Clinical trial NCT03170661
Conditions: Surgical Conditions
Sponsor: Leiden University Medical Center
Start date: 2017-06-14; Completion date: 2020-06-01
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A deep neuromuscular block (NMB) is often associated with improved surgical conditions especially in laparoscopic surgery. We previously showed that deep NMB is superior to a moderate NMB under propofol anesthesia. However, this may not apply to sevoflurane anesthesia and sevoflurane by itself produces some degree of muscle relaxation. We therefore plan to investigate the effect of deep NMB on surgical conditions under sevoflurane anesthesia maintenance.

Detailed description:
Neuromuscular blocking agents (NMBAs) are routinely administered during general anaesthesia to facilitate endotracheal intubation and to optimize surgical conditions. Increasing data suggest superiority of a deep neuromuscular block (defined by a post-tetanic count of 1-2 twitches) in creating optimal working conditions for the surgical team. However, it is unknown whether other aspects of the anaesthetic technique, most notably the choice of anaesthetic (for example, total intravenous versus inhalational anaesthesia), influence the relationship between the depth of the neuromuscular block and surgical conditions, particularly in laparoscopic surgery. Volatile anaesthetics are known for their ability to potentiate neuromuscular blocking agents an effect that is less existent with propofol. We previously showed that surgical working conditions in laparoscopic surgery during propofol anaesthesia are highly reliant on the depth of the neuromuscular block. Whether such a relationship also exists for inhalational anaesthetics, is unknown. To investigate this, we conducted a prospective, randomized, double blind study in which patients scheduled for laparoscopic renal surgery were randomized to receive either a moderate or a deep neuromuscular block during sevoflurane anaesthesia. The primary outcome was the intraoperative surgical condition assessed by a surgeon using the validated Leiden-Surgical Rating Scale. We hypothesized that the use of an inhalational anaesthetic would obviate the need for a deep NMB due to its intrinsic muscle relaxant potentiating properties to produce optimal working conditions.

Arms: arm 1: Subjects will receive moderate neuromuscular block, aimed at 1-2 twitches train of four arm 2: Subjects will receive deep neuromuscular block, aimed at 1-2 twitches post tetanic count
Interventions: intervention 1: Deep neuromuscular block
Intervention descriptions: intervention 1: Deep neuromuscular block will be achieved with high dose rocuronium to achieve a depth of 1-2 twitches post tetanic count

Protocol documents:
Prot_SAP_000.pdf: 
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The BLISS 4 trial – protocol v1.0 – January 28, 2017 
 
Protocol  
PROTOCOL nr: P17.049 
Date: November 1, 2017 
Version: 2.0 
CCMO nr NL60821.058.17 
 
Title: Effect of deep versus moderate neuromuscular block during sevoflurane 
anesthesia on intraoperative surgical conditions, hemodynamics and 
postoperative pain in patients undergoing laparoscopic (donor) nephrectomies 
– The BLISS 4 trial  
 
Investigators: 
F.S. Meijer MD, resident 
M. Boon MD, anesthesiologist 
C.H. Martini MD PhD, anesthesiologist 
L. Aarts MD PhD, Anesthesiologist 
A. Dahan MD PhD, Anesthesiologist 
Department of Anesthesiology, Leiden University Medical Center 
 
I. Alwayn MD PhD 
V. Huurman MD 
M. Nijboer MD 
Department of Surgery, Leiden University Medical Center 
 
R. Bevers MD, Urologist 
Department of Urology, Leiden University Medical Center 
 
External Subjects Advisor:  
Dr. E. Sarton, Department of Anesthesiology, Leiden University Medical Center 
 
Address for correspondence: 
Prof. dr. A. Dahan, Dept. of Anesthesiology 
LUMC, P5-Q, 2300 RC Leiden, The Netherlands 
FAX: +31 71 526 6230    e-mail: a.dahan@lumc.nl 


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**** Contents **** 
 
List of abbreviations and definitions 
 
 
 
 
 
4 
Summary  
 
 
 
 
 
 
 
 
6 
1. Ethics  
 
 
 
 
 
 
 
 
7 
2. Investigators and study personnel   
 
 
 
 
8 
3. Introduction 
 
 
 
 
 
 
 
 
9 
4. Objectives and hypothesis 
 
 
 
 
 
 
10 
• Major objective 
• Minor objectives 
• Hypotheses 
5. Study design 
 
 
 
 
 
 
 
 
11 
6. Patients and patient requirements/procedures 
 
 
 
12 
• Patient inclusion criteria 
• Patient exclusion criteria 
• Preoperative procedures 
•  Recruitment 
• Informed consent 
• Pre-study requirements 
• Withdrawal of an individual subject 
7. Anesthesia 
 
 
 
 
 
 
 
 
14 
• Anesthesia 
• Neuromuscular blocking agents 
8. Measurements 
 
 
 
 
 
 
 
15 
• Pre-study parameters/variables 
• Measurements/variables/images obtained during anesthesia 
▪ Surgical rating score 
▪ Video images 
▪ Neuromuscular monitoring 
▪ Hemodynamic monitoring 
▪ Intra-abdominal pressure 


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▪ Additional variables 
• Measurements/variables obtained during recovery 
▪ Respiration 
▪ Pain 
▪ Sedation/Alertness 
▪ Occurrence of nausea/vomiting 
 
9. Safety  
 
 
 
 
 
 
 
 
17 
• Adverse events 
• Reporting of adverse event 
• Criteria for assessing severity 
• Criteria for assessing causality 
• Serious adverse events 
• Reporting of SAEs 
• Expedited Reporting 
• Data Monitoring Committee (DMC) 
10. Sample size, randomization, blinding and statistical analysis 
 
23 
• Sample size calculation 
• Randomization, blinding and treatment allocation 
• Statistical analysis 
11. References 
 
 
 
 
 
 
 
 
24 


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List of abbreviations and definitions 
 
AE: Adverse event. Adverse events are defined as any undesirable experience occurring to a 
subject during the study, whether or not considered related to the investigational product 
and or the experimental treatment.  
CCMO: (Centrale commissie mensgebonden onderzoek) Central Human Ethics Committee 
CRF: Case record form. 
DNB: Deep neuromuscular block 
GCP: Good clinical practice 
ICH: International conference on harmonisation 
LOAA/S: Leiden Observer’s Assessment of Alertness/Sedation  
LUMC: Leiden University Medical Center 
METC: (Medisch Ethische Commissie) Medical Ethics Committee 
NMBA: non-depolarizing neuromuscular blocking agent 
VAS: Visual analogue score. Pain score measured on a 11-point scale from 0 (= no pain) to 10 
(worst pain imaginable). 
Train of four (TOF). Four supramaximal stimuli of 2 Hz are provided to the ulnar nerve via 
the skin at the wrist. The effect of the stimuli can be measured at upper arm (in our study 
with the TOF CUFF) as muscle contractions. With increasing muscle blockade a fade (i.e., the 
amplitude decreases) appears followed by the disappearance of muscle contractions. The 
reverse is true when the muscle blockade disappears. Under conditions of deep or profound 
neuromuscular blockade (with absence of any twitches) the TOF is of limited use.   
Train of four ratio (TOF ratio). The ratio of the amplitude of the last twitch of the TOF 
relative to the first twitch (i.e, T4/T1). The lower this ratio, the greater the extent (depth) of 
muscle relaxation.  


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Post Tetanic Count (PTC). In contrast to TOF stimulation, PTC can be used to determine the 
degree of neuromuscular blockade under conditions of a deep neuromuscular block. A 50 Hz 
stimulus, given for 5 seconds, is applied at the skin over the ulnar nerve. Three seconds after 
this stimulus, muscle contraction is counted in response to single 1 Hz stimulation. In an 
intense neuromuscular block, no PTC response may be observed. 
 


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Summary 
Rationale: A deep neuromuscular block (DNM) is often associated with improved surgical 
conditions especially in laparoscopic surgery. However, a deep block comes at the expense 
of a variety of items that may conflict with the use of a deep surgical muscle blockade 
including a long recovery phase, the need for muscle reversal, postoperative ventilation, 
impaired postoperative breathing. With the introduction of sugammadex there is now the 
possibility to reverse an even deep surgical block. This may overcome most if not all of the 
issues mentioned. We previously showed that DNM is superior to a moderate NMB under 
propofol anesthesia. However, this may not apply to sevoflurane anesthesia and sevoflurane 
by itself produces some degree of muscle relaxation.   
Objective:  To assess whether a deep neuromuscular block provides better surgical 
conditions than a moderately deep block as derived from a surgical rating score during 
sevoflurane anesthesia. 
Study design: Single center, double-blind randomized controlled trial. 
Study population:  100 ASA I-III patients scheduled for laparoscopic renal surgery, i.e. 
(donor) nephrectomies. 
Intervention: Fifty patients will receive a deep NMB with a continuous infusion of 
rocuronium causing a TOF score of 0 and PTC of 1-2. Fifty other patients will receive a 
moderate NMB using bolus administrations of rocuronium causing a TOF score of 1-2. 
Anesthesia induction is with propofol, while anesthesia maintenance is with sevoflurane 
1.5% end-tidal (ET) concentration. 
Main study parameters/endpoints:  To study the surgical conditions in patients undergoing 
laparoscopic renal surgery during deep versus less deep neuromuscular block as assessed by 
the surgical rating score. 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  Compared to current practice there will be no additional risk.  


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1. Ethics 
Ethics Committees. The protocol, possible protocol amendments, the patient information 
form, informed consent form and any other study related information or documents will be 
reviewed and approved by the LUMC ethics committee (METC) before subjects are screened 
for study entry. The Investigator will submit periodic reports and inform the METC of any 
reportable adverse events (AEs) per ICH guidelines and local ethical committee standards of 
practice. 
Ethical Conduct of the Study. This study will be conducted in accordance with LUMC 
standard operating practices, which are designed to ensure adherence to Good Clinical 
Practice (GCP) guidelines as required by the following: 
• Declaration of Helsinki, version 2013 (“WMA Declaration of Helsinki - Ethical Principles 
for Medical Research Involving Human Subjects”). 
• ICH Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of 
Medicinal Products, Committee for Proprietary Medicinal Products, International Conference 
on Harmonization of Pharmaceuticals for Human Use. (Note for Guidance on Good Clinical 
Practice, 2002). 
• European Union (EU) Clinical Trials Directive 2001/20/EC on the regulation of clinical 
trials in the EU and the implementation of GCP. 
• GCP Directive 2005/28/EC. 
This study will be conducted in accordance with national and local laws. 
Subject Information and Consent. All subjects will be provided with oral and written 
information describing the nature and duration of the study and the procedures to be 
performed. Each subject will be given a copy of the informed consent and written 
information. The subject will be asked to sign an informed consent form prior to any study-
specific procedures being performed.  


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2. Investigators and study personnel 
Qualified Investigators under the sponsorship of the Leiden University Medical Center will 
conduct this study. The names of the investigators, independent physician and contact 
person are given on page 1 of this protocol. The Principle Investigator is BROK certified.  
 


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3. Introduction  
In two independent studies we previously showed that deep NMB produces superior surgical 
rating scores compared to a moderate NMB [1,2]. In retroperitoneal surgery, for example, 
we showed that during propofol anesthesia deep NMB was associated with a mean surgical 
rating scale (SRS) of 4.7 (on a 5-point scale) compared to a score of 4.0 during moderate 
NMB. This difference was considered highly significant by the surgeon. Since both studies 
were performed during general anesthesia with the intravenous anesthetic propofol, it 
remains unknown what the influence is of the anesthesia type on the SRS scores. Therefore 
we will now study the effect of deep versus moderate NMB on SRS scores during sevoflurane 
in retroperitoneal surgery. We expect a difference in SRS scores albeit of smaller magnitude 
than in our first two studies since sevoflurane has neuromuscular relaxing properties.  
The main end-point of the study is the effect of the deep block on surgical conditions during 
sevoflurane anesthesia. To that end-the surgical team will be asked to rate the quality of the 
surgical field at 15-min intervals using the 5-point Leiden-Surgical Rating Scale (L-SRS), a 
scale that was previously developed at LUMC and recently validated [1,2].   
Secondary end-points of the study are hemodynamics (blood pressure and heart rate) and 
Nociception Level (NoL [3]) during anesthesia, and pain and sedation scores following 
surgery.   
 


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4. Objectives and hypothesis 
Main objective  
To study the surgical conditions in patients undergoing laparoscopic renal surgery: (donor) 
nephrectomies during deep versus moderate neuromuscular block as assessed by the Leiden 
Surgical Rating Scale during sevoflurane anesthesia. 
 
Minor objectives 
1. To study the hemodynamic conditions during deep versus moderate neuromuscular block. 
2. To study the nociception level during deep versus moderate neuromuscular block. 
3. To assess the effect of deep versus moderate NMB on pain, sedation and  
nausea/vomiting  in the recovery room (PACU).  
 
 
Hypotheses 
1. Deep neuromuscular block leads to excellent surgical condition in patients undergoing 
laparoscopic renal surgery. 
2. The difference in surgical conditions between deep or moderate neuromuscular block is 
absent during sevoflurane anesthesia; 
3. Deep neuromuscular block leads to favorable hemodynamic conditions; 
4. Deep NMB is associated with less postoperative pain. 
 


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5. Study design 
The study will be a randomized control trial (RCT) performed in 100 patients that will 
undergo elective laparoscopic surgery for (donor) nephrectomy. The trial starts after the 
medical ethical committee has approved the study protocol and will have a maximum 
duration of 2 years. 
Patients will be randomized to either receive a continuous infusion with rocuronium aimed 
at a deep block (TOF 0 twitches, PTC 1-2 twitches), or receive muscle relaxation aimed at a 
moderately deep neuromuscular block (TOF 1-2) 
Deep block is obtained with continuous rocuronium infusion: loading dose of 1.0 mg/kg, 
followed by 0.3-0.6 mg/kg per h. 
Moderate block is obtained with a bolus-dose rocuronium technique: loading dose of 0.5 
mg/kg followed by bolus doses of 5-10 mg when the TOF exceeds 2-3. 
Both the surgeon and the research team will be blinded to the muscle relaxant used and the 
level of muscle relaxation. The attending anesthesiologist will be made responsible for both 
the administration of the muscle relaxant and degree of NMB. He or she will not correspond 
about the NMB with the surgeon or the research team.   
Anesthesia induction is by propofol/sufentanil followed by sevoflurane maintenance 
(approx. 1.5% end-tidal concentration) and sufentanil for analgesia. Reversal is by 
sugammadex 4 mg/kg following a deep NMB and 2 mg/kg following a moderate NMB. 
Patients will be extubated when TOF ratio becomes 0.9 or larger. 
Note that both NMB techniques are standard-of-care at LUMC. 


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6. Patients and patient requirements/procedures 
A total of 100 patients will be included in this study.  
 
6.1 Patient inclusion criteria  
(i) Patients that will undergo an elective laparoscopic (donor) nephrectomy;  
(ii) ASA class I-III  
(iii) > 18 years of age; 
(iv) Ability to give oral and written informed consent. 
6.2 Patient exclusion criteria  
(i) Known or suspected neuromuscular disorders impairing neuromuscular function; 
(ii) Allergies to muscle relaxants, anesthetics or narcotics; 
(iii) A (family) history of malignant hyperthermia; 
(iv) Women who are or may be pregnant or are currently breast feeding; 
(v) Renal insufficiency, as defined by serum creatinine x 2 of normal, or urine output < 0.5 
ml/kg/h for at least 6 h. When available, other indices will be taken into account as well such 
as glomerular filtration rate < 60 ml/h and proteinuria (a ratio of 30 mg albumin to 1 g of 
creatinine). 
 (vi) Previous retroperitoneal surgery at the site of the current surgery. 
(vii) Body mass index > 35 kg/m2 
6.3 Preoperative procedures. Eligible patients who are scheduled to undergo a (donor) 
nephrectomy will be informed about the study and asked to participate and complete the 
informed consent. General preoperative examination and testing will be done as usual at the 
preoperative outpatient department.  


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6.4 Recruitment. Subjects will be recruited after approval of the study protocol by the 
medical ethics committee of the LUMC. Eligible subjects will be informed and recruited at 
the preoperative outpatient department by an anesthesiologist. 
6.5 Informed consent. Patients will receive verbal and written information about the study. 
A written informed consent must be completed for a subject to enter the study. 
6.6 Medical examination. Full medical examination and relevant blood laboratory tests will 
be completed at the preoperative outpatient department. 
6.7 Pre-study requirements. Pre study requirements will be no different compared to 
patients undergoing surgery under general anesthesia. This includes refraining from eating 
six hours before surgery and refraining from drinking two hours before surgery. 
6.8 Withdrawal of an individual subject. Subjects can decide to leave the study at any time, 
for any reason if they wish to do so, without any consequences. The responsible investigator 
can also decide to exclude a subject if by continuing participation the subject’s wellbeing is 
harmed in any way. Subjects can also be excluded in case of protocol violations and non-
compliance.  
In case of dropping out from the study at the subject’s own request, the subject is asked 
permission for using the data already collected. The subject is allowed to decline this 
request, without giving any reason, and again without any consequences. When permission 
is not granted to use already available data, this specific data is deleted from the database 
and any paperwork will be disposed of.  
In case of withdrawal the subject will be replaced by another patient. 
 


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7. Anesthesia 
Anesthesia. Induction and maintenance of anesthesia is by propofol combined with bolus 
doses of an opioid (sufentanil).  
Propofol will be given as bolus of 2-2.5 mg/kg, followed the administration of sevoflurane for 
the duration of surgery. The target end-tidal sevoflurane concentration = 1.5% 
The opioid use will be at the discretion of the attending anesthesiologist. Sufentanil will be 
administered in single bolus infusions of 0.25 to 0.6 g/kg.  
The dosage and moment of drug administrations will be collected on the CRF. 
Use of neuromuscular blocking agents and reversal agents is given in section 5. 
After the neuromuscular block has been given, the trachea of the patient will be intubated 
with an oro-tracheal tube. At the end of the case, after reversal of the NMB the patient will 
be extubated when the TOF ratio > 0.9. 
Teams in the operating room during the study. During the procedure there will be three 
teams present in the operating room: 
(1) The surgical team. They will be blinded to the patient treatment. 
(2) The anesthesia team (an attending anesthesiologist and anesthesia nurse). They will have 
knowledge on the treatment allocation of the subject. They will deliver the treatment to the 
patient and they will monitor the depth of the neuromuscular block with the TOF CUFF. 
(3) Some of the investigators. The junior investigator will be present and will monitor the 
case. He is blinded to the treatment and will not communicate with the anesthesiology team 
regarding the treatment allocation. 
 


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8. Measurements 
8.1 Pre-study parameters/variables  
Patient characteristics including age, gender, weight, height, ASA class, medication, 
comorbidity. 
8.2 Measurements/variables/images obtained during anesthesia  
A. Surgical rating. During the procedure, the surgical condition will be scored by the surgeon 
using a 5-point surgical rating scale. In order to reduce variability in the surgical rating all 
surgeries will be performed the surgical team. All members of the team are well trained in 
using the L-SRS. The rating scale will be a 5-point ordinal scale ranging from 1 = poor 
condition to 5 = optimal surgical conditions (see Table 1, below). The surgeon will score the 
condition at 15 minute intervals. In case of a sudden change in surgical conditions additional 
scores will be added to the CRF.  If conditions are poor (score 1 or 2), muscle relaxation will 
be increased, a score of 1 will be used. 
The surgical rating score 
1 
Extremely poor conditions 
2 
Poor conditions 
3 
Acceptable conditions 
4 
Good conditions 
5 
Optimal conditions 
In case of scorings 1 or 2 additional doses of rocuronium will be administered.  
C. Neuromuscular monitoring. For neuromuscular function monitoring the TOF CUFF will be 
applied at 15 min intervals. When no twitches are present the PTC will be assessed. 
Neuromuscular data will be collected via an arm cuff system. The data will be collected on 
the CRF.  
D. Haemodynamic monitoring. Blood pressure, heart rate and NoL will be measured using 
the monitoring devices available in the operating room.  


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E. Intra abdominal pressure. Intra abdominal pressure will be measured every 15 minutes 
from the retroperitoneal CO2 insufflation device. 
F. Additionally the following variables are included: 
• duration of surgery; 
• drug dosages (propofol, sevoflurane ET conc. opioid, muscle relaxant, reversal agent, 
any other agents used during anesthesia); 
• duration from reversal to extubation 
 
8.3 Measurements/variables obtained during recovery and on the ward 
A. Pain. Pain will be measured directly by asking for a visual analogue score (VAS) at 15 min 
intervals. Additionally opioid consumption will be collected. 
B. Sedation/Alertness. The level of sedation/alertness will be assessed in the recovery room 
using the validated Leiden Observer’s Assessment of Alertness/Sedation (LOAA/S) scale at 15 
min intervals. 
 
The LOOA/S 
0 = normal alertness, eyes open, responds normal to command 
1 = drowsy with open eyes, closed and opened on command 
2 = drowsy with closed eyes, opened in response to light auditory stimulus 
3 = eyes closed, opened in response to rubbing the shoulder or a loud auditory 
stimulus 
4 = eyes closed and opened only briefly in response to touching the subject 
5 = eyes closed, unarousable by touching the subject, aroused by a painful stimulus 
6 = unarousable by a painful stimulus 


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C. Occurrence of nausea/vomiting. The occurrence of nausea (yes/no) and vomiting 
(yes/no) will be scored at 15 min intervals. 


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9. Safety 
9.1 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, including placebo, and which does not necessarily 
have to have a causal relationship with treatment. An AE can be: 
• Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of study medication, whether or 
not considered related to the study medication. 
• Any new disease or exacerbation of an existing disease. 
• Any deterioration in protocol-required or non-protocol-required measurements of 
laboratory value or other clinical tests (e.g. ECG or X-ray) that results in symptoms, a 
change in treatment, or discontinuation from study medication. 
• 
Recurrence of an intermittent medical condition (e.g. headache) not present at baseline.  
Subjects with AEs that are ongoing at the subject’s completion/discontinuation visit (last 
treatment visit) will be followed up for 7 days and the follow up information will be recorded 
in the CRF. New AEs that are reported in the 7 days following the subject’s completion/ 
discontinuation visit will be recorded in the AE section of the CRF. Any AE that is still ongoing 
7 days after the completion/discontinuation visit will have an end date of ‘ongoing’ in the 
CRF, however the investigator will continue to follow up ongoing AEs and record information 
in the source documents. SAEs will be followed until the event resolves or the event or 
sequels stabilize and this information will be reported to the Sponsor using the SAE Data 
Form.  
9.2 Reporting of Adverse Events 
For subjects who receive study medication, all AEs (learned through spontaneous reports, 
subject interview) starting from providing informed consent for study participation through 
the period beyond study completion will be collected on the AE pages of the CRF. In 
addition, a note should be made in the source documentation of the subject.  


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For each AE on the AE pages of CRF, the following information will be recorded: AE (e.g. 
headache), start date, start time, stop time, severity, study medication action taken, other 
action taken, relationship to study medication, outcome, seriousness. A cluster of signs and 
symptoms that results from a single cause should be reported as a single AE (e.g. fever, 
elevated WBC, cough, abnormal chest x-ray, etc. can all be reported as “pneumonia.”). 
9.3 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to treatment in 
order that he/she may judge the true nature and severity of the AE. Severity refers to the 
accumulated intensity of discomfort/impairment of health since the last recording of AEs 
and will be assessed according to the following criteria: 
Mild: Awareness of sign, symptom, or event, but easily tolerated. 
Moderate: Discomfort enough to cause interference with usual activity and may warrant 
intervention. 
Severe: Incapacitating with inability to do usual activities or significantly affects clinical 
status and warrants intervention. 
The criteria for assessing severity are different to those used for seriousness (see below for 
the definition of an SAE). 
9.4 Criteria for Assessing Causality 
The question of the relationship of an AE to study medication should be determined by the 
Investigator after thorough consideration of all facts that are available. Assessment of 
causality is based on considering associative connections (time or place), pharmacological 
explanations, previous knowledge of the drug, presence of characteristic clinical or 
pathological phenomena, exclusion of other causes, and/or absence of alternative 
explanations. The causal relationship of an AE to study medication will be assessed according 
to the following criteria (based on World Health Organisation definitions): 
Not related: Temporal relationship to study medication administration is missing or 
implausible, or there is an evident other cause. 


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Related  
Unlikely to be related: Temporal relationship to study medication administration makes 
a causal relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations. 
Possibly related: Reasonable time sequence to administration of study drug, but event 
could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
Probably related: Reasonable time sequence to administration of study drug, but 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required. 
Definitely related: Plausible time relationship to study medication administration; event 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary. 
 
9.5 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
• Results in death; 
• Is life-threatening (i.e. the subject was at immediate risk of death from the AE as it  
occurred. This does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death); 
 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation; 
 
• Results in persistent or significant disability/incapacity; 


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• Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the  
 
study medication); 
 
• Is a medically important event or reaction (see below). 
 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalisation but may, based on appropriate medical judgment, jeopardize the 
subject or require intervention to prevent one of the outcomes in the definition of SAE listed 
above should also be considered SAEs. Examples of such events are intensive treatments in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or seizures that 
do not result in hospitalisation, or development of drug dependency or drug abuse. These 
events may be considered to need rapid reporting by the Sponsor to competent authorities. 
 
All SAEs, including those occurring up to 7 days following the subject’s completion/ 
discontinuation visit (subject’s last treatment visit), will be recorded on the AE pages of the 
CRF. In addition, SAEs must be reported to the Sponsor using the SAE Data Form. Subjects 
with SAEs must be followed until the event resolves or the event or sequels stabilize. 
 
9.6 Reporting of SAEs 
 
All SAEs must be reported to the Sponsor within one business day of first knowledge of the 
SAE using the SAE Data Form. In the initial report, all of the information requested that is 
available should be provided. The SAE Data Form must be signed by the Investigator prior to 
submission to the Sponsor. Follow-up information, or new information available after the 
initial report, should be actively sought and reported to the Sponsor as it becomes available 
using the SAE Data Form. SAE Data Forms must contain the following information, at a 
minimum: the reportable event, the study medication (if known), the protocol number, the 
subject number, and the Investigator name. 
 
 


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9.7 Expedited Reporting 
Adverse Reaction. Any untoward and unintended responses to an investigational medicinal 
product related to any dose administered. All AEs judged by either the reporting Investigator 
or the Sponsor as having a reasonable causal relationship to a medicinal product qualify as 
adverse reactions. The expression “reasonable causal relationship” means to convey in 
general that there is evidence or argument to suggest a causal relationship (i.e. causality is at 
least “unlikely”).  
Unexpected Adverse Reaction. An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator' Brochure for an 
unregistered investigational product or summary of product characteristics for a registered 
product). When the outcome of the adverse reaction is not consistent with the applicable 
product information this adverse reaction should be considered as unexpected. 
Suspected Unexpected Serious Adverse Reaction (SUSAR). A SUSAR is an adverse drug 
reaction, which is both serious and unexpected. If an SAE was assessed to be a SUSAR by the 
Sponsor, the Competent Authorities, ECs and Investigators must be informed as soon as 
possible but no later than 15 calendar days after the sponsor has first knowledge of the 
minimum criteria for expedited reporting. If the SUSAR was immediately life-threatening or 
fatal, it must be reported as soon as possible but no later than 7 calendar days after the 
sponsor has first knowledge of the minimum criteria for expedited reporting. Relevant 
follow-up information should be communicated to the competent authority and the Ethics 
Committee within an additional 8 calendar days. The Sponsor is responsible for expedited 
reporting of SUSARs and other reportable events and safety issues to the Competent 
Authorities, according to local legislations. Investigators will be informed by the Sponsor. The 
Investigator or Sponsor, depending on local regulations, must inform the EC/IRB about 
SUSARs and other reportable events and safety issues in accordance with ICH guidelines and 
the practices of the governing ECs. 
9.8 Data Monitory Committee (DMC) 
The DMC will receive the filled in CRF’s of the research team, make a copy of that data set 
and give the originals back to the research team (part of which is blinded).  


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The DMC will consist of three members of the Department of Anesthesiology not involved in 
the study (members are: Dr. E. Sarton, chair; Dr. J. Vuyk, member, and E. Olofsen MSc, 
statistician). The primary concern of the DMC is patient safety. If AEs or SAEs do occur they 
will advise the Investigator on the continuation of the study. Reporting to the DMC is 
independent of the reporting to sponsor, METC and CCMO. 
 
 
 


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10. Sample size, randomization, blinding and statistical analysis 
10.1 Sample size calculation. The sample size was based on the expectations of the clinical 
experts on a 5 point overall score of the surgical procedures. The a priori estimated mean 
difference between the treatment groups is 0.5 point on the 5-point L-SRS scale. Assuming a 
standard deviation of 0.75, a sample size of 47 subjects per group would provide at least 
90% power to observe the expected difference at alpha = 0.05. A sample size of 50 per group 
was chosen to take into account any margin of uncertainty around the effect size and SD. 
10.2 Randomization, blinding and treatment allocation 
Randomization will be performed by an independent person not involved in the study or its 
analysis. An envelope with the randomization code (deep or moderate) will be made 
available to the attending anesthesiologist. He or she will apply NMBs and reversal agents 
according to the instructions as dictated by the current protocol. Only the attending 
anesthesiology team will know the allocation and degree of muscle relaxation as measured 
by TOF CUFF. All others involved in the study (anesthesia research team and surgical team) 
will be blinded to the allocated treatment of the patient.  
After the patient has been sent to the recovery room all relevant syringes will be discarded 
by the anesthesiology team according to local protocol. 
The information regarding drug doses, TOF levels, and other items that may un-blind the 
allocation of the patient will be put on a separate sheet (part of the CRF) by the 
anesthesiology team and will be kept in a blinded envelope marked with the patient’s study 
number. It will be kept blinded in a separate CRF binder until the end of the study under 
supervision of by the DMC. 
10.3 Statistical Analysis 
Linear mixed effects model with ARMA1 (autoregressive moving average covariance 
structure) correction will be used to compare the L-SRS data. To estimate the variability (95% 
confidence interval) bootstrap analyses were performed. Comparisons of scores at fixed 
times points were done with Mann-Whitney-U tests. Statistical analysis will be performed 
using the SPSS statistical software package (version 23.0; SPSS Inc., Chicago, IL). P-values < 
0.05 were considered significant. 


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11. References 
1. Martini M, Boon M, Bevers R, Aarts L, Dahan A.  Evaluation of surgical conditions during laparoscopic 
surgery in patients with moderate versus deep neuromuscular blockade. Br J Anaesth 2014; 112: 498-505 
 
2. Torensma B, Martini C, Boon M, Olofsen E, in ‘t Veld B, Liem RSL, Knook MTT, Swank DJ, Dahan A. Deep 
neuromuscular block improves surgical conditions during bariatric surgery and reduces postoperative pain: a 
randomized double blind controlled trial. PLoS ONE 2016; 11: 20167907 
3. Martini C, Boon M, Broens SJL, Hekkelman EF, Oudhoff LA, Buddeke AW, Dahan A. Ability of the Nociception 
Level, a multiparameter composite of autonomic signals, to detect noxious stimuli during propofol-
remifentanil anesthesia. Anesthesiology 2015; 123: 524-534.