Level of neuromuscular blockade
After unblinding, the actual level of neuromuscular blockade was analysed for each individual patient, from start of surgery until 90 min. Within the profound group, a profound NMB (PTC 1 to 3) was achieved in 27 patients, and 14 patients achieved a deep NMB (TOF count 0, PTC ≥ 4). In five patients we failed to achieve a deep NMB, despite a continuous rocuronium infusion. In two patients from the profound NMB group, the data on the level of neuromuscular blockade were missing, due to failure of NMB level registration. Within the moderate NMB group, failure of NMB registration occurred in five patients. Overall, it appeared that in the profound NMB group, in 56% of the time an adequate depth of NMB was achieved. Therefore, we performed both an intention-to-treat analysis and an as-treated analysis, as described in our study protocol.10 In the as-treated analysis, we combined the patients with PTC 1 to 3 and patients with TOF count 0 and PTC at least 4 in the profound NMB group. The five patients (10.4%) in which a TOF count 0 wasn’t achieved, were analysed as moderate NMB. The two patients in the profound NMB group with missing data on their level of NMB were excluded from the as-treated analysis.
Primary outcome measure
The mean QoR-40 scores on postoperative day 1 in the profound NMB group and the moderate NMB group were 169 ± 18 and 169 ± 15, respectively (P = 0.95), as shown in Table 2. Correction for age, sex and side of nephrectomy did not affect the results. Also in the as-treated analysis, no differences were found in the mean QoR-scores on day 1 (P = 0.49).
Peroperative outcome measures
Peroperative data are shown in Table 3. There were no differences in operation time, warm ischaemia time or estimated blood loss between groups. The mean L-SRS scores in the profound NMB group and the moderate NMB group were 4.8 ± 0.3 and 4.7 ± 0.5, respectively (P = 0.23), Only the as-treated analysis showed less contractions in the profound NMB group when compared with the moderate NMB group (P = 0.03). In four patients in the profound NMB group, the surgeon requested an extra bolus of rocuronium, versus 13 patients in the moderate NMB group (P = 0.02). Two patients were converted to hand-assisted LDN, both in the moderate NMB group: the first to provide better sight during dissection of the renal arteries, the second because the large kidney did not fit in the extraction bag. Intra-operative adverse events were observed in one patient in the profound NMB group (i.e. venous bleeding), versus six patients in the moderate NMB group [i.e. venous bleeding (n = 2), arterial bleeding (n = 2), ureteral laceration (n = 1) and adrenal laceration (n = 1)].
Secondary outcome measures
There was no difference in the mean total QoR-40 score 48 h after extubation between groups in the intention-to-treat analysis. However, a larger proportion of the patients with profound NMB could be discharged on day 2 when compared with the moderate NMB group (50.0 versus 29.8%, P = 0.04). In the additional as-treated analysis, a difference of 7.2 was found in the mean QoR-40 score on day 2, with a mean score of 179 ± 13 in the profound NMB group versus 172 ± 19 in the moderate NMB group, P = 0.05.
Postoperative components of pain scores (NRS) are presented in Table 4. The profound NMB group experienced less intra-abdominal pain on the first postoperative day [2.9 ± 2.8 (profound), versus 4.1 ± 2.7 (moderate), P = 0.04] with a comparable amount of opiate consumption. In the as-treated analysis, we found the same results on day 1, but also reduced pain scores in the profound NMB group 6 h after surgery, and a reduction of overall pain scores and referred shoulder pain on days 1 and 2.
No influence of neuromuscular blockade was found on postoperative nausea, discharge criteria or the mean length of hospital stay. Follow-up after 30 days showed no differences between groups in postoperative pain scores, and return to daily activities and work (data not shown). Postoperative complications during hospital stay and after 30 and 60 days are shown in Table 5. One patient (from the moderate NMB group) was readmitted to the hospital, because of a postoperative infection treated with intravenous antibiotics.
The study did not show a significant effect of profound NMB during LDN on the quality of recovery at the first day after surgery, which was the primary outcome measure. Despite a clear protocol regarding neuromuscular monitoring and rocuronium dosing, in 14 patients allocated to a profound NMB more than 50% of the measurements reflected a deep NMB, instead of a profound NMB. In five patients within the profound NMB group, only a moderate NMB was achieved. Therefore, we performed an as-treated analysis, in which we compared profound NMB (including patients with TOF count 0, PTC ≥ 4) with moderate NMB (including patients with shallow NMB).
The as-treated analysis revealed that the quality of recovery was better at postoperative day 2 for those patients who received a profound NMB that was adequately maintained during surgery as compared with those receiving a moderate NMB. This improvement in quality of recovery in patients with a profound NMB may be attributed to significantly lower overall and referred shoulder pain scores. Furthermore, a larger proportion of the patients in the profound NMB group could be discharged at day 2 after surgery, when compared with the group with moderate NMB, although this did not lead to a significant reduction in the mean length of hospital stay. Finally, we observed less intra-operative adverse events within the profound NMB group when compared with the moderate NMB group, therefore we hypothesise that the use of profound NMB improves patient safety during the procedure.
The L-SRS is a Likert scale to score the intra-operative surgical conditions, ranging from 1 (extremely poor conditions) to 5 (optimal conditions).9 In contrast to our earlier published systematic review and meta-analysis,11 this study revealed no improvement in the overall surgical space conditions for the group allocated to profound NMB, when compared with moderate NMB. This can possibly be explained by the fact that the mean SRS was already very high (4.7/5) in patients receiving a moderate NMB. Possibly the use of standard IAP (12 mmHg) during transperitoneal laparoscopic procedures in nonobese patients, provides optimal surgical conditions in a majority of cases with moderate muscle relaxation. Moreover, the five-point L-SRS may not be able to detect subtle improvements in surgical conditions when profound NMB is applied. Nevertheless, we observed a small but significant improvement in the subscore for muscle contractions in patients allocated to a profound NMB.
The secondary analysis suggests that an adequately maintained profound NMB reduces postoperative pain scores after LDN, when compared with moderate NMB. A possible explanation is that profound NMB more effectively relaxes the abdominal wall as compared with moderate NMB, which leads to less pressure-induced tissue-injury, and hence less deep intra-abdominal pain and shoulder tip pain. Combining profound NMB with low-pressure PNP might lead to even further reduction of postoperative pain scores. Further research is required to study the beneficial impact of lower IAP combined with profound NMB on the quality of recovery after laparoscopic surgery.
The main strengths of this study are related to its double-blinded randomised controlled design, with computer-generated randomisation with allocation concealment and blinding for the assessment of the primary outcomes. Second, the multicentre design with different surgical teams and many different anaesthesiologists provides a good basis for the subsequent generalisation of our findings. And third, we published a study protocol beforehand. All the reported outcomes and analyses were described a priori in this protocol, which reduces the risk of reporting bias.
The main limitation of this study is related to the difficulty to achieve and maintain the intended depth of neuromuscular blockade. Patients allocated to the profound NMB group were titrated towards a PTC of 1 to 3. Despite high dosages of rocuronium with continuous infusion (on average a total of 1.2 ± 0.4 mg kg IBW−1 h−1 including the intubation dose and up to >300 mg total dose), achieving and/or maintaining the intended profound NMB was not successful in 21/48 patients who were allocated to the profound NMB group. Criteria for re-allocation of patients were defined in our study protocol that was published beforehand. The differences between the intention-to-treat and the as-treated analyses indicate that to achieve the maximum effect in pain reduction, quality of recovery and intra-operative safety, the profound NMB must be consistently maintained and continuously monitored to guide the necessary frequent additional dosing of neuromuscular blocking agent.
Possible explanations for our failure to reach or maintain an adequate depth of NMB in some patients could be that the initial intubation dose of rocuronium in the profound NMB group was too low to ensure an adequately profound block at the start of surgery. Because of differences between patients in sensitivity for and elimination of rocuronium, some patients need higher dosages to reach the same level of neuromuscular blockade.20
In our view, future studies should focus on the use of profound NMB to improve the safety during laparoscopic surgery. As pointed out by Biro et al.14 in certain operations, a PTC of 1 to 3 is required to prevent minor patient movements or diaphragm contractions, therefore it would be favourable to distinguish between deep (TOF count 0, PTC ≥ 4) and profound NMB (PTC 1 to 3). For translation into routine clinical practice, it is very important that anaesthesia staff are well trained in how to achieve and maintain an adequate profound NMB, guided by neuromuscular monitoring. When using an inhalational anaesthetic such as sevoflurane, instead of an infusion of propofol, lower (maintenance) doses of rocuronium might be sufficient for the maintenance of profound NMB during anaesthesia.21
In conclusion, our results did not show a beneficial effect of profound NMB on the quality of recovery after LDN at the first day after surgery, when compared with moderate NMB. Nevertheless, the secondary analysis indicates that an adequately maintained profound NMB during LDN improves postoperative pain scores and quality of recovery. To achieve the maximum effect in pain reduction, postoperative recovery and intra-operative safety during LDN, profound NMB must be consistently maintained with high dosages of neuromuscular blocking agent guided by vigilant neuromuscular monitoring.
Acknowledgements relating to this article
Assistance with the study: the authors thank the collaborators of the RELAX study group for their contribution to the study. We also thank Jutta van Rossum, Floor Kooijmans, Petra Cornelissen, Suzanne Pouwels, Inge Arnts, Monique Custers-van Lieshout, Rianne van Boekel and Esmee van Helden for their contribution to the data acquisition.
Financial support and sponsorship: this work was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.
Conflicts of interest: MCW received speakers/consultancy fee from Merck Sharp & Dohme; received a grant from Merck Sharp & Dohme for the submitted work; received grants from Merck Sharp & Dohme, outside the submitted work. AD received speakers/consultancy fee from Merck Sharp & Dohme; the LUMC received grants from Merck Sharp & Dohme for the performance of studies on preoperative care. MHDB, PK, CHM received speaker's fee from Merck Sharp & Dohme. JFL received speaker's fee from Astra Zeneca.
Presentation: preliminary data for this study were presented at the yearly meeting of the Dutch Association for Urologists (NVU), 25 May 2018, Nijmegen, The Netherlands.
Study collaborators of the RELAX study group: Kim I Albers, Department of Anaesthesiology, Radboudumc, Nijmegen, The Netherlands; Ian Alwayn, Department of Surgery, LUMC, Leiden, The Netherlands; Martijn Boon, Department of Anaesthesiology, LUMC, Leiden, The Netherlands; Andries E Braat, Department of Surgery, LUMC, Leiden, The Netherlands; Koen EA van der Bogt, Department of Surgery, LUMC, Leiden, The Netherlands; Ruth Dam, Department of Surgery, LUMC, Leiden, The Netherlands; Rogier ART Donders, Department of Health Evidence, Radboudumc, Nijmegen, The Netherlands; Luuk B Hilbrands, Department of Nephrology, Radboudumc, Nijmegen, The Netherlands; Graziella Kallenberg-Lantrua, Department of Surgery, LUMC, Leiden, The Netherlands; Christiaan Keijzer, Department of Anaesthesiology, Radboudumc, Nijmegen, The Netherlands; Anneke Kusters, Department of Urology, Radboudumc, Nijmegen, The Netherlands; David Lam, Department of Surgery, LUMC, Leiden, The Netherlands; Janneker Mulder, Department of Anaesthesiology, Radboudumc, Nijmegen, The Netherlands; Gert-Jan Scheffer, Simone Willems, Department of Anaesthesiology, Radboudumc, Nijmegen, The Netherlands.
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* Moira H.D. Bruintjes and Piet Krijtenburg contributed equally to the article.© 2019 European Society of Anaesthesiology