The Impact of Deep Versus Standard Muscle Relaxation on Intra-operative Safety During Laparoscopic Surgery: a Multicenter Strategy Study
Phase: NA
Conditions: Neuromuscular Blockade, Rocuronium, Anesthetics, Anesthesia Complication, Neuromuscular Blocking Agents, Surgery--Complications
Sponsor: Leiden University Medical Center

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PROTOCOL TITLE The impact of deep versus standard muscle relaxation on intra-operative safety 
during laparoscopic surgery: a multicenter strategy study – EURO RELAX STUDY 
 
 
Protocol ID 
P19.065 
Short title 
EURO RELAX STUDY 
EudraCT number 
N.A. 
Version 
1.6 
Date 
29-6-2021 
Principal investigators 
Local investigators 
M. van Velzen, PhD 
Leiden University Medical Centre 
Department of Anesthesiology 
Albinusdreef 2, 2333 AL 
Leiden, The Netherlands 
Tel no: 0031 71 526 2301 
E-mail: M.van_Velzen@lumc.nl 
Michiel C. Warlé, MD, PhD 
Department of Surgery 
Geert Grooteplein-Zuid 10, 6525 GA 
Nijmegen, The Netherlands 
Tel no: 0031 24 361 5333 
E-mail: Michiel.Warle@radboudumc.nl 
 
Hospital Universitari I Politecnic La Fe, Valencia, Spain 
Oscar Díaz Cambronero, MD 
Department of Anesthesiology 
Chairman Perioperative Medicine Research Group 
Instituto de Investigación Sanitaria La Fe (www.iislafe.es) 
Hospital Universitari I Politécnic La Fe. 
Avinguda de Fernando Abril Martorell, 106, 46026 
Valencia, Spain 
Tel no: 0034 656 99 4108 
E-mail: oscardiazcambronero@gmail.com / 
perioperativemedicine@iislafe.es 
Université De Lorraine 
Prof. Thomas Fuchs-Buder, MD, PhD 
Départment anesthesiologie 

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Réanimation, Medicine d’Urgence 
Nancy, France 
E-mail: t.fuchs-buder@chu-nancy.fr 
Istituto Nazionale Dei Tumori, Milano, Italy 
Prof. Franco Valenza, MD, PhD 
Department of Anesthesia and Critical Care 
Via Venezian 1, 20133 
Milano, Italy 
Tel no: 0039 022 390 2282 
E-mail: franco.valenza@istitutotumori.mi.it 
 
A.E. Braat, MD PhD 
Leiden University Medical Centre  
Department of Surgery 
Albinusdreef 2, 2333 AL 
Leiden, The Netherlands  
Tel no: 0031 71 526 6188 
E-mail: A.E.Braat@lumc.nl 
 
V.A.L. Huurman, MD PhD 
Leiden University Medical Centre  
Department of Surgery 
Albinusdreef 2, 2333 AL 
Leiden, The Netherlands  
Tel no: 0031 71 526 6188 
E-mail: V.A.L.Huurman@lumc.nl 
 
S. Broens, MD 
Antoni van Leeuwenhoek Medical Centre 
Plesmanlaan 121, 1066 CX 
Amsterdam, The Netherlands 
Tel no: 0031 20 512 9111 
E-mail: s.broens@nki.nl 
 
I.F. Panhuizen, MD 
Canisius Wilhelmina Medical Centre 
Weg door Jonkerbos 100, 6532 SZ  
Nijmegen, The Netherlands 
Tel no: 0031 24 365 8702 
Email: ivopan@hotmail.com  
 
M.H.J. Roozekrans, MD 
Noordwest Ziekenhuisgroep 

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Wilhelminalaan 12, 1815 JD 
Alkmaar, The Netherlands                                                   
Tel no: 0031 72 548 4444  
                                                                    Email: mhj.roozekrans@nwz.nl 
                                                                          
Project leaders 
G.H.M. Honing, MD, PhD Student 
Leiden University Medical Centre 
Department of Anesthesiology 
Room J5-37 
Albinusdreef 2, 2333 ZA Leiden, The Netherlands 
Tel no: 0031 71 526 4038 
E-mail: g.h.m.honing@lumc.nl 
G.T.J.A. Reijnders-Boerboom, MD, PhD student 
Radboudumc 
Department of Anesthesiology 
Geert Grooteplein-Zuid 10, 6525 GA 
Nijmegen, The Netherlands 
Tel no: 0031 24 361 5333 
E-mail: Gabby.Reijnders-Boerboom@radboudumc.nl  
Sponsor 
Leiden University Medical Centre, University of Leiden 
Albinusdreef 2, 2333 ZA Leiden, The Netherlands 
Independent expert (s) 
Elise Sarton, MD, PhD 
Leiden University Medical Centre 
Department of Anesthesiology 
Albinusdreef 2, 2333 AL 
Leiden, The Netherlands 
e.y.sarton@lumc.nl 

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PROTOCOL SIGNATURE SHEET 
 
 
 

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TABLE OF CONTENTS 
 
 
Table of Contents 
1. 
INTRODUCTION AND RATIONALE .................................................................................... 8 
2. 
OBJECTIVES ....................................................................................................................... 9 
Secondary Objectives: .......................................................................................................................... 9 
Primary hypothesis: .............................................................................................................................. 9 
Secondary hypotheses: ........................................................................................................................ 9 
3. 
STUDY DESIGN ................................................................................................................. 10 
4. 
STUDY POPULATION ....................................................................................................... 12 
4.1 
Population (base) ................................................................................................................ 12 
4.2 
Inclusion criteria .................................................................................................................. 12 
4.3 
Exclusion criteria ................................................................................................................. 14 
4.4 
Sample size calculation ...................................................................................................... 14 
4.5 
Pre-study requirements ...................................................................................................... 15 
5. 
TREATMENT OF SUBJECTS ............................................................................................ 16 
5.1 
Investigational treatment..................................................................................................... 16 
5.2 
Use of co-intervention ......................................................................................................... 16 
5.3 
Escape medication ............................................................................................................. 16 
6. 
INVESTIGATIONAL PRODUCT ......................................................................................... 16 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................... 16 
8. 
METHODS .......................................................................................................................... 16 
8.1.1 
Secondary study parameters/endpoints ............................................................................. 17 
8.1.2 
Other study parameters ...................................................................................................... 17 
8.2 
Randomization, blinding and treatment allocation .............................................................. 18 
8.3 
Study procedures ................................................................................................................ 18 
Preoperative procedures .................................................................................................................... 18 
Neuromuscular management ............................................................................................................. 19 
8.4 
Withdrawal of individual subjects ........................................................................................ 23 
8.4.1 
Specific criteria for withdrawal .................................................................................................... 23 
8.5 
Replacement of individual subjects after withdrawal .......................................................... 23 
8.6 
Follow-up of subjects withdrawn from treatment ................................................................ 23 
8.7 
Premature termination of the study .................................................................................... 23 
9. 
SAFETY REPORTING ....................................................................................................... 24 
9.1 
Temporary halt for reasons of subject safety ..................................................................... 24 
9.2 
AEs, SAEs and SUSARs .................................................................................................... 24 
9.2.1 
Adverse events (AEs) ......................................................................................................... 24 
9.2.2 
Serious adverse events (SAEs) .......................................................................................... 24 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ........................................... 25 
9.3 
Annual safety report ............................................................................................................ 25 
9.4 
Follow-up of adverse events ............................................................................................... 25 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ............................................... 25 

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10. 
STATISTICAL ANALYSIS .................................................................................................. 26 
10.1 
Primary study parameter .................................................................................................... 26 
10.2 
Secondary study parameters .............................................................................................. 26 
10.3 
Other study parameters ...................................................................................................... 26 
10.4 Interim analysis ................................................................................................................................... 26 
11. 
ETHICAL CONSIDERATIONS ........................................................................................... 27 
11.1 
Regulation statement .......................................................................................................... 27 
11.2 
Recruitment and consent .................................................................................................... 27 
11.3 
Benefits and risks assessment, group relatedness ............................................................ 27 
11.4 
Compensation for injury ...................................................................................................... 27 
11.5 
Incentives ............................................................................................................................ 27 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ................................ 28 
12.1 
Handling and storage of data and documents .................................................................... 28 
12.2 
Monitoring and Quality Assurance...................................................................................... 28 
12.3 
Amendments ....................................................................................................................... 28 
12.4 
Annual progress report ....................................................................................................... 29 
12.5 
Temporary halt and (prematurely) end of study report ....................................................... 29 
12.6 
Public disclosure and publication policy ............................................................................. 29 
13. 
STRUCTURED RISK ANALYSIS ....................................................................................... 31 
13.1 
Potential issues of concern ................................................................................................. 31 
13.2 
Synthesis ............................................................................................................................ 31 
14. 
Appendixes ......................................................................................................................... 32 
15. 
References ......................................................................................................................... 32 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
 
ABR 
General Assessment and Registration form (ABR form), the application form that is 
required for submission to the accredited Ethics Committee; in Dutch: Algemeen 
Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
ASA 
ASA Physical Status Classification System 
BAC 
Blinded Adjudication Committee 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
iAEs 
Intra-operative Adverse Events 
IC 
Informed Consent 
METC 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
NMB 
Neuromuscular block 
PTC 
Post Tetanic Count 
(S)AE 
(Serious) Adverse Event 
Sponsor 
TIVA 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising party. 
Total intravenous anesthesia 
TOF 
Train of Four 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in Dutch: 
Uitvoeringswet AVG 
NRS 
Numeric Rating Scale 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch- 
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
 
 
Rationale: Muscle relaxants are routinely applied during anesthesia to facilitate endotracheal 
intubation and to improve surgical working conditions. Several investigations have shown that a deep 
neuromuscular block (NMB) improves the surgical working conditions over a standard NMB and 
effectively precludes sudden deterioration of the surgical field. However, whether the improvement of 
surgical working conditions translates into less intra- and postoperative complications remains 
uncertain. Small prospective or retrospective studies shown an decrease of the incidence of 
intraoperative adverse events and postoperative complications after a deep NMB. There is a need to 
confirm these outcome data prospectively, in a large number of patients and clinics and during a 
variety of surgical procedures. 
Objective: To study the effect of deep neuromuscular block as compared to standard neuromuscular 
block on intra-operative adverse events during laparoscopic surgery. 
Study design: Multi center, randomized controlled clinical trial 
Study population: 922 patients planned for elective laparoscopic abdominal surgery. 
Intervention: Patients will be randomized between a deep NMB (group 1; aimed at PTC 1-2) and 
standard care (group 2; standard care NMB). 
Main study parameters/endpoints: Primary endpoint is the difference in incidence of intra-operative 
adverse events during laparoscopic surgery graded on the CLASSIC scale (ie. CLASSIC grade ≥ 2) 
between both groups 
Secondary endpoints include the surgical working conditions, 30 day post-operative complications and 
quality of recovery. 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: The aim of this study is to compare two targets of neuromuscular block that are currently 
interchangeably used (both deep and standard NMB are routine practice at the LUMC). 
Additionally, all other anesthesia and surgery related procedures (eg. medication and monitoring) 
follow routine practice. We therefore anticipate no additional risks from study related procedures. 
Before surgery a Quality of Recovery and Short Form Health Survey will be obtained.After surgery 
the QoR-40 will be repeated twice, and the SF-36 will be obtained at 30 days after surgery. 

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1. INTRODUCTION AND RATIONALE 
 
 
Muscle relaxants (ie. neuromuscular blocking agents; NMBAs) are routinely applied during anesthesia 
to facilitate endotracheal intubation and to improve surgical working conditions. However, as NMBAs 
have relatively long half lifes, the dosing of these agents is often restricted in clinical practice. 
Incomplete recovery of neuromuscular block (NMB) is associated with postoperative adverse events 
and should therefore be avoided at all costs. Hence, in standard clinical practice, NMB is often 
instituted only at the induction of anesthesia and hereafter allowed to recover spontaneously to limit 
the chance of residual NMB. Surgical procedures however have evolved to become increasingly 
complex. For instance, robotic surgery and increasingly complex laparoscopic surgery are now 
routinely performed. These types of surgery demand optimal working conditions to be successful and 
the standard use of NMBAs in these procedures may not be sufficient. Indeed, several investigations 
have shown that a deep neuromuscular block (ie. Post-tetanic-count of 1-2 twitches; PTC 1-2) during 
these procedures 1-2 twitches) improves the surgical working conditions over a standard NMB (ie. 
Train-of-four count > 0 twitches; TOF 1-3) and effectively precludes sudden deterioration of the 
surgical field.[1-8] Additionally, deep NMB has become feasible due to the availability of the selective 
reversal agent sugammadex. Sugammadex ensures quick and safe recovery of any depth of NMB and 
prevents residual NMB.[9] However, whether the use of a deep NMB translates into less intra- and 
postoperative complications remains uncertain. A recent retrospective analysis of neuromuscular 
management during laparoscopic retroperitoneal surgery showed a reduced rate of unplanned 30 day 
readmissions when a deep NMB over a moderate NMB was applied (3.8% vs. 12.7%).[10] In addition, 
a pooled analysis of 4 randomized controlled trials comparing different levels of intra-abdominal 
pressure and neuromuscular blockade during laparoscopic donor nephrectomy, showed a significant 
reduction in the incidence of intra-operative surgical complications from 12.6% with moderate NMB to 
4.8% with deep NMB. [11-14]These previous observations were made in small prospective or 
retrospective studies. There is a need to confirm these outcome data prospectively, in a larger 
prospective trial for a variety of surgical procedures. We therefore propose a multi-center, randomized 
controlled trial, to study the effect of a deep NMB (PTC 1-2 twitches) versus standard NMB (single 
induction dose rocuronium) in a variety of laparoscopic surgical procedures on the incidence of 
intraoperative adverse events and postoperative outcome data. 

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2. OBJECTIVES 
 
 
Primary Objectives: 
To study the effect of deep neuromuscular block compared to standard neuromuscular block on intra- 
operative adverse events during laparoscopic surgery using the CLASSIC score system; see Table 2. 
 
 
Secondary Objectives: 
To study the effect of deep neuromuscular block as compared to standard neuromuscular block on: 
• 
Surgical working conditions (using the validated Leiden surgical rating scale: L-SRS, Table 3) 
• 
30-day post-operative complications (using the Clavien-Dindo classification, Table 6) 
• 
30-day post-operative complications according to the Comprehensive Complication Index 
(https://www.assessurgery.com/) 
• 
30-day unplanned readmission rates 
• 
Quality of recovery at post-operative day 1, 2 and 30 after laparoscopic surgery. 
o 
Quality-of-recovery (QoR-40 questionnaire at postoperative day 1 and 2 (Appendix 1) 
o 
Quality-of-life at postoperative day 30 (SF36 questionnaire, Appendix 2) 
 
 
 
Primary hypothesis: 
Deep neuromuscular blockade reduces the incidence of intra-operative adverse events as measured 
by the CLASSIC score during laparoscopic surgery as compared to standard neuromuscular blockade. 
 
Secondary hypotheses: 
Deep neuromuscular blockade improves surgical working conditions and the early quality of recovery 
and reduces 30-day post-operative complications and unplanned readmissions after laparoscopic 
surgery, as compared to standard neuromuscular blockade. 

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3. STUDY DESIGN 
The EURO Relax is a multi-center, randomized controlled trial in patients undergoing laparoscopic 
abdominal surgery. Patients undergoing elective laparoscopic surgery in different fields of 
abdominal surgery will be randomized 1:1 in blocks of 2 and 4 to the deep or standard 
neuromuscular block group. Randomization will be stratified per center and BUPA category 
(MAJOR, MAJOR PLUS or COMPLEX MAJOR; for examples see table 1). 
 
Patient inclusion  will occur competitively in each center. Due to differences in inclusion rate, final 
inclusion could differ slightly in comparison with the proposed inclusion number per center. 

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Figure 1. Inclusion flowchart EURO Relax study. QoR: quality of recovery; iAE: intraoperative adverse 
event; L-SRS: Leiden Surgical Rating Scale; CCI: composite complication index. 

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12 
 
4. STUDY POPULATION 
 
4.1 
Population (base) 
922 ASA class 1-3, aged > 18 years, scheduled for elective laparoscopic abdominal surgery (such 
as, but not restricted to upper gastrointestinal tract-, lower gastrointestinal tract-, urological- and 
gynecological surgery) 
 
 
4.2 
Inclusion criteria 
In order to be eligible to participate in this study, a patient must meet all of the following criteria: 
• 
Patients scheduled for elective laparoscopic abdominal procedure with a complexity according 
to the BUPA classification for case complexity: ‘MAJOR’, ‘MAJOR PLUS’ or ‘COMPLEX 
MAJOR’. Several examples of eligible procedures are stated in Table 1. Procedures not listed in 
Table 1 that are of listed in https://codes.bupa.co.uk/procedures as a Surgeon’s Category ≥ 
‘Major 3’, can be enrolled to the trial. The BUPA class of the specific procedure is listed under 
BUPA hospital category. 
• 
ASA class I-III 
• 
≥ 18 years of age 
• 
Ability to give oral and written informed consent 
 
 
Table 1. Examples of cases with BUPA classification for case complexity major, major plus 
or complex major used for the Classic validation study. (with permission of dr. Salome Dell-
Kuster (principle investigator of the CLASSIC validation study; NCT03009929). 
• BUPA MAJOR: 
-cholecystectomy 
• BUPA MAJOR PLUS: 
-colorectal resection 
-nephrectomy 
-hysterectomy 
-adrenalectomy (uni) 
-right colectomy 
-partial nephrectomy 
-gastric sleeve 
-gastric bypass 
-donor nephrectomy 
-left colectomy 
-sigmoidectomy 
-laparoscopic partial stomach resection 
-myomectomy 

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13 
 
• BUPA COMPLEX MAJOR: 
-low anterior resection 
-partial hepatectomy 
-prostatectomy 
-hemi hepatectomy 
-esophagostomy 
-laparoscopic pyeloplasty 
-laparoscopic stomach resection 
-total cystectomy 

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14 
 
4.3 
Exclusion criteria 
• 
Low or intermediate complexity laparoscopic procedures (BUPA ‘SIMPLE’ or ‘INTER’) 
• 
Known or suspected neuromuscular disorders impairing neuromuscular function 
• 
Allergies to muscle relaxants, anesthetics or narcotics mentioned in paragraph 8.3 
• 
A (family) history of malignant hyperthermia 
• 
Women who are or may be pregnant or are currently breast feeding 
• 
Chronic use of any type of opioid or psychotropic drug for the treatment of chronic pain 
• 
Use of NSAID’s shorter than 5 days before surgery for the treatment of chronic pain 
• 
Indication for rapid sequence induction 
• 
Contra-indication for sugammadex use (e.g. known sugammadex allergy or GFR<30 ml/min) 
 
 
4.4 
Sample size calculation 
 
Preliminary data of the CLASSIC validation study as confidentially provided by dr. S. Dell-Kuster 
(principle investigator; NCT03009929) confirm that the incidence of GRADE ≥ 2 iAEs (Table 2) is 20% 
for BUPA categories (unpublished data). 
 
Table 2. Adapted version of the CLASSIC classification for intra-operative adverse events (with 
permission of dr. Salome Dell-Kuster (principle investigator of the CLASSIC validation study; 
NCT03009929). 
 
Grade 0 
No deviation from the ideal intraoperative course 
Grade 1 
Any deviation from the ideal intraoperative course without the need for any 
additional treatment or intervention; patient asymptomatic or mild symptoms 
Grade 2 
Any deviation from the ideal intraoperative course with the need for any additional 
minor treatment or intervention; patient with moderate symptoms, not 
life- threatening and not leading to permanent disability 
Grade 3 
Any deviation from the ideal intraoperative course with the need for any 
additional moderate treatment or intervention; patient with severe symptoms, 
potentially life- threatening and/or potentially leading to permanent disability 
Grade 4 
Any deviation from the ideal intraoperative course with the need for any 
additional major treatment or intervention; patient with life-threatening symptoms 
and/or leading to permanent disability 
Grade 5 
Any deviation from the ideal intraoperative course with intraoperative death of 
the patient 
The following events are not defined as intraoperative complications: sequelae, failures of cure, events related to 
the underlying disease, wrong-site or wrong-patient surgery or errors in indication 
 
 
 
• 
To date, the minimal clinically important difference (MCID) for intra-operative adverse events ac- 
cording to the CLASSIC classification has not been published. We consider a relative reduction in 
intra-operative adverse events, CLASSIC grade ≥ 2, of 40% a clinically relevant difference. As de- 

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15 
 
scribed above the reported average rate of grade 2 intra-operative Adverse Events (iAEs) is 20%. 
• 
With an alpha of 5% and beta of 90%, 439 patients are required in each arm of the study (in total 
878 patients). 
o 
Assuming a 5% rate of drop-out a total of 922 patients should be randomized 1:1 in 
this study. Reasons for drop-out are: 
• 
conversion to open surgery within the first 20 minutes of the procedure due 
to unforeseen adhesions, tumor progression, (peritoneal) metastases or 
other diagnosis  
• 
pre-incision alteration of surgical plan to laparotomy instead of laparoscopy 
after patient randomization to deep NMB or standard-of-care group 
• 
patient safety concerns at induction of anesthesia, e.g. anaphylaxis at 
induction of anesthesia or unanticipated difficult airway 
o 
Patients with a conversion to deep NMB due to intra-operative adverse events will 
not be excluded. 
 
 
4.5 
Pre-study requirements 
There are no specific study requirements. 

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5. TREATMENT OF SUBJECTS 
There are no specific study-related pre-study requirements. On the day of surgery, patients will be 
randomized between the two treatment groups. Anesthesia and postoperative care follow routine local 
protocol, apart from neuromuscular management. Neuromuscular management during surgery 
depends on the treatment allocation; patients will be randomized between one of the following groups: 
Group 1 (experimental): Deep neuromuscular block. 
- 
Muscle relaxation with rocuronium (Esmeron, MSD BV), target depth: post-tetanic-count of 1-2 
twitches from start of surgery until the end 
- 
Induction dose rocuronium: 0.6 – 1.0 mg/kg, aimed at PTC 1-2 at surgery start  
- 
Maintenance: continuous infusion of rocuronium at 0.2-0.6 mg/kg/hr, titrated to maintain PTC 1-2 
- 
Reversal of NMB with sugammadex 4 mg/kg at the end of surgery 
 
Group 2 (comparator): standard care 
- 
Muscle relaxation with rocuronium (Esmeron, MSD BV), target depth: train-of-four count of > 0 
twitches from start of surgery until the end. 
- 
Induction dose rocuronium: 0.3-0.6 mg/kg, aimed at a TOF count of > 0 twitches at surgery start 
- 
Repeated doses of rocuronium 10 mg on request by the surgeon only 
- 
Reversal of NMB with sugammadex 2 mg/kg at the end of surgery, when TOF ratio < 0.9 at 
surgery end. 
 
 
5.1 
Investigational treatment 
Not applicable. 
 
5.2 
Use of co-intervention 
Not applicable 
 
5.3 
Escape medication 
Not applicable 
 
 
6. INVESTIGATIONAL PRODUCT 
Not applicable. 
 
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable. 
 
 
8. METHODS 
 
8.1  Study parameters/endpoints 

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17 
 
Main study parameter/endpoint 
Incidence of intra-operative adverse events during laparoscopic surgery (CLASSIC grade ≥ 2, 
Table 2) in both groups  
 
 
8.1.1 Secondary study parameters/endpoints 
To study the effect of deep neuromuscular block as compared to standard neuromuscular block on: 
• 
Surgical working conditions (L-SRS, Table 3) 
• 
30-day post-operative complications (Clavien-Dindo, Table 6) 
• 
30-day post-operative complications according to the Comprehensive Complication Index 
• 
30-day unplanned readmission rates 
• 
Quality of recovery at post-operative day 1, 2 and 30 after laparoscopic surgery. 
o 
Quality-of-recovery (QoR-40 at postoperative day 1 and 2; Aldrete score (Table 5) at 
the PACU) 
o 
Quality-of-life at postoperative day 30 (SF36, Appendix 2) 
 
 
8.1.2 Other study parameters 
• 
Patient age, gender, length and weight, ASA class, underlying disease(s), planned procedure, 
blood pressure and heart rate, center of admission 
• 
Pre-operative NRS, QoR-40 and SF 36 
• 
Per operative the following variables will be noted, after installation of the pneumoperitoneum 
at 15 minute intervals until the end of the surgery. At these moments the L-SRS is also scored: 
o 
Heart rate (/min), blood pressure in mmHg 
o 
Intra-abdominal pressure in mmHg and total insufflations volume (in Liters) 
o 
Depth of anesthesia: Bispectral Index and end-tidal sevoflurane 
o 
Depth of NMB (TOF count and/or PTC) 
o 
Duration of surgery and anesthesia 
o 
Time of extubation 
o 
Cumulative drug dosages (propofol, opioids, muscle relaxant, reversal agent, 
inotropics, NSAIDS’s or metamizol) 
o 
Core temperature in degrees Celsius 
o 
Surgical satisfaction with the anesthesia: ‘very dissatisfied’, ‘dissatisfied’, ‘satisfied’ 
tot ‘very satisfied’. 
• 
Postoperative recovery scores: 
o 
Time to discharge readiness (Aldrete score≥9 and NRS<5) 
o 
Heart rate (/min), blood pressure in mmHg 
o 
peripheral oxygen saturation, respiratory rate (/min), use of supplemental O2 (in 
liters/minute) 
o 
NRS and administration of analgesic medication 
o 
Ramsay sedation scale and Aldrete score 
o 
Nausea or vomiting 

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18 
 
• 
Length of admission at the PACU and/or ICU (if applicable) and duration of hospital admission 
o 
Pain scores (numeric rating scale; NRS 0 no pain – 10 worst pain imaginable) at 
movement (and rest) three times daily until discharge or to a maximum of 72 
hours will be extracted from the patient clinical charts. 
o 
Medication use (three times daily until discharge or to a maximum of 72 hours) will be 
extracted from the patient clinical charts. 
▪ 
Cumulative opiate use 
▪ 
Cumulative use of other analgesics and anti-emetics 
 
 
8.2 
Randomization, blinding and treatment allocation 
Patient will be randomized between group 1 (deep NMB) or group 2 (standard care) just prior to surgery 
by an independent research nurse. Randomization will be performed using a dedicated, password 
protected website. The randomization sequence is generated by a dedicated computer randomization 
software; Castor (Castor EDC, CIWIT B.V., www.castoredc.com), stratified per center and BUPA 
category (MAJOR, MAJOR PLUS or COMPLEX MAJOR). To ensure a balanced distribution block, 
randomization will be used with 2 and 4 cases per block.  
Blinding: 
During every procedure, an unblinded researcher will be present to ensure adherence to the study 
protocol. Specifically, he or she will be responsible for maintaining the desired level of NMB. The 
researcher will not be involved in scoring of the Classic events (primary outcome). Classic scorings will 
be done by the attending anesthesiologist and surgeon who will be blinded.  
To avoid deblinding of the surgical team in the standard NMB group (by noting the absence of a 
rocuronium perfusion), a syringe pump with NaCl 0.9% will substitute the rocuronium infusion. 
Postoperative care nurses and the investigator assessing postoperative endpoints are blinded to 
group allocation. Additionally, data analysis will be performed by blinded researchers. 
 
8.3 
Study procedures 
 
    Informed consent procedure 
Patients will be screened for eligibility on the routine preoperative visit at the anesthesia outpatient 
department. Should a patient be eligible, than he or she will be contacted by one of the researchers by 
phone to receive oral and written information about the study. This contact will take place at least 2 weeks 
prior to the surgical procedure. If the patient is willing to participate, written consent will be obtained 
 
Preoperative procedures 
After informed consent has been obtained, baseline QoR-40 and SF36 questionnaires will be taken 
prior to surgery and randomization. 
 
Perioperative procedures 
 
Anesthesia procedures: Anesthesia procedures will follow local protocol on all aspects, except for 

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the neuromuscular block. Standard anesthesia iv access and standard monitoring according to local 
institutional protocol will be applied. General anesthesia will be induced and maintained with propofol 
or sevoflurane or desflurane. Intraoperative antinociceptive treatment will be with sufentanil, fentanyl 
or remifentanil. The choice regarding the type of hypnotic and opioid is upon the discretion of the 
attending anesthesiologist and is not influenced by this study. Hypnotic depth of all patients will be 
routinely monitored with bispectral index monitoring (BIS module, Philips, Eindhoven, The 
Netherlands) or entropy assessment to assess the level of hypnosis. The target level of the BIS is 50 
+/- 5 during the procedure, and propofol dosage or end-tidal sevoflurane/desflurane will be steered to 
maintain the target BIS level to avoid under- or overdosing of the hypnotic agent. 
Postoperative pain relief will be ensured with morphine, or equivalent (eg. Piritramide or methadone), 
and NSAIDs (eg. Diclofenac 50 - 75 mg) or metamizole 1g, and acetaminophen 1g. Lidocaine iv, 
magnesium, β-blocking agents, and/or loco-regional infiltration / techniques are not allowed. 
 
Ventilation: will be adjusted to maintain end-tidal pCO2 of 4.5 to 5.5 kPa.  
 
Postoperative pain relief. Pain relief at the PACU is left to at discretion of the attending 
anesthesiologists. All analgesics that are administered will be recorded in the e-CRF 
 
Neuromuscular management 
All patients will receive neuromuscular monitoring according to international guidelines for 
neuromuscular monitoring in research.[15] Neuromuscular monitoring will exclusively be applied at 
the m. adductor pollicis of one of the free moving thumbs  The following devices are allowed in this 
study: TOF-scan, Idmed, France, CE 0459 TOF-Watch, Organon, Ireland, CE 0543; or 
electromyography; GE NMT, GE-healthcare, Finland, CE 0537 . 
All monitors will be applied in accordance with the guidelines of the manufacturer, including any 
baseline and calibration procedures; these will take place after the patient has been put under 
general anesthesia, but before the administration of any NMBA. Baseline TOF ratio will be noted in 
the CRF.  All monitor types can be used interchangeably in practice of this study. Patients may 
only be extubated when the TOF ratio is at least 0.9. 
 
Surgical procedures: All laparoscopic procedures will exclusively be performed at standard 
insufflation pressures (IAP 12 mmHg). After insufflation, intra- abdominal volume will be recorded. 
This provides an indirect measure of abdominal wall compliance and workspace.  
 
 
Intra operative scoring procedures 
 
 
Intra operative adverse events 
 
Intra operative adverse events will be scored using the CLASSIC score (see table 2). This score has 
recently been developed and validated in a Delphi study (NCT03009929). Scoring of the CLASSIC scale 

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will be done by the blinded surgeon and blinded attending anesthesiologist (based on consensus) at the 
end of every procedure. Notably, the unblinded researcher on the OR is NOT involved in the scoring. 
CLASSIC classification is only applicable for events that have occurred during the procedure, any adverse 
event at PACU and beyond will be scored using Clavien Dindo scale (see table 6). 
 
All surgeons will be trained prior to inclusion to objectively score CLASSIC grades consistently over the 
different centers. This will be done by a group of investigators that will form a blinded adjudication 
committee (BAC) that will review each case based on the operative report. The first two to three cases in 
each center will be attended by the BAC to evaluate whether the surgeons are able to score reliably after 
the initial training phase. Furthermore, interim evaluation of consistent reporting of the primary outcome will 
be performed by the BAC after N=10, N=20, N=50, and N=100 cases to check for discrepancies. Further 
training of surgeons after interim evaluation moments may be warranted 
 
 
 
Intraoperative surgical conditions 
 
Surgical working conditions will be scored by the blinded surgeon at 15 minutes intervals during the 
procedure, using the validated Leiden surgical rating scale (see table 3)[16].  
 
Surgeons involved in the study will be trained in L-SRS scoring prior to study start by the local sub-PI 
 
Table 3. L-SRS classification in laparoscopic surgery[6, 17]. 
 
1 
Extremely poor conditions: The surgeon is unable to work due to coughing or due to the 
inability to obtain a visible laparoscopic field because of inadequate muscle relaxation. 
Additional muscle relaxants are given. 
2 
Poor conditions: There is a visible laparoscopic field but the surgeon is severely hampered by 
inadequate muscle relaxation with continuous muscle contractions and/or movements with the 
hazard of tissue damage. Additional muscle relaxants are given. 
3 
Acceptable conditions: There is a wide visible laparoscopic field but muscle contractions 
and/or movements occur regularly causing some interference with the surgeon’s work. There is 
the need for additional muscle relaxants to prevent deterioration. 
4 
Good conditions: There is a wide laparoscopic working field with sporadic muscle 
contractions and/or movements. There is no immediate need for additional muscle relaxants 
unless there is the fear for deterioration. 
5 
Optimal conditions: There is a wide visible laparoscopic working field without any movement 
or contractions. There is no need for additional muscle relaxants. 
 
 
In case of suboptimal surgical working conditions (deterioration of the L-SRS) or an adverse event 
CLASSIC ≥ 2, the following measures may be taken (and will be recorded): 
1. Administration of rocuronium: 10 mg (repeated on request) 
2. Administration of propofol 20-50 mg 

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3. Additional bolus of opioids (remifentanil, sufentanil, fentanyl) 
4. Increasing the intra-abdominal pressure (with a maximum of 16 mmHg) 
 
 
Immediate postoperative measurements 
These postoperative measurements will be recorded by an independent and blinded nurse/researcher at 
the post anesthesia care unit (PACU). The measurements include: 
 
At 15 minutes intervals 
Oxygen saturation and use of any supplemental oxygen 
Hart rate and blood pressure 
Pain: using numeric rating scale (NRS: 0 no pain to 10 worst pain imaginable) 
Sedation scores: using ramsey sedation score (see table 4) 
 
Other variables recorded: 
Medication use, including analgesic consumption 
Time until discharge readiness: Aldrete score ≥9 (see table 5) and NRS <5 
 
Adverse events at the PACU and beyond will be recorded using the Clavien Dindo scale (see table 6). 
These events will be scored by a blinded researcher.  
 
Table 4. Ramsay sedation score.[18, 19] 
 
Score 
Response 
1 
Awake and anxious, agitated, or restless 
2 
Awake, cooperative, accepting ventilation, oriented, or tranquil 
3 
Awake, responds only to commands 
4 
Asleep, brisk response to light, glabella tap, or loud noise 
5 
Asleep, sluggish response to light, glabella tap, or loud noise 
6 
Asleep, no response to light, glabella tap, or loud noise 
 
Table 5. Aldrete score[20] 
 
Activity 
Respiration 
Circulation 
Consciousness 
Oxygen 
Saturation 
2: Moves all 
extremities 
voluntarily/ on 
command 
2: Breaths deeply 
and coughs 
freely. 
2: BP + 20 mmHg 
of preanesthetic 
level 
2: Fully awake 
2: SpO2 > 92% on 
room air 
1: Moves 2 
extremities 
1: Dyspnoeic, 
shallow or limited 
breathing 
1: BP + 20-50 
mmHg of 
preanesthetic 
level 
1: Arousable on 
calling 
1: Supplemental 
O2 required to 
maintainSpO2 
>90% 

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0: Unable to 
move extremities 
0: Apnoeic 
0: BP +50 mmHg 
of preanesthetic 
level 
0: Not responding 
0: SpO2 <90% 
with O2 
supplementation 
 
Table 6. Clavien-Dindo Classification.[21] 
 
Grade I 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic and radiological 
intervention. Allowed therapeutic regimens are: drugs as antiemetics, 
antipyretics, analgetics, diuretics and electrolytes and physiotherapy. This 
grade also includes wound 
infections opened at the bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed 
for grade I complications. 
Blood transfusions and total parenteral nutrition are also included 
Grade III 
Requiring surgical, endoscopic or radiological 
intervention IIIa Intervention not under general 
anaesthesia 
IIIb Intervention under general anaesthesia 
Grade IV 
Life-threatening complication (including CNS complications)‡ requiring 
IC/ICU IVa Single organ dysfunction (incl. dialysis) 
IVb Multi organ dysfunction 
Grade V 
Death of a patient 
Suffix ‘d’ 
If the patient suffers from a complication at the time of discharge, the suffix 
‘d’ (for ‘disability’) is added to the respective grade of complication. 
‡ brain haemorrhage, ischaemic stroke, subarachnoidal bleeding, but excluding transient ischaemic attacks 
(TIA); IC: Intermediate care; ICU: Intensive care unit 
 
    
 
Other postoperative measurements 
Pain scores (NRS) at movement (and rest) three times daily at the ward until discharge or to a 
maximum of 72 hours, which will be extracted from the patient clinical charts. 
 
Adverse events on the ward will be evaluated daily at hospitalization until discharge by a blinded 
researcher using the Clavien Dindo scale. 
 
The quality of recovery score (QOR-40 questionnaire, appendix 1)[22] are filled in by the patient at day 
1 and 2 after surgery. 
 
30 days after surgery, a blinded researcher will evaluate any unplanned readmissions. In addition, 
patients will be contacted whether or not they have been readmitted in this period in any other hospital. 

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Also the SF36[23] questionnaire will be taken during this contact. 
Additionally, the Comprehensive Complication Index (https://www.assessurgery.com/) will be used to 
grade postoperative complications [24] 
 
8.4 
Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent medical 
reasons such as anaphylaxis or unanticipated difficult airway at induction of anesthesia.  
 
8.4.1 Specific criteria for withdrawal 
Not applicable in this study 
 
 
8.5 
Replacement of individual subjects after withdrawal 
Patients who are not randomized (the surgery is cancelled due to logistic or patient factors) are 
replaced by new subjects. Patients that underwent surgery will not be replaced. 
 
 
8.6 
Follow-up of subjects withdrawn from treatment 
Patients who are withdrawn (conversion to deep NMB) by their physician will be subjected to follow up 
according to the intention to treat principle. When a patient withdraws their consent they will not be 
subjected to follow–up. 
Patient that met the drop-out criteria stated in paragraph 4.4 will not reach the studies primary outcome. 
 
 
 
8.7 
Premature termination of the study 
In case the study is ended prematurely, the investigator will notify the accredited IRB or METC within 
15 days, including the reasons for the premature termination. Within one year after the end of the 
study, the investigator/sponsor will submit a final study report with the results of the study, including 
any publications or abstracts of the study, to the accredited METC. 

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9. SAFETY REPORTING 
 
9.1 
Temporary halt for reasons of subject safety 
 
 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there 
is sufficient ground that continuation of the study will jeopardize subject health or safety. The 
sponsor will notify the accredited METC without undue delay of a temporary halt including the 
reason for such an action. The study will be suspended pending a further positive decision by the 
accredited METC. The investigator will take care that all subjects are kept informed. 
 
 
9.2 
AEs, SAEs and SUSARs 
 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the trial procedure. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded, only 
if judged to be substantial deviating from expected standard 
clinical course. This includes severe adverse events that influence 
postoperative recovery or clinical outcome. 
 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that 
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events. Subjects will be followed up for AEs and SAEs until the final study 
procedures or 7 days after discontinuation of the study. All reports will be digitally filed in the 
electronic clinical research form; Castor ((Castor EDC, CIWIT B.V., www.castoredc.com ). 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited. METC 
that approved the protocol, within 7 days of first knowledge for SAEs that result in death or are life 
threatening followed by a period of maximum of 8 days to complete the initial preliminary report. 

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All other SAEs will be reported within a period of maximum 15 days after the sponsor has first 
knowledge of the serious adverse events. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable as in this study there is no investigational medicinal product. 
 
 
9.3 
Annual safety report 
Not applicable as in this study there is no investigational medicinal product. 
 
 
9.4 
Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol 
 
 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee 
In this strategy study, which compares two standard-of-care rocuronium dosage regimens, there 
are no additional risks for the patients. We therefore see no need for a DSMB in this low risk study. 

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10. STATISTICAL ANALYSIS 
 
 
10.1 Primary study parameter 
Data will be analyzed comparing the incidence of adverse events during laparoscopic surgery, 
following the Classic criteria using χ2 test with p < 0.05 considered significant. Data analysis will 
be performed using R Studio, Boston, MA, USA. 
 
 
10.2 Secondary study parameters 
Continuous normally distributed variables will be expressed by their mean and standard deviation 
or when not normally distributed as medians and their interquartile ranges. Categorical variables 
will be expressed as n (%). To test groups Student’s t test will be used, if continuous data are not 
normally distributed the Mann-Whitney U test will be used. Categorical variables will be compared 
with the Chi-square test or Fisher’s exact tests. P-values < 0.05 will be considered significant for 
the primary outcome. A cut off p-value of < 0.01 will be applied for secondary outcomes. 
Data analysis will be performed using R Studio, Boston, MA, USA.. 
 
 
Longitudinal data (heart rate, blood pressure, L-SRS, BIS levels compared to the depth of NMB at 
the given moment) will be analyzed using linear mixed models. NONMEM (ICON Development 
Solutions, Ellicott, MD, USA), will be used for statistical analysis. 
 
 
10.3 Other study parameters 
Demographic data, pre-operative NRS scores, perioperative administered cumulative drugs 
dosage and length of admission (at PACU, ICU and/or ward) will be reported. 
Continuous normally distributed variables will be expressed by their mean and standard deviation 
or when not normally distributed as medians and their interquartile ranges. Categorical variables 
will be expressed as n (%). To test groups Student’s t test will be used, if continuous data are not 
normally distributed the Mann-Whitney U test will be used. Categorical variables will be compared 
with the Chi-square test or Fisher’s exact tests. P-values < 0.05 will be considered significant. 
Data analysis will be performed using R Studio, Boston, MA, USA.. 
 
 
10.4 Interim analysis 
No planned interim analysis will be performed. 

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11. ETHICAL CONSIDERATIONS 
 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki as stated in 
the current version of Fortaleza, Brazil, 2013 and in accordance with the Medical Research 
Involving Human Subjects Act (WMO). 
 
 
11.2 Recruitment and consent 
Only adults who are not incapacitated are recruited after initial screening at the preoperative 
screening visit. All possible study candidates will receive a copy of the patent information sheet 
and a copy of the consent form, at a considerable time before surgery. Patient consent will be 
obtained, in person, before surgery by one of the researchers. 
 
 
11.3 Benefits and risks assessment, group relatedness 
Not applicable 
 
 
11.4 Compensation for injury 
In this study two common practices are compared that are deemed safe. Hence there are no 
potential issues of concern and insurance according to Article 7 WMO is not required in this study. 
 
 
11.5 Incentives 
Not applicable 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
12.1 Handling and storage of data and documents 
The principle investigators have responsibility with regard to the data at every site. MW and MvV 
hold final responsibility with regard to the pooled data. Castor will be used to minimize errors and 
to ensure traceability. An independent statistician will provide assistance for data-analysis of the 
blinded data. 
All patients will be addressed to with a random patient identification code. Patient identifying data 
will be omitted. The codebook will be stored digitally and in paper and will be safeguarded by the 
investigator. The paper version will be stored behind a lock and the digital form will be encrypted. 
Source data will be stored at the specific study site where it originated and will be safeguarded by 
the local investigator. Data sent to the investigator will only contain this code and will not contain 
patient identifying data. Other involved parties (monitor, Inspectie Gezondheidszorg en Jeugd) 
could be granted access to patient data, also patient identifying data, to review if the research is 
being executed safely. These involved parties will handle the patient identifying data in a 
confidential manner. The sponsor, local researchers and project leader are responsible for data 
processing. When a subject withdraws consent, data collected until that moment will be used. All 
data will be stored for the length of the study and for 15 years afterwards, for further publication. 
All handling of personal data will comply with the Dutch Act on Implementation of the General 
Data Protection Regulation. 
 
The Functionaris Gegevensbescherming from the LUMC has been informed about the data 
handling in the EURO-Relax-trial. When subjects have questions or complaints about data 
handling they can contact the Functionaris Gegevensbescherming (contact information is 
mentioned in the patient information letter). Additionally, the Functionaris Gegevensbescherming 
will assess if our data are handled in compliance with the law. 
 
Data needed to assess primary- and secondary objectives will be collected (see paragraph 8.1.1, 
8.1.2 and 8.1.3) 
 
 
12.2 Monitoring and Quality Assurance 
On-site monitoring will comprise controlling presence and completeness of the research dossier 
and the informed consent forms, source data checks will be performed as described in the 
monitoring plan. Every participating centre will be visited at least once every year. The monitor of 
this study in the LUMC is selected out of the monitoring pool of the LUMC. The other study sites 
will be monitored by a trained monitor not involved in the study. The details of monitoring will be 
described in the monitoring plan. 
12.3 Amendments 

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A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or 
to the protocol or any other supporting documentation, that is likely to affect to a significant 
degree: 
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor. 
12.4 Annual progress report 
 
 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse events/ 
serious adverse reactions, other problems, and amendments. 
 
 
12.5 Temporary halt and (prematurely) end of study report 
 
 
The investigator/sponsor will notify the accredited METC of the end of the study within a period of 
8 weeks. The end of the study is defined as the last patient’s last visit. 
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the accredited 
METC. 
 
 
12.6 Public disclosure and publication policy 
 
 
 
The study protocol and analysis plan will be published before start of the study on clinicaltrial.gov 
(trialnumber: tbd). The results of the study will find their way into (inter–) national scientific journals 

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and guidelines. We will submit analyses to scientific journals in the field of anaesthesiology. The re- 
sults of this study will be disclosed unreservedly according to the Central Committee on Research 
Involving Human Subjects (CCMO) statement on publication policy (http://www.ccmo.nl/attach- 
ments/files/ccmo-statement-publicatiebeleid-3-02-en.pdf). 
 
Material for public dissemination will be submitted to the sponsor for review prior to submission for 
publication. 

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13. STRUCTURED RISK ANALYSIS 
 
13.1 Potential issues of concern 
In this study two common practices are compared that are deemed safe. Hence there are no 
potential issues of concern. 
 
 
13.2 Synthesis 
The aim of our this is to compare two common anesthesia practices. The patient population is able 
to provide consent and without an increased risk for any unwanted effects stated below. The types 
of surgery in this study are not associated with a high risk of complications. Hence, there will be no 
additional risks to the patient that participate in this study. 

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14. Appendixes 
QOR-40 questionnaire, appendix 1 
SF36 questionnaire, appendix 2 
 
15. References 
 
1. 
Blobner, M., et al., Neuromuscular blockade improves surgical conditions (NISCO). Surg 
Endosc, 2015. 29(3): p. 627-36. 
2. 
Boon, M., et al., Influence of variations in arterial PCO2 on surgical conditions during 
laparoscopic retroperitoneal surgery. Br J Anaesth, 2016. 117(1): p. 59-65. 
3. 
Bruintjes, M.H., et al., Deep neuromuscular block to optimize surgical space conditions 
during laparoscopic surgery: a systematic review and meta-analysis. Br J Anaesth, 2017. 
118(6): p. 834-842. 
4. 
Madsen, M.V., et al., Optimising abdominal space with deep neuromuscular blockade in 
gynaecologic laparoscopy--a randomised, blinded crossover study. Acta Anaesthesiol 
Scand, 2015. 59(4): p. 441-7. 
5. 
Madsen, M.V., et al., Influence of deep neuromuscular block on the surgeons assessment 
of surgical conditions during laparotomy: a randomized controlled double blinded trial with 
rocuronium and sugammadex. Br J Anaesth, 2017. 119(3): p. 435-442. 
6. 
Martini, C.H., et al., Evaluation of surgical conditions during laparoscopic surgery in 
patients with moderate vs deep neuromuscular block. Br J Anaesth, 2014. 112(3): p. 498-
505. 
7. 
Torensma, B., et al., Deep Neuromuscular Block Improves Surgical Conditions during 
Bariatric Surgery and Reduces Postoperative Pain: A Randomized Double Blind 
Controlled Trial. PLoS One, 2016. 11(12): p. e0167907. 
8. 
Yoo, Y.C., et al., The Intraocular Pressure under Deep versus Moderate Neuromuscular 
Blockade during Low-Pressure Robot Assisted Laparoscopic Radical Prostatectomy in a 
Randomized Trial. PLoS One, 2015. 10(8): p. e0135412. 
9. 
Brueckmann, B., et al., Effects of sugammadex on incidence of postoperative residual 
neuromuscular blockade: a randomized, controlled study. Br J Anaesth, 2015. 115(5): p. 
743-51. 
10. 
Boon, M., et al., Impact of high- versus low-dose neuromuscular blocking agent 
administration on unplanned 30-day readmission rates in retroperitoneal laparoscopic 
surgery. PLoS One, 2018. 13(5): p. e0197036. 
11. 
Bruintjes, M.H., et al., Effectiveness of deep versus moderate muscle relaxation during 
laparoscopic donor nephrectomy in enhancing postoperative recovery: study protocol for a 
randomized controlled study. Trials, 2017. 18(1): p. 99. 
12. 
Ozdemir-van Brunschot, D.M.D., et al., Deep neuromuscular blockade improves surgical 
conditions during low-pressure pneumoperitoneum laparoscopic donor nephrectomy. Surg 
Endosc, 2018. 32(1): p. 245-251. 
13. 
Ozdemir-van Brunschot, D.M.D., et al., Quality of Recovery After Low-Pressure 
Laparoscopic Donor Nephrectomy Facilitated by Deep Neuromuscular Blockade: A 
Randomized Controlled Study. World J Surg, 2017. 41(11): p. 2950-2958. 
14. 
Warle, M.C., et al., Low-pressure pneumoperitoneum during laparoscopic donor 
nephrectomy to optimize live donors' comfort. Clin Transplant, 2013. 27(4): p. E478-83. 
15. 
Fuchs-Buder, T., et al., Good clinical research practice in pharmacodynamic studies of 
neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand, 2007. 
51(7): p. 789-808. 
16. 
Boon, M., et al., The use of surgical rating scales for the evaluation of surgical working 
conditions during laparoscopic surgery: a scoping review. Surg Endosc, 2019. 33(1): p. 19-
25. 
17. 
Boon, M., et al., The use of surgical rating scales for the evaluation of surgical working 
conditions during laparoscopic surgery: a scoping review. Surg Endosc, 2018. 

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18. 
American Society of Anesthesiologists Task Force on, S. and N.-A. Analgesia by, Practice 
guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology, 2002. 
96(4): p. 1004-17. 
19. 
Newton, T., I. Pop, and E. Duvall, Sedation scales and measures--a literature review. 
SAAD Dig, 2013. 29: p. 88-99. 
20. 
Phillips, N.M., et al., Post-anaesthetic discharge scoring criteria: key findings from a 
systematic review. Int J Evid Based Healthc, 2013. 11(4): p. 275-84. 
21. 
Dindo, D., N. Demartines, and P.A. Clavien, Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg, 
2004. 240(2): p. 205-13. 
22. 
Gornall, B.F., et al., Measurement of quality of recovery using the QoR-40: a quantitative 
systematic review. Br J Anaesth, 2013. 111(2): p. 161-9. 
23. 
Antonescu, I., et al., Validation of the SF-36 as a measure of postoperative recovery after 
colorectal surgery. Surg Endosc, 2014. 28(11): p. 3168-78. 
24. 
Clavien, P.A., et al., The Comprehensive Complication Index (CCI(R)): Added Value and 
Clinical Perspectives 3 Years "Down the Line". Ann Surg, 2017. 265(6): p. 1045-1050.