The Effectiveness of Deep Versus Moderate Muscle Relaxation During Laparoscopic Donor Nephrectomy in Enhancing Postoperative Recovery
Phase: PHASE4
Conditions: Neuromuscular Block, Renal Transplant Donor of Left Kidney, Renal Transplant Donor of Right Kidney, Surgery
Sponsor: Radboud University Medical Center

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RESEARCH PROTOCOL 
 
The effectiveness of deep versus  
moderate neuromuscular blockade  
  
 during laparoscopic donor nephrectomy  
 
in enhancing postoperative recovery. 
 
 
A blinded, randomized controlled study 
 
 
RELAX study 
 
 
 

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PROTOCOL TITLE  
The effectiveness of deep versus moderate neuromuscular blockade  
during laparoscopic donor nephrectomy in enhancing postoperative recovery. 
 
Protocol ID 
The effectiveness of deep versus moderate 
neuromuscular blockade during laparoscopic donor 
nephrectomy in enhancing postoperative recovery. 
Short title 
RELAX study 
EudraCT number  
Not applicable 
Version 
1 
Date 
23-08-2016 
Coordinating investigator 
 
M.H.D. Bruintjes, MD  
Department of Surgery, route 618  
Geert Grooteplein Zuid 10  
6525 GA Nijmegen, the Netherlands  
E-mail: Moira.Bruintjes@radboudumc.nl  
Telephone number: +(31)-6-22536733 or (+)31-24-
3615333  
Fax number: +31-24-3635115 
Principal investigators 
 
M.C. Warlé, MD PhD  
Department of Surgery, route 618  
Geert Grooteplein Zuid 10  
6525 GA Nijmegen, The Netherlands  
E-mail: Michiel.Warle@radboudumc.nl  
Telephone number: (+)31-24-3615333  
Fax: +31-24-3635115 
 
Prof. G.J, Scheffer, MD PhD 
Department of Anesthesiology, route 598 
Geert Grooteplein 10 
6525 GA Nijmegen, The Netherlands 
E-mail: GertJan.Scheffer@radboudumc.nl 
Telephone number: (+)31-24 365 56 53 
Fax: (+)31-24-3616958 

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A.E. Braat, MD PhD  
Department of Surgery, D6-Q  
Albinusdreef 2  
2333 ZA Leiden, The Netherlands  
E-mail: a.e.braat@lumc.nl  
Telephone number: (+)31-71-5266188  
Fax number: +(31)-71-5266750 
 
Prof. A. Dahan, MD Phd 
Department of Anesthesiology 
Albinusdreef 2, P5-Q 
2333 ZA Leiden, The Netherlands 
E-mail: a.dahan@lumc.nl  
Telephone number: (+31)-71 5262301 
Fax number: +(31)-71-5266230 
Sponsor  
Radboudumc Nijmegen 
Subsidising party 
Merck Sharp & Dohme BV,  
Waarderweg 39, 2031 BN Haarlem, The Netherlands 
E-mail: info@MSD.nl 
Telephone number: (+)31-23-5153153 
Fax-number: (+)31-23-5148000   
Independent expert  
Prof. M.J.R. Edwards, MD PhD  
Department of Surgery, route 618  
Geert Grooteplein Zuid 10  
6525 GA Nijmegen, The Netherlands  
E-mail: Michael.Edwards@radboudumc.nl  
Telephone number: (+)31-24-3613871  
Fax number: +31-24-3635115 
Laboratory sites  
Not applicable 
Pharmacy 
Not applicable 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
 Prof. C.J.H.M. van Laarhoven, MD, PhD  
 Department of Surgery, route 618  
 Geert Grooteplein Zuid 10  
 6525 GA Nijmegen, The Netherlands  
 E-mail: 
Kees.vanLaarhoven@radboudumc.nl  
 Telephone number: (+)31-24-3616421  
 Fax number: +31-24-3635115 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator: 
M.C. Warlé, MD PhD  
Department of Surgery, route 618  
Geert Grooteplein Zuid 10  
6525 GA Nijmegen, The Netherlands  
E-mail: Michiel.Warle@radboudumc.nl  
Telephone number: (+)31-24-3615333  
Fax: +31-24-3635115 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population ..............................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................15 
4.4 
Sample size calculation ..........................................................................................15 
5. 
TREATMENT OF SUBJECTS .......................................................................................17 
5.1 
Investigational treatment ........................................................................................17 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................19 
6.1 
Name and description of investigational  product(s) ...............................................19 
6.2 
Summary of findings from non-clinical studies ........................................................19 
6.3 
Summary of findings from clinical studies ...............................................................19 
6.4 
Summary of known and potential risks and benefits ...............................................20 
6.5 
Description and justification of route of administration and dosage .........................21 
6.6 
Dosages, dosage modifications and method of administration ...............................22 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................22 
6.8 
Drug accountability .................................................................................................22 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................22 
8. 
METHODS ....................................................................................................................23 
8.1 
Study parameters/endpoints ...................................................................................23 
8.1.1 
Main study parameter/endpoint .......................................................................23 
8.1.2 
Secondary study parameters/endpoints ..........................................................23 
8.1.3 
Other study parameters ...................................................................................24 
8.2 
Randomisation, blinding and treatment allocation ..................................................25 
8.3 
Study procedures ...................................................................................................25 
8.4 
Withdrawal of individual subjects ............................................................................25 
8.5 
Replacement of individual subjects after withdrawal ...............................................25 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................25 
8.7 
Premature termination of the study .........................................................................26 
9. 
SAFETY REPORTING ..................................................................................................26 
9.1 
Temporary halt for reasons of subject safety ..........................................................26 
9.2 
AEs, SAEs and SUSARs ........................................................................................26 
9.2.1 
Adverse events (AEs) ......................................................................................26 
9.2.2 
Serious adverse events (SAEs) .......................................................................26 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................27 
9.3 
Annual safety report ...............................................................................................28 
9.4 
Follow-up of adverse events ...................................................................................28 
9.5 
Data Safety Monitoring Board (DSMB) ...................................................................29 
 

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10. 
STATISTICAL ANALYSIS ..........................................................................................30 
10.1 
Primary study parameter(s) and secondary study parameter(s) .............................30 
10.2 
Interim analysis ......................................................................................................30 
11. 
ETHICAL CONSIDERATIONS ...................................................................................31 
11.1 
Regulation statement .............................................................................................31 
11.2 
Recruitment and consent........................................................................................31 
11.3 
Objection by minors or incapacitated subjects ........................................................31 
11.4 
Benefits and risks assessment, group relatedness .................................................31 
11.5 
Compensation for injury .........................................................................................33 
11.6 
Incentives ...............................................................................................................33 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................34 
12.1 
Handling and storage of data and documents ........................................................34 
12.2 
Monitoring and Quality Assurance ..........................................................................34 
12.3 
Amendments ..........................................................................................................34 
12.4 
Annual progress report ...........................................................................................34 
12.5 
Temporary halt and (prematurely) end of study report ............................................34 
12.6 
Public disclosure and publication policy ..................................................................35 
13. 
STRUCTURED RISK ANALYSIS...............................................................................35 
14. 
REFERENCES ..........................................................................................................35 
Table 1………………………………………………………………………………………………..37 
Table 2………………………………………………………………………………………………..38 
Table 3 …………………………………………………………………………………………….....39 
Table 4………………………………………………………………………………………………..39 
Figure 1……………………………………………………………………………………………….40 
Appendix 1……………………………………………………………………………………………41 
Appendix 2 …………………………………………………………………………………………...43

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee (In 
Dutch, ABR = Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
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 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
LDN 
LUMC 
Investigational Medicinal Product Dossier  
Laparoscopic Donor Nephrectomy 
Leids Universitair Medisch Centrum 
METC 
 
NMB 
PNP 
POD 
PTC 
QOR 
RCT  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
Neuromuscular Block 
Pneumoperitoneum 
Post Operative Day 
Post Tetanic Count 
Quality of Recovery 
Randomized Controlled Trial 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie 
IB1-tekst) 
Sponsor 
 
 
 
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 

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SRS 
regarded as the sponsor, but referred to as a subsidising party. 
Surgical Rating Scale 
SUSAR 
TOF 
Suspected Unexpected Serious Adverse Reaction 
Train of Four (measurement) 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: As both patients with end-stage kidney disease as society benefit tremendously 
from living kidney donors, their safety and well-being are highly important objectives in living 
kidney donation. In this randomized controlled clinical trial we will compare the use of deep 
neuromuscular blockade versus moderate neuromuscular blockade – with standard pressure 
pneumoperitoneum – during laparoscopic donor nephrectomy. 
 
Objective: To establish the relationship between the use of deep neuromuscular blockade 
(NMB) during laparoscopic donor nephrectomy (LDN) - with standard pressure 
pneumoperitoneum (PNP) -  and the early quality of recovery. 
 
Study design: A multi-center, blinded, randomized controlled clinical trial. 
 
Study population: Adult individuals who are scheduled for living kidney donation are eligible 
for this study. All types of donors, including related, unrelated, anonymous and donors who 
participate in the “cross-over” exchange program are eligible. 
 
Intervention:  2 treatment groups:  
 deep neuromuscular blockade and standard pressure pneumoperitoneum  
 moderate neuromuscular blockade and standard pressure pneumoperitoneum 
 
Main study endpoint: Quality of recovery score (QOR-40 questionnaire) at 24 hours after 
extubation. 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
The burden for participants in this study is mainly related to the evaluation of the endpoints 
during the early postoperative phase. Assessment of the differential pain scores and the 
QOR-40 questionnaire will take approximately 10 minutes per time-point (-18h, 1h, 6h, 24h 
and 48h after detubation). As the use of a deep NMB with a standard insufflations pressure 
improves the quality of the surgical field, there are no risks related to the surgery. A deep 
neuromuscular block can be achieved by higher doses of rocuronium as compared to the 
routine intubation dose. A higher dose of rocuronium in living kidney donors is safe, as renal 
function is only slightly reduced which does not have a clinically relevant impact on the 
clearance of rocuronium. 

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To overcome the extended effects of deep neuromuscular blockade that may lead to airway 
obstruction, hypoxia, pneumonia and/or atelectasis, sugammadex is administered to 
antagonize the effects of rocuronium. Sugammadex is a rapid antagonist of neuromuscular 
blockade by rocuronium that is given immediately after surgery. Randomized controlled trials 
have shown that sugammadex can be safely administered in patients, without dose 
adjustments for young, elderly or obese patients and that it can also be safely administered 
in patients with suboptimal renal function. 
 
A recent study performed by Martini et al. has shown that deep neuromuscular blockade 
improves surgical conditions with reduced postoperative pain scores after laparoscopic 
surgery (1). Moreover, preliminary data of our recently performed Leopard-3 study, show that 
the mean SRS (surgical rating scale) was significantly better during deep NMB with less 
opiate consumption (2). Altogether, we expect that the use of deep NMB during LDN reduces 
postoperative pain scores and/or analgesia consumption. This may improve the early quality 
of recovery of living kidney donors. 

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1. INTRODUCTION AND RATIONALE 
 
In our previous pilot study (acronym: Leopard-1 study) low-pressure pneumoperitoneum 
during LDN reduced postoperative pain scores as compared to standard pressure 
pneumoperitoneum (3). This finding is in line with our recent meta-analysis which shows that 
the use of low-pressure pneumoperitoneum (7 mmHg) provides a clinically relevant reduction 
in postoperative pain scores after laparoscopic surgery (4). Despite this evidence and the 
fact that international consensus guidelines state that the lowest possible intra-abdominal 
pressure should be used during laparoscopic procedures (5, 6), almost all laparoscopic 
surgeons use a fixed standard insufflation pressure (10-15 mmHg) instead of the lowest 
possible pressure (<10 mmHg). In our view, the main reason for this is that low-pressure 
PNP may compromise the quality of the surgical field.  
 
Staehr-Rye et al. showed that the use of a deep NMB improves surgical conditions during 
low-pressure PNP laparoscopy as compared to a moderate NMB (7). To investigate whether 
the use of low-pressure PNP facilitated by profound muscle relaxation not only improves 
postoperative pain but also the early quality of recovery, we performed a blinded RCT in 
patients undergoing LDN (Leopard-2 study; NCT02146417) (8, 9). Results from this study 
show that live kidney donors allocated to the low-pressure group mobilized earlier and were 
sooner physically independent. This led to a remarkably shorter length of hospital stay. In the 
low-pressure group, 45% of live kidney donors went home at postoperative day 2 as 
compared to 20% in the standard-pressure group. However, patients in the low-pressure 
group did not have lower overall pain scores, nor reduced analgesia consumption (9).  
 
We recently completed a randomized controlled study (Leopard-3 study) in which low-
pressure PNP was used and the intra-abdominal pressure was increased step-wise in case 
of insufficient surgical conditions during LDN (2). Preliminary data show that the use of a 
deep NMB led to a mean intra-abdominal pressure of 7.5 mmHg, whereas a mean pressure 
of 9 mmHg was required to achieve sufficient conditions with a moderate NMB (paper in 
preparation). Moreover, the mean SRS score was significantly better in during deep NMB. In 
our view this shows that a step-wise approach combined with deep NMB enables the use of 
low-pressure PNP without compromising the quality of the surgical field during laparoscopic 
procedures. Interestingly, we also observed a reduced cumulative opiate consumption during 
the first 24 hours after surgery in the deep NMB group. In our view, this finding could not be 
attributed to the slight difference in mean intra-abdominal pressure (7.5 versus 9 mmHg). 
Therefore, this observation appears to contradict the results from the Leopard-2 study in 
which no difference was found between low- and standard pressure PNP with regard to 

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postoperative pain and analgesia use (please see table 1). However, results from both 
studies could be brought in line if the use of deep NMB independently reduces postoperative 
pain after laparoscopy. Therefore we hypothesize that the use of a deep NMB during LDN 
with standard pressure PNP (12 mmHg) reduces postoperative pain scores and/or analgesia 
consumption which leads to an improved early quality of recovery. 
 
 

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2. OBJECTIVES 
 
Primary Objective:  
To establish the relationship between the use of deep neuromuscular blockade (NMB) during 
laparoscopic donor nephrectomy (LDN) -with standard pressure pneumoperitoneum of 12 
mmHg- and the early quality of recovery. 
 
Secondary Objective:  
To study whether deep NMB during LDN influences postoperative pain and/or analgesia 
consumption. 

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3. STUDY DESIGN 
 
Study design and duration:  
A multi-center, blinded, randomized controlled clinical trial. 
 
A multicenter design was chosen to optimize generalizability and to guarantee patient 
enrollment within 12 months. 
 
Participating centers: 
 
Radboudumc, Nijmegen (M.C. Warlé, surgeon and G.J. Scheffer, anesthesiologist) 
 
LUMC, Leiden (A.E. Braat, surgeon and A. Dahan, anesthesiologist) 
 

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4. STUDY POPULATION 
4.1 Population  
Adult individuals who are scheduled for live kidney donation are eligible for this study. All 
types of donors, including related, unrelated, anonymous and donors who participate in 
the “cross-over” exchange program are eligible. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
 
obtained informed consent 
 
age over 18 years 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
 
insufficient control of the Dutch language to read the patient information and to fill   
out the questionnaires 
 
chronic use of analgesics or psychotropic drugs 
 
use of NSAIDs shorter than 5 days before surgery 
 
known or suspect allergy to rocuronium of sugammadex 
 
neuromuscular disease 
 
indication for rapid sequence induction 
 
deficiency of vitamin K-dependent clotting factors, coagulopathy or use ofcoumarin 
derivates. 
 
Peri-operative use of fusidic acid or flucloxacilline 
 
Severe renal impairment (creatinine clearance <30ml/min) 
 
Morbid obesity (BMI>35 kg/m2) 
 
4.4 Sample size calculation 
A sample size of 48 patients per group is needed to provide 90% power to detect a 10-
point difference in the quality of recovery score at 1 day after extubation (alpha 5%). A 
10-point difference represents a minimal relevant difference (8). Based upon our previous 
study, the standard deviation is 15 points (9).  

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At the Radboudumc and LUMC, respectively 90 and 45 laparoscopic donor nephrectomies 
are performed annually. All eligible donors will be screened. With an inclusion rate of 
approximately 80%, we expect that the screening (and inclusion period) will be 11 months. 
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational treatment 
 
The patient will be randomly assigned to one of the two treatment groups (1:1):  
 Deep neuromuscular block/group A  
 Moderate neuromuscular block/group B 
 
Intra-operative protocol 
 induction with remifentanil, propofol and rocuronium (intubation dose 0.6 mg/kg). 
Anesthesia is aimed at a bispectral index score between 45-55. Tracheal intubation is 
performed 2 minutes after administration of 0.6 mg/kg rocuronium in both groups. In 
case of a BMI>30 kg/m2 the dose rocuronium will be adjusted taking into account ideal 
body weight. In group A (deep NMB), an infusion of rocuronium (0.3 to 0.4 mg/kg) is 
started and titrated towards PTC 0-1. In group B (moderate NMB), no additional 
rocuronium is administered after tracheal intubation and the neuromuscular function 
was allowed to recover spontaneously. PTC and TOF measurements every 5 minutes. 
 in case of insufficient surgical conditions due to (severe) muscle contractions (SRS 1-
2), the protocol allows a 0.6 mg/kg bolus of rocuronium. In case of insufficient surgical 
conditions (SRS 1 or 2), the surgeon only decides to convert to an open- or hand-
assisted procedure if the safety of the patient is compromised. 
 pressure-regulated volume-controlled ventilation through an endotracheal tube with a 
mixture of oxygen in air with 5 cmH2O PEEP and tidal volume between 6 and 8 ml/kg 
is used. Minute ventilation is adjusted to main end-tidal carbon dioxide between 31 
and 43 mmHg by changing respiratory rate during surgery. 
 neuromuscular function will be monitored in a standardized fashion by an 
acceleromyograph at the wrist (TOF-watch-SX, MIPM GmbH). 
 blood loss will be compensated with colloid solution; for 100 ml blood loss, 120 ml 
colloid solution is given. 
 after induction and intubation, patient is positioned in lateral decubitus position 
 nasogastric tube for gastric decompression; removed before the end of surgery 
 core temperature is measured continuously, aiming at 36-37 C 
 no local infiltration of surgical wounds 
 the use of drains is avoided 
 One hour before the end of the procedure, a loading dose morphine of 0.2mg/kg will 
be administered. 

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 In group A, the rocuronium perfusor will be stopped after removal of the trocars.  
 After skin closure, the NMB is reversed with sugammadex using 4 mg/kg in group A 
and 2mg/kg in group B. When the patients have a stable TOF ratio of more than 0.9 
for 2 minutes and were fully awake, extubation is performed.  
Post-operative protocol equal for all patients 
 postoperative pain management: patient-controlled analgesia (morphine, 1 mg 
morphine per bolus, lock-out 6 minutes) and acetaminophen. On day 1 PCA morphine 
will be replaced by oral analgesics. 
 ondansetron 4 mg intravenous (maximum 12 mg/day) or, second choice, 
metoclaprimide (10 mg p.o.) is administered in case of nausea and/or vomiting 
 removal of urine catheter on day 1 
 immediate start of normal diet 
 immediate mobilization  
 
 
 
 

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6. INVESTIGATIONAL PRODUCT  
6.1 
Name and description of investigational  product(s) 
a) Rocuronium 10 mg/ml solution for infusion 
Rocuronium bromide is indicated as an adjunct to general anaesthesia to facilitate 
tracheal intubation during routine sequence induction and to provide skeletal muscle 
relaxation during surgery.   
 
b) Sugammadex (Bridion®) 100 mg/mL solution for injection 
Bridion reverses neuromuscular blockade induced by rocuronium or vecuronium in 
adults, by selective binding with the relaxant agent. 
 
6.2 
Summary of findings from non-clinical studies 
 
a) Rocuronium: 
Preclinical data reveal no special hazard for humans based on conventional studies of 
safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and 
development. Carcinogenicity studies have not been performed with rocuronium 
bromide (11). 
 
b) Sugammadex: 
Preclinical data reveal no special hazard for humans based on conventional studies of 
safety pharmacology, repeated dose toxicity, genotoxicity potential, and toxicity to 
reproduction, local tolerance or compatibility with blood. 
Sugammadex is rapidly cleared in preclinical species, although residual sugammadex 
was observed in bone and teeth of juvenile rats. Preclinical studies in young adult and 
mature rats demonstrate that sugammadex does not adversely affect tooth colour or 
bone quality, bone structure, or bone metabolism. Sugammadex has no effects on 
fracture repair and remodelling of bone (12).  
 
6.3 
Summary of findings from clinical studies 
a) Rocuronium: 
The standard intubation dose for geriatric patients and patients with hepatic and/or 
biliary tract disease and/or renal failure during routine anaesthesia is 0.6 mg/kg 
rocuronium bromide. Regardless of the anaesthetic technique used, the recommended 
infusion rate is 0.3-0.4 mg/kg/h. For children and adolescents the recommended 
intubation dose during routine anaesthesia and maintenance dose are similar to those 

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in adults. When used in overweight or obese patients (defined as patients with a body 
weight of 30% or more above ideal body weight) doses should be reduced taking into 
account 
ideal 
body 
weight. 
The 
following 
conditions 
may 
influence 
the 
pharmacokinetics and/or pharmacodynamics of Rocuronium: hepatic and/or biliary tract 
disease and renal failure, prolonged circulation time, neuromuscular disease, 
hypothermia, obesity, burns, hypokalaemia, hypermagnesaemia, hypocalcaemia, 
hypoproteinaemia, dehydration, acidosis, hypercapnia and cachexia (11). 
 
b) Sugammadex: 
The use of sugammadex in patients with severe renal impairment (including patients 
requiring dialysis (CrC1 < 30 mL/min)) is not recommended (see section 4.4). 
Studies in patients with severe renal impairment do not provide sufficient safety 
information to support the use of sugammadex in these patients (see also section 5.1).  
For mild and moderate renal impairment (creatinine clearance ≥ 30 and < 80 mL/min): 
the dose recommendations are the same as for adults without renal impairment. 
Even though the recovery times in elderly tend to be slower, the same dose 
recommendation as for adults should be followed. 
In obese patients, the dose of sugammadex should be based on actual body weight. 
The same dose recommendations as for adults should be followed. For mild to 
moderate hepatic impairment are no dose adjustments required, as sugammadex is 
mainly excreted renally (12). 
 
6.4 
Summary of known and potential risks and benefits. 
a) Rocuronium: 
 
The most commonly occurring adverse drug reactions include injection site 
pain/reaction, changes in vital signs and prolonged neuromuscular block. The most 
frequently reported serious adverse drug reactions during post-marketing surveillance 
is 'anaphylactic and anaphylactoid reactions' and associated symptoms (11). 
 
b) Sugammadex: 
 
Sugammadex is administered concomitantly with neuromuscular blocking agents and 
anaesthetics in surgical patients. The causality of adverse events is therefore difficult to 
assess. The most commonly reported adverse reactions in surgical patients were 
cough, airway complication of anaesthesia, anaesthetic complications, procedural 
hypotension and procedural complication (Common (≥ 1/100 to < 1/10)).  

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The following adverse reactions were reported in placebo controlled trials where 
subjects received anaesthesia and/or neuromuscular blocking agents (1,078 subject 
exposures to sugammadex versus 544 to placebo) (12):  
 
[Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 
1/100), rare (≥ 1/10,000 to <1/1,000), very rare (< 1/10,000)] 
 
System organ class  
Frequencies  
Adverse reactions (Preferred terms)  
Immune system disorders  
Uncommon  
Drug hypersensitivity reactions (see section 4.4)  
Respiratory, thoracic and 
mediastinal disorders  
Common  
Cough  
Injury, poisoning and procedural 
complications  
Common  
Airway complication of anaesthesia  
Anaesthetic complication (see section 4.4)  
Procedural hypotension  
Procedural complication  
 
6.5 
Description and justification of route of administration and dosage 
a) Rocuronium: 
Rocuronium bromide is administered intravenously (i.v.) either as a bolus injection or 
as a continuous infusion. 
The standard intubating dose during routine anaesthesia is 0.6 mg rocuronium bromide 
per kg body weight, which results in adequate intubation conditions within 60 seconds 
in nearly all patients.  
If rocuronium bromide is administered by continuous infusion, it is recommended to 
give a loading dose of 0.6 mg rocuronium bromide per kg body weight and, when the 
neuromuscular block starts to recover, to start administration by infusion. In adults 
under intravenous anaesthesia, the infusion rate required to maintain the 
neuromuscular block ranges from 0.3 - 0.6 mg/kg/h. Under inhalational anaesthesia the 
infusion rate ranges from 0.3 - 0.4 mg/kg/h (11).  
 
b) Sugammadex: 
Sugammadex should be administered intravenously as a single bolus injection. 
A dose of 4 mg/kg sugammadex is recommended if recovery has reached at least 1-2 
post-tetanic counts (PTC) following rocuronium or vecuronium induced blockade.  
A dose of 2 mg/kg sugammadex is recommended, if spontaneous recovery has 
occurred up to at least the reappearance of T2 following rocuronium or vecuronium 
induced blockade (12). 
 

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6.6 
Dosages, dosage modifications and method of administration 
 
a) Rocuronium: 
In group A (deep NMB) and group B (moderate NMB), a bolus of 0.6 mg/kg rocuronium 
is administered intravenously before tracheal intubation. After tracheal intubation, 
intravenous infusion of rocuronium (0.3 to 0.4 mg/kg) is started in group A (deep NMB), 
when PTC is more than 0 and titrated towards PTC 0-1. In group B (moderate NMB), 
no additional rocuronium is administered after tracheal intubation. 
 
b) Sugammadex: 
The NMB is reversed with an intravenous bolus injection of 4 mg/kg in group A and 2 
mg/kg in group B.  
 
6.7 
Preparation and labelling of Investigational Medicinal Product 
Due to limited funding, use of known drugs with known effects and limited risks in this trial, 
we request a waiver for annex 13 labelling of the IMPs. The IMPs that will be used will be 
prepared, labelled and administered at the bedside as described in the summary of 
product characteristics and according to local protocols for routine patient care. The 
medication will be administered by the anaesthesiologist, who is not blinded. The syringes 
with the IMPs cannot be directly observed by the blinded researchers as they will be 
covered by use of the sterile drapes.  
 
6.8 
Drug accountability 
The IMPs that will be used (Rocuronium and Sugammadex) are dispensed by the clinical 
trials unit of the pharmacy of the Radboudumc. The anaesthesiologists that prepare and 
administer the drug will perform drug accountability by logging the administered products 
and their corresponding batch numbers on patient level. We will store this information in 
the trial master file.  
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Quality of recovery score (QOR-40 questionnaire) at 24 hours after extubation 
(appendix 1). 
8.1.2 Secondary study parameters/endpoints  
Questionnaires: 
 Quality of recovery-40 score at 48 hrs after extubation, (appendix 1) 
 
Medication use: 
 Cumulative opiate use 
 Cumulative use of other analgesics and anti-emetics 
Intra-operative parameters: 
 Surgical conditions; the Surgical Rating Scale (please see Table 2) is used to 
quantify the quality of the surgical field during the pneumoperitoneum phase 
(after introduction of the Hasson trocar, after introduction of all trocars and then 
every 15 minutes). 
 Intra-operative complications (e.g.major bleeding, spleen or liver injury) 
 
Operation time, length of pneumoperitoneum, first warm ischemia time 
 
Estimated blood loss 
 
Conversion to open donor nephrectomy 
 
Conversion to hand-assisted donor nephrectomy 
 
Clinical parameters: 
 Components of pain scores (NRS 0-10): 
 Superficial wound pain score at 1, 6, 24, 48 hours (after extubation) 
 Deep intra-abdominal pain score at 1, 6, 24, 48 hours 
 Referred shoulder pain score at 1, 6, 24, 48 hours 
 
 Post-operative nausea and/or vomiting (NRS) 
 Time to reach discharge criteria* 
* discharge criteria are: adequate pain control with oral medication, passage of 
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independent and patient accepts discharge. Discharge criteria will be evaluated 
daily. If the donor for social reasons wants to stay longer (e.g. long distance from 
partner of child who are still hospitalized) the ‘virtual’ discharge date is listed. A 
physician who is independent and blinded (ward physician) is responsible for the 
actual discharge date. 
Follow up after 4 weeks:  
 30 day complications 
 Pain scores (NRS 0-10) 
 Werk en zorg Questionnaire (appendix 2) 
8.1.3 Other study parameters  
Baseline parameters: age, gender, length, weight, body mass index, comorbidity, 
side of nephrectomy. 
 
 
 
 

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8.2 
Randomisation, blinding and treatment allocation 
Randomisation: 
Computer-generated randomization (supported by our statistician) will be used with 
stratification for center. To ensure a balanced distribution, we will use block 
randomization. 
 
Blinding and treatment allocation: 
Blinding of the surgeons to the level of NMB is ensured by covering the hand with the 
neuromuscular monitoring equipment under the sterile drapes and the nerve stimulator 
and computer are placed behind the sterile drapes away from the surgeons. All study 
medications are prepared (and labeled ‘study medicine’)  by the anesthesiologist or 
his/her assistant after opening the envelope containing the allocation of treatment. This 
will be done in the operating room before the surgeons enter. Surgeons, scrub nurses, 
postoperative care nurses and the investigator assessing the postoperative endpoints are 
blinded to group allocation. The attending anesthetic staff in the operating room is not 
blinded.  
 
8.3 
Study procedures 
The peri-operative flowchart is shown in figure 1. 
 
With regard to the primary hypothesis the QOR-40 score at pod 1 is the primary variable. 
 
With regard to the secondary hypotheses variables and time-points of interest are shown 
in Table 3 and Table 4. 
 
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. 
 
8.5 
Replacement of individual subjects after withdrawal 
Patients withdrawing will be replaced, with a maximum of 10 patients. 
 
8.6 
Follow-up of subjects withdrawn from treatment 
In case of withdrawal the patient will not be followed. 

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8.7 
Premature termination of the study 
 
Not applicable. 
 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the investigator will inform the 
subjects and the reviewing accredited METC if anything occurs, on the basis of which it 
appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal. The study will be suspended pending further review by 
the accredited METC, except insofar as suspension would jeopardise the subjects’ 
health. 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 components of the 
intervention group (deep neuromuscular block). All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect at any dose: 
 
Results in death 
 
If life threatening (at any 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 
 
Any other important medical event that may not result in death, be life 
threatening, or require hospitalization, may be considered a serious adverse 
experience when, based upon appropriate medical judgement, the event may 
jeopardize the subject or may require an intervention to prevent one of the 
outcomes listed above. 
 

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SAEs that result in death or are life threatening should be reported expedited. The 
expedited reporting will occur not later than 7 days after the coordinating investigator 
has first knowledge of the adverse reaction. This is for a preliminary report with 
another 8 days for completion of the report. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline  to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 

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The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 
In case of a SUSAR  in the participating center LUMC, the responsible investigator 
of LUMC will inform the Radboudumc within the legal terms and the coordinating 
investigator of Radboudumc will report the SUSAR to the METC. 
 
In case of a SUSAR the anesthesiologist will uncover the randomization.  
9.3 
Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
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. 
 

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9.5 Data Safety Monitoring Board (DSMB)  
The need for a DSMB is assessed taking the EMEA guidelines on data monitoring 
committees into consideration. We believe that an interim evaluation does not increase 
patient safety, because safety of the procedure has already been proven. Study conduct 
and progress will be monitored according a monitor plan. Thus, a DSMB is not beneficial 
considering the proposed study design and will therefore not be established  
 
 
 
 
  
 
 

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10. STATISTICAL ANALYSIS 
 
The principle investigator (MW) has final responsibility with regard to the data; a web-
based data management system will be used to minimize errors and to ensure 
traceability. An independent statistician will provide assistance for data-analysis. The data 
will be unblended after completion of the follow-up period and identification of protocol 
violations. 
 
10.1 Primary study parameter(s) and secondary study parameter(s)  
For the primary analysis group A and B will be compared with regard to the primary end-
point (QOR-40 score at day 1). Factorial ANOVA will be used to compare groups and to 
adjust for co-variates i.e. age, gender and side of nephrectomy. P-values < 0.05 will be 
considered statistically significant. All analyses will be performed on an intention-to-treat 
basis. 
 
 
Study parameters/endpoints 
Presentation of data 
(quantitative/qualitative) 
Quality of recovery 
Quantitative 
Medication use 
Quantitative 
Pain 
Quantitative 
Surgical rating score 
Quantitative 
Nausea/vomiting 
Quantitative 
Surgical parameters 
Quantitative 
Evaluation of post-operative 
complications 
Quantitative 
 
10.2 Interim analysis  
 
Not applicable. 

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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 (59th 
version, Seoul, October 2008) and in accordance with the Medical Research involving 
Human Subjects Act (WMO) and other guidelines, regulations and Acts. 
 
11.2 Recruitment and consent 
At the Radboudumc and LUMC, respectively 90 and 45 laparoscopic donor 
nephrectomies are performed annually. All eligible donors will be screened. With an 
inclusion rate of approximately 80%, we expect that the screening (and inclusion period) 
will be 11 months.  
 
Informed consent is obtained at least two weeks after providing written information about 
the study. During this two-week interval, an independent physician can be consulted for 
questions. At the day of hospital admission, one day before surgery, informed consent 
will be obtained. Then, one, unique number will be assigned (study number). 
 
11.3 Objection by minors or incapacitated subjects  
Not applicable. 
 
11.4 Benefits and risks assessment, group relatedness 
The burden for participants in this study is mainly related to the evaluation of the 
endpoints during the early postoperative phase. Assessment of the differential pain 
scores and the QOR-40 questionnaire will take approximately 10 minutes per time-point 
(-18h, 1h, 4h, 8h, 24h and 48h after detubation). As the use of a deep NMB with a 
standard insufflations pressure improves the quality of the surgical field, there are no 
risks related to the surgery. A deep neuromuscular block can be achieved by higher 
doses of rocuronium as compared to the routine intubation dose.  
The participants of this study are approved for live kidney donation. One of the selection 
criteria is a glomerular infiltration rate above 59-85 ml/min/1.73m2 (depending on age) to 
provide sufficient residual (donor) renal function post donation. According to Li et al the 
early decrease of the glomerular filtration rate after kidney donation is approximately 15-
20 ml/min/1.73m2 (10). Therefore a higher dose of rocuronium in living kidney donors is 
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dysfunction is only slightly reduced (1ml/kg/min) as compared to patients with normal 
renal function (rocuronium clearance 3.7 ml/kg/min).  
To overcome the extended effects of deep neuromuscular blockade that may lead to 
airway obstruction, hypoxia, pneumonia and/or atelectasis, sugammadex is administered 
to antagonize the effects of rocuronium. Sugammadex is a rapid antagonist of 
neuromuscular blockade by rocuronium that is given immediately after surgery. 
Randomized controlled trials have shown that sugammadex can be safely administered 
in patients, without dose adjustments for young, elderly or obese patients and that it can 
also be safely administered in patients with mild or moderate renal impairment (creatinine 
clearance ≥ 30 and < 80 mL/min) (12). 
Elimination of the rocuronium-sugammadex will take longer in donors, because of the 
slightly decreased glomerular filtration rate, but since the rocuronium is inactivated by 
sugammadex, there is no risk at recurrence of neuromuscular blockade. 
 
A recent study performed by Martini et al. has shown that deep neuromuscular blockade 
improves surgical conditions with reduced postoperative pain scores after laparoscopic 
surgery (1). Moreover, preliminary data of our recently performed Leopard-3 study, show 
that the mean SRS (surgical rating scale) was significantly better during deep NMB with 
less opiate consumption (2). Altogether, we expect that the use of deep NMB during LDN 
reduces postoperative pain scores and/or analgesia consumption. This may improve the 
early quality of recovery of live kidney donors. 
 
 

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11.5 Compensation for injury 
The Radboudumc has an insurance in accordance with the legal requirements in the 
Netherlands (Article WMO and the Measure regarding Compulsory Insurance for Clinical 
Research in Humans of 23th June 2003). This insurance provides cover for damage to 
research subjects though injury or death caused by the study. 
  
1. € 650.000,-- (i.e. sixhundred and fifty thousand Euro) for death or injury for each 
subject who participates in the Research  
2. € 5.000.000,-- (i.e. five million Euro) for death or injury for all subjects who participate 
in the Research  
3. € 7.500.000,-- (i.e. seven million fivehundredthousand Euro) for the total damage 
incurred by the organisation for all damage disclosed by scientific research for the 
Sponsor as ‘verrichter’ in the meaning of said Act in each year of insurance coverage  
 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
. 
 
11.6 Incentives  
Not applicable. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Subjects will be coded by a numeric code in order to create and anonymous dataset. A 
Castor database will be developed and used for data management. Investigators have 
access to this code and will store the subject identification code list at a separate location 
from the dataset.  
Data will be securely stored in the database of the department of surgery of the Radboud 
university medical center accessible to the investigators, in accordance with the Dutch 
Personal Data Protection Act.  
 
12.2 Monitoring and Quality Assurance  
In our opinion, this study adds a small chance (“kleine kans”) of mild damage (“lichte 
schade”) and consequently adds a negligible risk (“verwaarloosbaar risico”) according to 
the risk classification of the “Nederlandse Federatie van Universitair Medische Centra” 
(NFU). Monitoring will be conducted in accordance with negligible risk monitoring 
guidelines of the NFU, which will be reported in a monitorplan.  
 
Risk classification in relation to the chance and severity of damage (Dutch versions) 
 
Lichte schade 
Matige schade 
Ernstige schade 
Kleine kans 
Verwaarloosbaar risico 
Verwaarloosbaar risico 
Matig risico 
Matige kans 
Verwaarloosbaar risico 
Matig risico 
Hoog risico 
Grote kans 
Matig risico 
Hoog risico 
Hoog risico 
 
 
12.3  Amendments  
Not applicable. 
 
12.4 Annual progress report 
The 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 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.  

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The investigator 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 investigator 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/ 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 will be registered at ClinicalTrials.gov. Results will be published in a peer-
reviewed international journal.  
 
 
13. STRUCTURED RISK ANALYSIS  
Not applicable. 
 
 
14. REFERENCES 
 
1. Martini CH, Boon M, Bevers RF, Aarts LP, Dahan A. Evaluation of surgical conditions 
during laparoscopic surgery in patients with moderate vs deep neuromuscular block. Br J 
Anaesth. 2014;112(3):498–505. 
2. Özdemir- van Brunschot DMD, Braat AE, van der Jagt MFP, Scheffer GJ, Martini CH,  
Langenhuijsen JF, Dam RE, Huurman VA, Lam D, d’Ancona FC, Dahan A, Warlé MC. 
Deep neuromuscular blockade improves surgical conditions during low pressure 
pneumoperitoneum laparoscopic donornephrectomy. Submitted. 
3. Warlé MC, Berkers AW, Langenhuijsen JF, van der Jagt MF, Dooper PM, Kloke HJ, 
Pilzecker D, Renes SH, Wever KE, Hoitsma AJ, van der Vliet JA, D'Ancona FC. Low-
pressure pneumoperitoneum during laparoscopic donor nephrectomy to optimize live 
donors' comfort. Clin Transplant. 2013 Jul-Aug;27(4):E478-83. 
4. Özdemir-van Brunschot DM, van Laarhoven KC, Scheffer GJ, Pouwels S, Wever KE, 
Warlé MC. What is the evidence for the use of low-pressure pneumoperitoneum? A 

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systematic review. Surg Endosc. 2015 Aug 15. [Epub ahead of print] 
5. la Chapelle CF, Bemelman WA, Rademaker BM, van Barneveld TA, Jansen FW; on 
behalf of the Dutch Multidisciplinary Guideline Development Group Minimally Invasive 
Surgery. A multidisciplinary evidence-based guideline for minimally invasive surgery.: 
Part 1: entry techniques and the pneumoperitoneum. Gynecol Surg. 2012 Sep;9(3):271-
282. Epub 2012 Feb 22. 
6. Neudecker J1, Sauerland S, Neugebauer E, Bergamaschi R, Bonjer HJ, Cuschieri A, 
Fuchs KH, Jacobi Ch, Jansen FW, Koivusalo AM, Lacy A, McMahon MJ, Millat B, 
Schwenk W. The European Association for Endoscopic Surgery clinical practice guideline 
on the pneumoperitoneum for laparoscopic surgery. Surg Endosc. 2002 Jul;16(7):1121-
43. Epub 2001 May 20. 
7. Staehr-Rye AK, Rasmussen LS, Rosenberg J, Juul P, Lindekaer AL, Riber C, et al. 
Surgical space conditions during low-pressure laparoscopic cholecystectomy with deep 
versus moderate neuromuscular blockade: a randomized clinical study. Anesth Analg. 
2014;119(5):1084–92. 
8. Özdemir-van Brunschot DM, Scheffer GJ, Dahan A, et al. Comparison of the 
effectiveness of low-pressure pneumoperitoneum with profound muscle relaxation during 
laparoscopic donor nephrectomy to optimize the quality of recovery during the early 
postoperative phase: a randomized controlled clinical trial. Trials 2015; 16: 345. 
9. Özdemir-van Brunschot DM, Scheffer GJ, van der Jagt MF, Langenhuijsen JF, Dahan A, 
Mulder JEEA, Willems S, Hilbrands LB,  Donders R, van Laarhoven CJHM, D’Ancona 
FC, Warlé MC. Low pressure pneumoperitoneum facilitated by deep neuromuscular 
blockade during laparoscopic donor nephrectomy is associated with reduced length of 
hospital stay. Submitted. 
10. Li SS, Huang YM, Wang M, Shen J, Lin BJ, Sui Y, Zhao HL. A meta-analysis of renal 
outcomes in living kidney donos. Medicine. 2016 Jun;95(24):e3847 
11. https://www.medicines.org.uk/emc/medicine/5166 
12. https://www.medicines.org.uk/emc/medicine/21299/SPC/Bridion+100+mg+ml+solution+fo
r+injection/ 
 
  
 
 

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Table 1. 
Overview of RCTs regarding low-pressure PNP and deep NMB in LDN. 
*  ‘Leopard-1 study’ 
  - design: single center, blinded, randomized controlled pilot study. 
  - main results: lower pain scores after low-pressure PNP. Longer operation time due to the  
    use of low-pressure PNP. 
 
** ‘Leopard-2 study’ 
  - design: single center, blinded, randomized controlled trial. 
  - main results: no difference in pain/analgesia consumption. Improved quality of  
    recovery and shorter length of stay after low-pressure PNP. 
 
*** ‘Leopard-3 study’ 
  - design: multi-center, blinded, randomized controlled trial. 
  - main results: better quality of the surgical field (primary endpoint) and a tendency towards   
    reduced analgesia consumption in the deep NMB group. 
 
# This study proposal 
  - design: multi-center, blinded, randomized controlled trial. 
  - hypothesis: enhanced quality of recovery by deep NMB. 
 
 

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Table 2. 
 
Assessment of surgical space conditions (SRS) according to Martini et al. (8) 
 
Scale   
Description 
1 
Extremely poor 
conditions 
 
The surgeon is unable to work because of 
coughing or the inability to obtain a visible 
laparoscopic field because of inadequate 
muscle relaxation. 
2 
Poor conditions 
There is a visible laparoscopic field, but the 
surgeon is severely hampered by 
inadequate muscle relaxation with 
continuous muscle contractions, movements 
or both with the hazard of tissue damage. 
3 
Acceptable 
conditions 
There is a wide visible laparoscopic field but 
muscle contractions, movements or both 
occur regularly causing some interference 
with the surgeon’s work. 
4 
Good conditions 
There is a wide laparoscopic field with 
sporadic muscle contractions, movements 
or both. 
5 
Optimal conditions 
There is a wide visible laparoscopic working 
field without any movement or contractions. 
 
 
 

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Table 3. 
 
Overview of variables and time-points. 
 
 
-18h 
1h 
4h 
8h 
24h 
48h 
 
QOR-40  
x 
 
 
 
x 
x 
Components of pain  
x 
x 
x 
x 
x 
x 
Analgesia use 
x 
x 
x 
x 
x 
x 
Discharge criteria 
 
 
 
x 
x 
x 
Evaluation of complications 
 
 
 
 
x 
x 
 
 
Table 4. 
Overview of variables and procedures/techniques. 
 
 
 
Study parameters/endpoints 
Procedure, technique and/or tests 
Quality of recovery 
Quality of recovery 40 questionnaire (appendix 1) 
Surgical rating score 
Peri-operative evaluation (table 2) 
Pain 
Components of pain 
Medication use 
Daily evaluation of electronic patient dossier 
Nausea/vomiting 
Daily evaluation during hospital admission 
Surgical parameters 
Intra-operative evaluation by the surgeon 
Evaluation of post-
operative complications 
Daily evaluation during hospital admission 
 
 

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Figure 1. 
 
Study Flow Chart  
 
 
 

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Appendix 1. 
QOR-40 questionnaire. 
 
Vragenlijst over kwaliteit van herstel 
Om een inzicht te krijgen in het herstel na de operatie die u heeft ondergaan, vragen wij u 
deze vragenlijst in te vullen.  
Geeft u daarvoor alstublieft bij elke vraag het antwoord dat het beste weergeeft hoe u zich de 
laatste 24 uur voelde. Dit gebeurt op een schaal van 1-5. Boven de gevallen staat de 
betekenis van de getallen. 
 
Welbevinden 
 
 
 
 
Helemaal niet waar 
 
Helemaal waar  
Ik kan gemakkelijk ademhalen 
 
 
1 
2 
3 
4 
5 
Ik heb goed geslapen 
 
 
 
1 
2 
3 
4 
5 
Het eten heeft me gesmaakt  
 
 
1 
2 
3 
4 
5 
Ik voel me uitgerust  
 
 
 
1 
2 
3 
4 
5 
 
Gevoelens 
 
 
 
 
Helemaal niet waar 
 
Helemaal waar  
Ik voel me over het algemeen goed  
 
1 
2 
3 
4 
5 
Ik heb de situatie/mezelf in de hand  
 
1 
2 
3 
4 
5 
Ik voel me op mijn gemak 
 
 
 
1 
2 
3 
4 
5 
 
Zelfredzaamheid 
 
 
 
Helemaal niet waar 
 
Helemaal waar  
Ik kan goed een gesprek voeren 
 
 
1 
2 
3 
4 
5 
Ik kan mezelf wassen en tanden poetsen 
 
1 
2 
3 
4 
5 
Ik kan mezelf verzorgen 
 
 
 
1 
2 
3 
4 
5 
Ik kan schrijven  
 
 
 
 
1 
2 
3 
4 
5 
Ik kan werken/ werkzaamheden thuis verrichten 
1 
2 
3 
4 
5 
 
Steun 
 
 
 
 
Helemaal niet waar 
 
Helemaal waar  
Het is mogelijk in het ziekenhuis met artsen 
1 
2 
3 
4 
5 
en verpleegkundigen te spreken 
 
 
Het is mogelijk met familie en vrienden te spreken 1 
2 
3 
4 
5 
Ik wordt gesteund door de artsen in het ziekenhuis 1 
2 
3 
4 
5 
Ik word gesteund door de verpleegkundigen in 
1 
2 
3 
4 
5 
het ziekenhuis 
 
 
 
 
Ik wordt gesteund door familie en vrienden  
1 
2 
3 
4 
5 
Ik begrijp uitleg en adviezen  
 
 
1 
2 
3 
4 
5 

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PAS OP: HELEMAAL WAAR EN WAAR ZIJN NU OMGEDRAAID! 
 
Welbevinden 
 
 
 
 
Helemaal  waar 
 
Helemaal niet waar  
Ik heb last van misselijkheid  
 
 
1 
2 
3 
4 
5 
 
Ik heb overgegeven  
 
 
 
1 
2 
3 
4 
5 
Ik moet kokhalzen 
 
 
 
 
1 
2 
3 
4 
5 
Ik voel me rusteloos  
 
 
 
1 
2 
3 
4 
5 
 
Ik heb last van trillen of beven 
 
 
1 
2 
3 
4 
5 
Ik heb last van rillerigheid 
 
 
 
1 
2 
3 
4 
5 
Ik heb het te koud 
 
 
 
 
1 
2 
3 
4 
5 
Ik heb last van duizeligheid  
 
 
1 
2 
3 
4 
5 
 
Gevoelens 
 
 
 
 
Helemaal  waar 
 
Helemaal niet waar 
Ik heb naar gedroomd 
 
 
 
1 
2 
3 
4 
5 
 
Ik voel me angstig 
 
 
 
 
1 
2 
3 
4 
5 
Ik ben boos 
 
 
 
 
 
1 
2 
3 
4 
5 
Ik voel me somber 
 
 
 
 
1 
2 
3 
4 
5 
 
Ik voel me alleen  
 
 
 
 
1 
2 
3 
4 
5 
Ik heb moeite om in slaap te komen  
 
1 
2 
3 
4 
5 
 
Steun 
 
 
 
 
Helemaal  waar 
 
Helemaal niet waar 
Ik voel me verward 
 
 
 
 
1 
2 
3 
4 
5 
 
Pijn en klachten  
 
 
 
Helemaal  waar 
 
Helemaal niet waar 
Ik heb matige pijn 
 
 
 
 
1 
2 
3 
4 
5 
 
Ik heb ernstige pijn 
 
 
 
 
1 
2 
3 
4 
5 
Ik heb hoofdpijn  
 
 
 
 
1 
2 
3 
4 
5 
Ik heb spierpijn  
 
 
 
 
1 
2 
3 
4 
5 
 
Ik heb rugpijn 
 
 
 
 
 
1 
2 
3 
4 
5 
Ik heb een pijnlijke mond 
 
 
 
1 
2 
3 
4 
5 
Ik heb een pijnlijke keel 
 
 
 
1 
2 
3 
4 
5 
 
 

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Appendix 2. 
Vragenlijst over werk en zorg. 
 
Vragenlijst over werk en zorg 
In deze vragenlijst wordt u gevraagd in hoeverre u weer in staat bent om te werken en 
hoeveel extra zorg u de afgelopen week nodig hebt gehad.  
 
1. Heeft u de afgelopen week de huisarts vanwege de operatie bezocht? 
0 nee 
0 ja,  
Hoe vaak?  
 
 
 
 
 
 
 
 
 
 
Waarom?  
 
 
 
 
 
 
 
 
 
 
 
2. Heeft u de afgelopen week een dokter in het ziekenhuis bezocht vanwege de 
operatie? 
0 nee 
0 ja, 
Hoe vaak?  
 
 
 
 
 
 
 
 
 
 
Waarom?  
 
 
 
 
 
 
 
 
 
 
 
3. Bent u de afgelopen week nogmaals opgenomen in het ziekenhuis vanwege de 
donor operatie? 
0 nee 
0 ja,  
Hoeveel dagen?   
 
 
 
 
 
 
 
 
 
Waarom?  
 
 
 
 
 
 
 
 
 
 
 
4. Heeft u de afgelopen week hulp nodig gehad van familie, vrienden of kennissen? 
0 nee 
0 ja,  
Hoeveel uur?  
 
 
 
 
 
 
 
 
 
 
 
5. Heeft u de afgelopen week thuiszorg gehad? 
0 nee 

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0 ja,  
Hoeveel uur?  
 
 
 
 
 
 
 
 
 
 
 
6. Heeft u de afgelopen week betaalde hulp in de huishouding gehad? 
0 nee 
0 ja,  
Hoeveel uur? 
 
 
 
 
 
 
 
 
 
 
 
7. Heeft u de afgelopen week gewerkt? 
0 nee, in verband met de operatie 
 
 
 
ga verder naar vraag 8 
0 nee, reeds voor de operatie niet (meer) werkzaam 
 
ga verder naar vraag 8 
0 nee, omdat  
 
 
 
 
 
 
ga verder naar vraag 8 
0 ja,  
Op welke datum bent u weer gaan werken? 
 
 
 
 
 
 
Hoeveel uur heeft u de afgelopen week gewerkt?  
 
 
 
 
 
8. Hoeveel procent van uw dagelijkse bezigheden, die u voor de operatie ook deed, 
heeft u kunnen uitvoeren deze week? (zoals huishoudelijke werkzaamheden, hobby’s en 
persoonlijke verzorging) 
    
 
 
 
 
 
 
(tussen 0 en 100%) 
 
 
 
Dank u wel voor het invullen!