In the deep block group, 85.3% of patients improved their surgical conditions compared with just 12.9% in the moderate block group. Moreover, of the 12 patients with unacceptable conditions at E1, seven were randomised to group A, and with the transition to deep block, the surgical conditions improved in all cases. However, surgical conditions did not improve in any of the five patients who were randomised to moderate block. Of interest in this context, after the E2 evaluation, these five patients received a rescue dose of rocuronium and this led to deep neuromuscular block with improved surgical conditions in all cases. Thus, compared with moderate block, the transition to deep neuromuscular block reliably improved surgical conditions. Moreover, optimising neuromuscular block may be of particular importance in those patients with difficult surgical conditions, as it may allow the laparoscopic procedure to be completed without the need to switch to an open procedure.
These study data could be explained by the fact that the sensitivity to neuromuscular blocking agents varies greatly among various muscles in humans. Thus, the dose needed to block the diaphragm and abdominal wall muscles is about 1.5 to 2 times greater than the dose needed to block the adductor pollicis.31,32
Two questions still remain to be answered in this context: does deep neuromuscular blockade improve patient's outcome and should anaesthesiologists routinely strive for deep block in patients undergoing gastric bypass surgery? Blobner et al.33 showed in patients undergoing laparoscopic cholecystectomy that deep block compared with no neuromuscular block led to an absolute risk reduction of adverse surgical events such as diaphragm movements or abdominal muscle contractions of 44%. Of interest in this context, first emerging evidence suggests a significant reduction in unplanned 30-day readmission in patients who underwent various surgical procedures under deep block compared with moderate block controls.34
In the present study, well established and validated classifications for intra-operative adverse events and postoperative surgical complications were applied.24,25 Moreover, only complications needing treatment or intervention (grades 2 to 5) were taken into account whilst less relevant complications (grade 1) were not considered. Overall, when intra-operative surgical conditions were poor at one or both evaluations, the risk of clinically relevant peri-operative surgical complications significantly increased (Table 4). However, this preliminary result needs to be confirmed in future studies. It remains to be answered whether deep block should be instigated routinely or only as required? In the present study, the surgical conditions were acceptable in the majority of patients, even with a moderate neuromuscular block, thus one might propose limiting the use of deep block to those patients in whom surgical conditions are unacceptable. However, our findings suggest that even a single, short period of unacceptable surgical operating conditions significantly increases the risk of clinically relevant peri-operative complications. Consequently, to improve patient outcome, any period of unacceptable conditions should be prevented. Whether preventing such unacceptable conditions means the routine induction of a deep neuromuscular block ab initio, or whether the deep block should be limited to only a particular key time during surgery needs to be assessed in future studies.
The present study has several limitations. Firstly, the findings do not support a direct relationship between moderate neuromuscular block and peri-operative complications but a relationship between poor surgical conditions and peri-operative complications. Secondly, the study's conclusions relate only to morbidly obese patients undergoing gastric bypass surgery. Whether this is the case for other laparoscopic procedures should be evaluated in future studies. Thirdly, to evaluate specifically the impact of the intensity of neuromuscular block on surgical conditions, other factors known to improve surgical conditions should be controlled (e.g. intra-abdominal pressure). In the present study, no conclusions on the impact of deep neuromuscular block on intra-abdominal pressure can be drawn. Moreover, there is still no gold standard on how to rate surgical conditions during laparoscopic surgery, 4-point, 5-point or even 10-point rating scales have been used.30 All such scales suffer to some degree from subjectivity and more objective endpoint should be integrated into rating scales used for the assessment of surgical space conditions. Finally, it has to be emphasised that the routine use of deep neuromuscular block should only be attempted when sugammadex is freely available. Although this may increase costs, it may reduce residual paralysis and reduce operating room turnover times.35,36
In conclusion, the present study shows that switching from moderate to deep neuromuscular block improves surgical conditions and poor surgical conditions were associated with a higher incidence of surgical complications.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: the study was supported by an unrestricted grant from Merck Investigator Initiated Studies Program. Merck company did not interfere with the study design, data collection, analysis, interpretation and manuscript writing.
Conflicts of interest: TF-B has received honoraria for lectures from Merck. CM has received honoraria for lectures from Merck.
Presentations: this study was presented (oral presentations) in part at the American Society of Anesthesiologists Annual Meeting 2016 in Chicago and at the French Society of Anesthesiologists Annual Meeting 2017 in Paris.
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