Erector Spinae Plane Block for Reduction of Early Postoperative Pain Scores and Opioid Use in Lumbar Spinal Fusion Surgery, a Prospective Double-blinded Randomized Placebo-controlled Trial
Phase: PHASE4
Conditions: Spondylolisthesis, Lumbar Disc Herniation, Lumbar Spinal Stenosis, Lumbar Disc Disease, Lumbar Spondylolisthesis, Lumbar Spondylosis, Lumbar Spine Disease, Lumbar Radiculitis, Spinal Fusion, Fusion of Spine, Spondylosis Lumbosacral Region
Sponsor: Ilse van de Wijgert

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Research protocol 
 
 
Erector spinae plane block for reduction of 
early postoperative pain scores and opioid use 
in lumbar spinal fusion surgery, a prospective 
double-blinded randomized placebo-controlled 
trial 
(February 2023) 
 
 
 
 
 
 
 
 
 

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Erector spinae plane block for reduction of early postoperative pain scores and opioid 
use in lumbar spinal fusion surgery, a prospective double-blinded randomized placebo- 
controlled trial 
 
Protocol ID
984
Short title
RCT-ESPB
EudraCT number
2021-003679-32
Version
2.0
Date
14-02-2023
Coordinating investigator/project 
leader 
Ilse H. van de Wijgert, MD
Department of Anesthesiology, Sint Maartenskliniek 
P.O. Box 9011, 6500 GM Nijmegen, the Netherlands 
+31 24 327 2593 
i.vandewijgert@maartenskliniek.nl 
Principal 
investigator(s) 
(in 
Dutch: 
hoofdonderzoeker/ 
uitvoerder) 
Miranda L. van Hooff, PhD
Department of Research, Sint Maartenskliniek 
Nijmegen, the Netherlands  
m.vanhooff@maartenskliniek.nl 
Investigators
Kris C.P. Vissers, MD, PhD, FIPP, jPL, PI
Department of Anesthesiology Radboudumc & Sint 
Maartenskliniek Nijmegen, the Netherlands 
Maaike G.E. Fenten, MD, PhD 
Sint Maartenskliniek, Department of Anesthesiology 
Rianne L.M. van Boekel, PhD, RN 
Department of Anesthesiology, Radboudumc 
Nijmegen, the Netherlands 
Sponsor
(in
Dutch: 
verrichter/opdrachtgever) 
Sint Maartenskliniek Nijmegen
Department of Anesthesiology 
Subsidising party
n/a
Independent expert (s)
Jessica Wegener, MD, PhD
Laboratory sites
n/a
Pharmacy
Maartensapotheek,
Sint
Maartenskliniek, 
Nijmegen 
Address for correspondence
Ilse H. van de Wijgert, MD
Sint Maartenskliniek, Department of Anesthesiology 
P.O. Box 9011, 6500 GM Nijmegen 
i.vandewijgert@maartenskliniek.nl 

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PROTOCOL SIGNATURE SHEET 
 
 
Name
Signature
Date
Head of Department:
I.J.
Bruaset,
MD, 
anesthesiologist 
Sint Maartenskliniek 
 
Department of Anesthesiology 
14-2-2023
Coordinating
Investigator/Project 
leader: 
I.H. van de Wijgert, MD, 
researcher 
Sint Maartenskliniek 
 
Department of Anesthesiology 
14-2-2023

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TABLE OF CONTENTS 
SUMMARY ................................................................................................... 8 
1. 
INTRODUCTION AND RATIONALE ................................................................... 9 
2. 
OBJECTIVES .......................................................................................... 10 
2.1 
Primary objectives and response variable ................................................. 10 
2.2 
Secondary objectives ......................................................................... 10 
3. 
STUDY DESIGN ....................................................................................... 11 
4. 
STUDY POPULATION ................................................................................ 13 
4.1 
Population (base) ............................................................................. 13 
4.2 
Inclusion criteria .............................................................................. 13 
4.3 
Exclusion criteria .............................................................................. 13 
4.4 
Sample size calculation ...................................................................... 13 
Mono-centre inclusion ................................................................................ 14 
5. 
TREATMENT OF SUBJECTS ......................................................................... 16 
5.1 
Investigational product/treatment ......................................................... 19 
5.2 
Escape medication ............................................................................ 20 
6. 
INVESTIGATIONAL PRODUCT ...................................................................... 21 
6.1 
Name and description of investigational product(s) ..................................... 21 
7. 
METHODS ............................................................................................ 22 
7.1 
Study parameters/endpoints ................................................................ 22 
7.1.1 Main study parameter/endpoint ............................................................ 22 
7.1.2 Secondary study parameters/endpoints .................................................... 22 
7.1.3 Tertiary study parameters/endpoints ........................................................ 22 
7.1.4 Other study parameters ...................................................................... 23 
7.2 
Randomisation, blinding and treatment allocation ....................................... 23 
7.3 
Study procedures .............................................................................. 23 
7.4 
Withdrawal of individual subjects .......................................................... 24 
7.5 
Replacement of individual subjects after withdrawal ................................... 24 
7.6 
Follow-up of subjects withdrawn from treatment ........................................ 24 
7.7 
Premature termination of the study........................................................ 24 
8. 
SAFETY REPORTING ................................................................................. 25 
8.1 
Temporary halt for reasons of subject safety ............................................. 25 
8.2 
AEs, SAEs and SUSARs ......................................................................... 25 
8.2.1 Adverse events (AEs) ......................................................................... 25 
8.2.2 Serious adverse events (SAEs) ............................................................... 25 
8.2.3 Suspected unexpected serious adverse reactions (SUSARs) ............................. 26 
8.3 
Annual safety report .......................................................................... 27 
8.4 
Follow-up of adverse events ................................................................. 27 
8.5 
Data Safety Monitoring Board (DSMB) ...................................................... 27 
9. 
STATISTICAL ANALYSIS ............................................................................. 28 
9.1 
Primary study parameter..................................................................... 28 
9.2 
Secondary study parameters ................................................................. 28 
9.3 
Other study parameters ...................................................................... 28 

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9.4 
Analysis of covariates ......................................................................... 29 
9.5 
Interim analysis ................................................................................ 29 
10. ETHICAL CONSIDERATIONS ......................................................................... 30 
10.1 
Regulation statement ......................................................................... 30 
10.2 
Recruitment and consent .................................................................... 30 
10.3 
Compensation for injury ..................................................................... 30 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .................................. 31 
11.1 
Handling and storage of data and documents ............................................. 31 
11.2 
Monitoring and Quality Assurance .......................................................... 31 
11.3 
Amendments ................................................................................... 32 
11.4 
Annual progress report ....................................................................... 32 
11.5 
Temporary halt and (prematurely) end of study report ................................. 32 
11.6 
Public disclosure and publication policy ................................................... 33 
12. STRUCTURED RISK ANALYSIS ...................................................................... 34 
12.1 
Synthesis........................................................................................ 34 
13. REFERENCES ......................................................................................... 36 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
ACOVA 
Analysis of Covariates 
AE 
Adverse Event 
AR 
Adverse Reaction 
ASA 
American Society of Anesthesiologists 
BMI 
Body Mass Index 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CRF 
Case Report Forms 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EMR 
Electronic Medical Records 
ESPB 
Erector Spinae Plane Block 
EU 
European Union 
EudraCT 
European drug regulatory affairs Clinical Trials 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
LAST 
Local Anesthetic Systemic Toxicity 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
MAC 
Minimum Alveolar Concentration 
MEQ 
Morphine Equivalents 
METC 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
NFU 
Dutch Federation of University Medical Centres 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
ODI 
Oswestry Disability Index 
PACU 
Post-Anesthesia Care Unit 
PCIA 
Patient Controlled Intravenous Analgesia 
PONV 
Postoperative Nausea and Vomiting 
PROM 
Patient Reported Outcome Measure 
RASS 
Richmond Agitation-Sedation Scale 
RCT 
Randomized Clinical Trial 
(S)AE 
(Serious) Adverse Event 
SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie 
IB1-tekst 

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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 regarded 
as the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
VATS 
Video Assisted Thoracoscopy Surgery 
WKR 
Spine Registry 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch- 
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
 
Rationale: Lumbar spine surgery is associated with high postoperative pain scores and 
analgesic use, despite use of multimodal analgesia. The erector spinae plane block (ESPB) is 
a promising locoregional anesthetic technique for this type of surgery. The literature is not 
yet conclusive about the effectiveness of this technique on reducing postoperative pain 
intensity. 
 
Objective: The objective of this study is to evaluate the analgesic effect of ESPB as add-on 
therapy to multimodal analgesia on early postoperative pain intensity after lumbar spinal 
fusion surgery compared to placebo. 
 
Study design: The study is designed as a prospective mono-centre, randomized, double- 
blinded, placebo-controlled trial. 
 
Study population: 76 patients ≥ 18 years of age requiring elective lumbar spinal fusion 
surgery involving one to four fusion levels. 
 
Intervention: Patients will receive ultrasound-guided ESPB with either ropivacaine or 
placebo at the end of surgery. 
 
Main study parameters/endpoints: Main study parameter is pain intensity upon emergence 
from anesthesia measured with the Numeric Rating Scale. A minimal clinically important 
difference is considered to be a decrease of 1.5 points. Secondary endpoints are 
acceptability of pain, pain intensity during hospital stay and after 30 days, opioid use during 
hospital stay and after 30 days, opioid side effects, use of anti-emetics, time to first opioid 
use/request, length of hospital stay, quality of recovery at discharge 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The Sint Maartenskliniek is experienced in applying locoregional 
analgesia, the use of ropivacaine and using sonography. The procedure of administering ESPB 
has a very low risk of complications. Receiving placebo is justifiable because this group will 
not be withhold standard treatment. The risks of receiving placebo are negligible. The 
patients will visit the clinic at regular follow-up moments. 

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1. INTRODUCTION AND RATIONALE 
 
Lumbar spine surgery is associated with high postoperative pain scores and analgesic use.1 
Despite multimodal pain treatment, time to first rescue treatment with opioids is often short 
and necessary on the Post Anesthesia Care Unit (PACU). Latest scientific insights show most 
pain interventions produce mild analgesic effects, and advise a multimodal regimen based 
upon systemic analgesics consisting of at least gabapentoids, ketamine and opioids.2 
Therefore, in our clinic (Sint Maartenskliniek, Nijmegen, the Netherlands), multimodal 
analgesia in spine surgery is now gold standard, with opioids as first choice postoperative 
rescue treatment. However, despite multimodal treatment, patients who underwent lumbar 
spine surgery still develop severe postoperative pain. 
 
A different possible measure to lower the risk of postoperative pain is locoregional 
anesthesia. The Sint Maartenskliniek has a long history of applying locoregional anesthesia 
in orthopedic surgery. Locoregional anesthesia provides effective analgesia without systemic 
side-effects like drowsiness or nausea, thereby reducing perioperative systemic drug use and 
possibly reducing the risk of persistent postsurgical pain. A novel locoregional anesthetic 
technique is the erector spinae plane block (ESPB). Good quality evidence exists for the 
effectiveness of this technique in breast cancer surgery and video assisted thoracoscopy 
(VATS).3 Although ESPB seems a promising analgesic technique for lumbar spine surgery 
patients not responding to the multimodal pain treatment regimen, sufficient high quality 
evidence is lacking. A recent systematic review summarized the evidence of ESPB for lumbar 
spine surgery, including two randomized clinical trials (RCT), showing beginning evidence of 
reduced postoperative opioid consumption and decreased pain scores.4–6 However, these 
trials contained a small sample size, were not blinded or lacked a comparator. Furthermore, 
little information on postoperative hospital stay is provided. This results in ESPB not being 
widely accepted in lumbar spine surgery. The larger, double-blinded, placebo-controlled 
methodology in this proposed trial aims to contribute to the scientific evidence for the 
effectiveness of EPSB in a multimodal analgesia management setting. 

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2. OBJECTIVES 
 
2.1 Primary objectives and response variable 
The primary objective of the study is to evaluate the analgesic effect of ESPB on early 
postoperative pain after lumbar spinal fusion surgery. Therefore the pain intensity in the 
postoperative care unit upon emergence, using the Numeric Rating Scale (NRS) for pain, will 
be the primary outcome parameter of this study. 
 
The null hypothesis states there is no difference in effectiveness of the ESPB compared to 
placebo on early postoperative pain intensity measured with NRS in patients that underwent 
lumbar spinal fusion surgery. This hypothesis will be tested two-sided, with α = 0.05. 
 
2.2 Secondary objectives 
The secondary objectives are to assess the effect of ESPB on: 
- 
Acceptability of pain; 
- 
Opioid use in cumulative morphine equivalent dose (MEQ) in the postoperative care 
unit and in the first 24 hours after surgery; 
- 
Opioid side effects such as nausea, vomiting and use of anti-emetics in the 
postoperative care unit and in the first 24 hours after surgery; 
- 
Time to first opioid use/request; 
- 
Length of hospital stay; 
- 
Pain intensity on postoperative admission days, before discharge from hospital, and 
after 30 days; 
- 
Opioid use 30 days after surgery; 
- 
Quality of recovery on postoperative day 1 and before discharge; 
- 
Complications up to 30 days postoperative. 
When postoperative pain is controlled, postoperative recovery is better. Therefore not only 
postoperative pain scores and opioid use are of interest, but also the quality of recovery 
after surgery and length of hospital stay. Quality of recovery will be measured using the QoR-
15 questionnaire. The QoR-15 provides a valid, reliable, responsive and easy-to-use method 
of measuring the quality of a patients’ postoperative recovery.7 

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3. STUDY DESIGN 
 
This study is designed as a prospective, mono-center, double-blinded, randomized, placebo- 
controlled trial. The study will be performed at the Sint Maartenskliniek, Nijmegen, the 
Netherlands. The study will be performed in accordance with the ICH E6(R1) Good Clinical 
Practice (GCP) guidelines. The duration of the study will be determined according to the 
progress of inclusion. Patients scheduled for elective lumbar spinal fusion surgery will be 
studied. Subject of investigation is the locoregional anesthetic technique ESPB. Subjects will 
be randomized to receive either ESPB with a long-acting local anesthetic or normal saline 
(placebo). 
The staff involved (doctors, nurses, OR-personal), as well as the research team and the 
patient will be blinded for treatment allocation. The study period includes in-hospital time 
after surgery and follow-up 30 days after surgery. Placement of the ESPB will be performed 
according to the study protocol, at the end of surgery, after wound closure. The placement 
of the ESPB is performed according to daily clinical practice as described by Forero et al.8 
Postoperative treatment of patients will be according to standard hospital protocol for 
lumbar spinal fusion surgery. 
 
Table 1 displays an overview of the study design and the main procedures that subjects will 
undergo in the course of research. The trial is registered at http://trialregister.nl/ (NL 9640) 
and will be monitored. 

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Table 1: Schedule of enrollment, allocation, interventions/assessments and collection via 
electronic medical file 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ESPB = erector spinae plane block, PACU = post anesthesia care unit, POD = postoperative day 
Timepoint
Preoperative
Day of 
surgery 
PACU
POD 
1 
POD 
2 
POD
3/discharge 
POD 30
Variable
Enrollment
 
 
 
 
 
 
 
o  Eligibility screening 
x
 
 
 
 
 
 
o  Informed consent 
x
 
 
 
 
 
 
Allocation (ESPB vs. placebo)
 
x
 
 
 
 
 
Assessment/intervention
 
 
 
 
 
 
 
o Intervention (ESPB or 
placebo)
 
x
 
 
 
 
 
o Surgical 
procedure/anesthesia
 
x
 
 
 
 
 
o  NRS for pain
x
 
x
x
x
x
x
o  Acceptability of pain 
 
 
x
 
 
 
 
o  Opioid side effects 
 
 
x
 
 
 
 
o  Quality of recovery 
 
 
 
x
 
x
 
Electronic Medical File
 
 
 
 
 
 
 
o  Opioid use 
x
x
x
 
 
 
x
o  Use of anti-emetics
 
x
x
x
x
x
 
o  Time to first opioid use 
 
 
x
 
 
 
 
o  Length of hospital stay 
 
 
 
 
 
x
 
o Adverse 
events/complications
 
x
x
x
x
x
x
o  Drain wound leakage 
 
 
x
x
x
x
Up to
14 days 
o  Other study parameters 
x
 
 
 
 
 
x

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4. STUDY POPULATION 
4.1 Population (base) 
The study population of this trial will be recruited from the patients planned to undergo 
elective lumbar spinal fusion surgery with a dorsal surgical approach in the Department of 
Orthopedics of the Sint Maartenskliniek Nijmegen. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
• 
Age ≥ 18 years; 
• 
Patients planned for elective lumbar spinal fusion surgery with a dorsal surgical 
approach; 
• 
1-4 level spine fusion surgery; 
• 
Written informed consent. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
• 
A Body Mass Index (BMI) > 40 kg/m²; 
• 
ASA physical health classification > 3; 
• 
Patients who will undergo spine surgery involving more than 4 levels of fusion, 
scoliosis surgery*; 
• 
Patients who will undergo minimally invasive surgery; 
• 
Patients who will undergo circumferent spine surgery; 
• 
Patients with an active, local infection or systemic infection; 
• 
Patients with an allergy to one or more medications used in the study; 
• 
Patients with any contraindication to a regional anesthetic technique; 
• 
Kidney- or liver failure inhibiting the systemic use of paracetamol and/or NSAIDs; 
• 
Acute surgeries; 
• 
Patients with a history of drugs or alcohol abuse; 
• 
Pregnancy; 
• 
Cognitive impairment; 
• 
Inability to speak or understand the Dutch language. 
 
* Patients undergoing fusion surgery on more than 4 levels of fusion are excluded because it 
is unclear whether the ESPB will spread over such wide area. To pursue homogeneity in 
expected spread of the local anesthetic the inclusion is limited to one to four levels of fusion. 
Analgesia protocol for scoliosis surgery is different and contains epidural analgesia and is 
therefore not comparable to the pursued study population. 
 
4.4 Sample size calculation 
For sample size calculation an internal database (not published) containing 76 patients who 
underwent lumbar spinal fusion surgery with dorsal approach containing 1-4 fusion levels 

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was used. The incidence of NRS ≥ 4 upon emergence in this database was 65%, with a mean 
NRS score of 4.5 (SD ±2.1). 
Level of significance was established to be 0.05. The sample size required having a 80% 
probability of detecting a difference of at least 1.5 points (NRS 0-10) on the primary outcome 
early pain intensity between the groups. Breivik et al.9 described a minimal clinically 
important difference to be a decrease of 1.5 points on the NRS (scale 0 to 10). Applying the 
SD of 2.1 from internal data, this translates into an effect size of 0.7. The sample size was 
calculated using G*Power. 
 
Required sample size to find at least a 1.5 point difference in NRS with an 80% probability 
and an effect size of 0.7 was calculated to be 68 patients in total. Ten percent withdrawal 
of the patients (n=7) during the study period is taken into consideration. In order to achieve 
two equal groups, this is rounded up to a total of 76 patients. The patients will be distributed 
in a 1:1 ratio. 
 
Mono-centre inclusion 
All patients will be recruited in Sint Maartenskliniek as it is a mono-centre study. In 2019 and 
2020 approximately 50-60 patients operations meeting our inclusion criteria have been 
conducted in the Sint Maartenskliniek. Assuming 50-60 patients per year would be eligible 
for inclusion, with the estimation that 80% of these patients would be included in the study, 
an inclusion period of 1,5 – 2 years is to be expected. 
 
Addendum 19-01-2023: inclusion rates have been lower than expected (Figure 1). The project 
team has reviewed the possibility of expanding the inclusion criteria from 2-4 fusion levels to 
1-4 fusion levels. Internal data as well as scientific literature show no significant difference in 
acute pain scores between single- or multilevel surgery.[1] Operation technique is comparable 
because in both cases open surgical approach is used to carry out the fusion of the vertebrae. 
Therefore the project team has decided to expand the inclusion criteria. 
 
In 2022, approximately 20 patients per month are operated for single- or multilevel lumbar 
fusion with a dorsal approach. Assuming 80% of the patients would be eligible for inclusion (no 
exclusion criteria present) and 50% gives informed consent (based on current inclusion rate), 
an inclusion period for the remaining 57 patients of ≈ 7 months is estimated (8 patients per 
month). Figure 1 shows the course of inclusion thus far and extrapolated for the upcoming 
year. What is shown is the expected/realized inclusion rate for multilevel only (blue and light 
green), vs. the inclusion rate including single level (purple), compared to the initial inclusion 
planning (red).  
 
 
 
 
 
 
 
 

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Figure 1: Course of inclusion of patients for the RCT-ESPB 
 
 
 
0
10
20
30
40
50
60
70
80
90
mei-22
jun-22
jul-22
aug-22
sep-22
okt-22
nov-22
dec-22
jan-23
feb-23
mrt-23
apr-23
mei-23
jun-23
jul-23
aug-23
sep-23
okt-23
nov-23
Course of inclusion patients RCT-ESPB
Initial planning
Realisation
Expected course based on
average inclusion rate per month
(multilevel only)
Extrapolation including single
level

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5. TREATMENT OF SUBJECTS 
Pre-, peri- and postoperative treatment of patients will be according to a standard protocol 
for lumbar spinal fusion surgery and is elaborated below. The protocol is also displayed in 
Table 2. 
 
Preoperative care: 
During the study, patients receive standard preoperative care. Basic oral pain treatment will 
be started preoperatively at the day of the surgery: gabapentine 300 mg, paracetamol 1000 
mg and etoricoxib 90 mg. One to two hours before entering the operating room patients 
receive midazolam 3.75mg orally to relieve stress, if considered contributing by the 
anesthesiologist and the patient. 
 
General anesthesia, induction: 
All surgeries will be performed by nine experienced orthopedic spine surgeons. Intravenous 
access and routine monitoring will be established in all patients. Induction of anesthesia is 
according to standard protocol using propofol 1.5-2 mg/kg, sufentanil 15-25 mcg, single dose 
dexamethasone 8 mg and a single dose of esketamine (10 mg). Endotracheal intubation is 
facilitated by a single administration of rocuronium (0.3-0.6 mg/kg). Ventilation and 
hemodynamics are regulated at the discretion of the attending anesthesiologist and/or 
anesthesia assistant. Patients are placed in prone position after induction. 
 
General anesthesia, maintenance: 
Peroperatively, anesthesia via sevoflurane (MAC 0.7-1), esketamine (2.5 mcg/kg/min) and 
sufentanil (5-25 mcg/h) is continuously administered. Thirty minutes before the end of 
surgery, esketamine and sufentanil is discontinued and ondansetron 4 mg is administered to 
prevent postoperative nausea and vomiting (PONV). Thirty to sixty minutes before the end 
of surgery, a loading dose of morphine (0.1 mg/kg), or in case of contra-indications to 
morphine, dipidolor (0.2 mg/kg), is given. 
 
The ESPB: 
Patients will receive locoregional analgesia via ESPB either with injectate consisting of 
ropivacaine 0.375 mg/mL with no additives (total dose of 225 mg), which is the intervention 
group, or injection with NaCl 0.9% (normal saline) with no additives, called the control (or 
placebo) group. This will occur according to a computer generated randomization list. 
At the beginning of the surgery, the orthopedic surgeon marks the transverse processes of 
the T12 spine level using X-ray and a skin marker, which are used as routine practice to 
orient before the start of the surgery. The injection will be placed at the end of the surgery 
in all patients, after wound closure, on both sides of the spine at T12 level (Figure 2). The 

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patient is still in a prone position (operation positioning), receiving general anesthesia. The 
placement of the ESPB is performed according to daily clinical practice as described by 
Forero et al.8 (Figure 210). The ESPB will be placed ultrasound guided with an in-plane 
technique. A needle (Tuohy 18Gx5” needle; B Braun, Melsungen, Germany) will be inserted 
paravertebral at the pre-defined T12 spine level. The needle will be inserted until the 
transverse process is touched. The needle is then retracted slightly, aspiration will be 
performed, if no blood returns, 30 mL of the study medication will be injected. The same 
will be performed on the contralateral side. Patients will receive either a total of 60 mL 
ropivacaine 0.375 mg/mL (total dose of 225 mg, intervention), or 60 mL NaCl 0.9% (placebo), 
depending on randomization allocation. 
Patients are then placed in supine position and general anesthesia is discontinued. According 
to normal anesthetic procedure, patients are woken up and extubated. Patients are brought 
to the Post Anesthesia Care Unit (PACU). 
 
Figure 2: The ESPB is placed bilaterally at T12 level (left). The ultrasound is placed dorsally just 
lateral from the spine process (right). It shows the transverse process with the erector spinae muscle 
on top. The injection will be placed in the green marked area and is supposed to anesthetize the 
dorsal (and ventral) ramus. The injectate spreads caudally and cranially and likewise anesthetizes the 
dorsal rami at that levels. 
 

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Postoperative analgesia regimen: 
The postoperative analgesia regimen is according to hospital protocol. Directly post-surgery, 
on the PACU, specialized PACU nurses can load patients with morphine (or dipidolor in case 
of contra-indication for morphine) until the patient is comfortable. If respiratory depression 
occurs, but the patient is still not comfortable, escape medication consists of clonidine 
intravenously (75-150 mcg) AND/OR recontinuation of esketamin infusion (5-10 mg/hr) 
AND/OR diazepam (2.5 mg iv or 5 mg p.o.). 
 
The basic postoperative analgesia regimen consists of paracetamol 1000 mg every 6 hours 
and etoricoxib 90 mg once daily. This is supplemented by a morphine PCIA (patient controlled 
intravenous analgesia) pump (or dipidolor in case of contra-indication for morphine). The 
PCIA pump is programmed according to the standard hospital protocol, which is bolus 1 mg, 
lockout 5 min, max. 32 mg/24h. 
Pre- peri- and postoperative treatment of patients will be according to a standard protocol 
for lumbar spinal fusion surgery and is displayed in Table 2: 
 
Table 2: Anesthesia protocol for lumbar spinal fusion at the Sint Maartenskliniek 
 
Preoperative
General
anesthesia,
induction 
General
anesthesia,
maintenance 
Postoperative
Gabapentin 300
mg 
Propofol 1.5-2 mg/kg
Sevofluraan (MAC 0.7-1)
Morphine
titrated
until
comfortable 
Paracetamol 
1000 mg 
Sufentanil 15-25 mcg
Sufentanil (5-25 mcg/h) until
30 minutes before end of 
surgery 
Paracetamol 1000 mg every 6 
hours 
Etoricoxib 90 mg
Esketamine 10 mg
Esketamine (2.5 mcg/kg/min) 
until 30 minutes before the end 
of surgery 
Etoricoxib 90 mg once daily
Midazolam 3.75 
mg (optional) 
Dexamethason 8 mg
Loading 
dose 
morfine
0.1 
mg/kg (or dipidolor 0.2 mg/kg) 
30-60 minutes before end of 
surgery 
Morphine PCIA-pomp (bolus 1 
mg, lockout 5 min, max. 32 
mg/24h) (or dipidolor) 
 
Rocuronium 
0.3-0.6
mg/kg 
Ondansetron 4 mg (30 minutes 
before end of surgery) 
Escape medication:
o Clonidine (75-150mcg) 
o Esketamin (5-10mg/h) 
o Diazepam (2.5-5mg) 
o Ondansetron/droperidol 
MAC = Minimum alveolar concentration, PCIA = patient-controlled intravenous analgesia 

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5.1 Investigational product/treatment 
Ropivacaine 
Our study will evaluate the impact of ropivacaine (0.375 mg/mL) in the application of the 
ESPB in patients who will undergo lumbar spine surgery. Use of ropivacaine as a locoregional 
analgesic is widely accepted and therefore not a new study drug. However, the application 
of this drug is not evidence based for this area of injection. 
 
Mechanism of Action 
Ropivacaine causes reversible inhibition of sodium ion influx, thereby blocking impulse 
conduction in nerve fibers. This action is potentiated by dose-dependent inhibition of 
potassium channels.11 Ropivacaine is metabolized extensively in the liver. The kidney is the 
main excretory organ for ropivacaine, accounting for 86% of the excretion of the drug in 
urine after a single intravenous dose administration. It has a mean ±SD terminal half-life of 
1.8±0.7 h and 4.2±1.0 h after intravenous and epidural administration, respectively. 
 
Bupivacaine is a well-established long-acting regional anesthetic, which like all amide 
anesthetics has been associated with cardiotoxicity when used in high concentration or when 
accidentally administered intravascularly. Ropivacaine is a long-acting regional anesthetic 
that is structurally related to bupivacaine. It is a pure S(-)enantiomer, unlike bupivacaine, 
which is a racemate, developed for the purpose of reducing potential toxicity and improving 
relative sensory and motor block profiles.11 This toxic dose is established to be max 300 
mg/dose and 700 mg/24h. 
 
Unlike prior studies, evaluating the effect of ESPB using (levo)bupivacaine in lumbar spine 
surgery, in this study ropivacaine is used.5,6,12 The choice for ropivacaine as regional 
anesthetic in this study is due to this reduced cardiotoxicity and therefore safer drug 
profile.11 In the Sint Maartenskliniek ropivacaine 0.375 mg/mL is routinely used as a lower 
concentration in a higher volume has lower risk of systematic toxicity. 
 
Placebo 
The placebo arm of this study will receive 30 mL 0.9% saline bilaterally. 
 
Dose Rationale and Risk/Benefits 
The treatment arm of this study will receive single shot injections of 30 mL 0.375% 
ropivacaine bilaterally on T12 spine level. This encounts for a total dose of 225 mg 
ropivacaine, which is considered to be a safe dose. The placebo arm of this trial will receive 

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single shot injections of 30 mL saline 0.9% bilaterally on T12 spine level. Little risk is likely 
to be associated with this procedure.13 
 
5.2 Escape medication 
If NRS pain scores exceed three points (scale 0-10) or the patient has unacceptable pain in 
the postoperative ward, morphine (or dipidolor in case of contra-indication to morphine) can 
be titrated until the patient is comfortable. If respiratory depression occurs, but the patient 
is still not comfortable, escape medication consists of clonidine intravenously (75- 150 mcg) 
AND/OR recontinuation of esketamin infusion (5-10 mg/hr) AND/OR diazepam (2.5 mg iv or 5 
mg p.o.). 
 
In case of nausea and/or vomiting, ondansetron or droperidol can be administered. In 
patients with high risk of PONV ondansetron is preventatively administered during surgery. 
 
This escape medication is part of standard post-anesthesia care protocol. There are no 
deviations from the standard protocol in terms of choice of medication or dosage. 

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6. INVESTIGATIONAL PRODUCT 
 
 
6.1 Name and description of investigational product(s) 
• 
Ropivacaine HCl 7.5 mg/mL solution for infusion (Fresenius Kabi Nederland B.V. 
Schelle, Belgium)14 
• 
NaCl 0.9% solution for injection (B Braun Melsungen AG, Melsungen, Germany)15 
For product information, we refer to the Summary of Product Characteristics (SPC). 

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7. METHODS 
 
7.1 Study parameters/endpoints 
 
7.1.1 Main study parameter/endpoint 
The main study parameter of this study is the early pain intensity in the 
postoperative care unit after emergence from general anesthesia. Pain scores will 
be measured using NRS, a scale ranging from 0 to 10 (0 meaning no pain at all; 10 
being the worst pain ever experienced). The NRS will be asked by a trained nurse 
not earlier than one hour after the patient emerges from general anesthesia in the 
PACU. The patient must have a Richmond Agitation-Sedation Scale (RASS) of 0 to 
minus 1 in order to determine NRS. If a patient is asleep, no NRS is measured until 
patient is awake. 
 
7.1.2 Secondary study parameters/endpoints 
Secondary endpoints are: 
• 
Acceptability of pain (yes/no); 
• 
Opioid use in cumulative morphine equivalent (MEQ) dose in the postoperative 
care unit and in the first 24 hours after surgery, extracted from the EMF and 
PCIA pump (MEQ, dose); 
• 
Presence of opioid side effects: nausea, vomiting and use of anti-emetics in the 
postoperative care unit and in the first 24 hours after surgery (yes/no); 
• 
Time to first opioid use/request (minutes); 
• 
Length of hospital stay (days); 
• 
Pain intensity on postoperative admission days, before discharge from hospital, 
and after 30 days (NRS for pain; 0-10); 
• 
Opioid use 30 days after surgery (yes/no, dose); 
• 
Quality of recovery (QoR) using the QoR-15 questionnaire7 (Dutch version QoR- 
15NL validation upcoming; 0-150) on postoperative day 1 and before discharge; 
• 
Complications up to 30 days postoperative. 
 
7.1.3 
Tertiary study parameters/endpoints 
• 
Drain wound leakage up to 14 days postoperatively. 

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7.1.4 Other study parameters 
• 
General patient demographics (gender, age, weight, height, ASA classification, 
comorbidities); 
• 
Baseline biopsychosocial parameters using the STarT Back Screening Tool 
(Dutch version)16; 
• 
Surgery indication, type of surgery, duration of surgery (minutes), total 
amount of blood loss during surgery (millilitres); 
• 
Preoperative use of analgesics (type, dose, route of administration); 
• 
Presence of chronic pain (NRS pain >3 and pain duration ≥ 6 months); 
• 
Preoperative opioid use (yes/no); 
• 
Use of anticoagulants (yes/no). 
 
 
7.2 Randomisation, blinding and treatment allocation 
After obtaining informed consent, the coordinating researcher creates a study case. 
Patients will be randomly allocated in a 1:1 ratio to either the study group (ESPB) or 
the control group (placebo) by the hospital’s pharmacist on the day of surgery. 
Permuted block randomization with varying permuted block sizes will be used. This 
block randomization list will be created by Sealed EnvelopeTM and managed by the 
hospital’s pharmacist. Only the hospital’s pharmacist will have access to the 
randomization list. The staff involved (doctors, nurses, operation room personal), as 
well as the research team and the patient will be blinded for treatment allocation. 
The hospital’s pharmacist prepares the medication on the morning of surgery, 
delivers it at the operation complex and collects empty syringes after injection in 
terms of drug accountability. 
 
7.3 Study procedures 
After inclusion and informed consent patients’ demographical data will be collected 
via extraction from our spine registry database. This spine registry is part of the 
Nijmegen Decision Tool for Chronic Low Back Pain (NDT-CLBP), an internally validated 
clinical decision tool for low back pain patients, and standard care in the Sint 
Maartenskliniek.17,18 The spine registry is implemented in the electronic medical 
record. 
Table 1 displays an overview of moments and procedures of data collection. Data 
from the electronic medical file (EMF) are collected by the researcher. PACU 
assessments are conducted by PACU nurses and registered in de EMF: NRS scores, 
acceptability of pain and presence of opioid side effects in terms of standard care. 
NRS scores on postoperative days are collected for standard care by the caring nurses 
on clinical indication. The amount and frequency of opioid usage via PCIA pump will 
be extracted from the PCIA pump by the researcher. The researcher takes the QoR15 

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questionnaires from the patient on the first postoperative day and before discharge. 
Patients will be contacted by the researcher 30 days after surgery to assess pain 
intensity, opioid use and occurrence of complications. 
 
All surgeries will be performed by one of nine experienced orthopedic spine surgeons. 
The study intervention (ESPB vs. placebo) will be performed by an experienced 
anesthesiologist at the end of surgery. 
 
7.4 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. 
 
7.5 Replacement of individual subjects after withdrawal 
Subjects withdrawn from the study before randomization will be replaced by new 
included patients. Patients withdrawn after randomization will be lost to follow-up. 
 
7.6 Follow-up of subjects withdrawn from treatment 
When patients decide to withdraw from the study, treatment will continue as per 
hospital protocol. All reasonable efforts should be made to keep in contact with the 
patient for the duration of the study, to evaluate the clinical condition. 
If serious adverse events occur or other adverse events lead to withdrawal, the 
patient will be treated according to good medical practice and will be closely 
monitored until recovery. 
 
7.7 Premature termination of the study 
The trial can be terminated due to the appearance of (serious) adverse events of a 
nature, severity and duration previously unknown or if known (serious) adverse 
events occur with an unexpected high frequency. The study coordinator thus has to 
keep close track of the adverse events. 

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8. SAFETY REPORTING 
 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study 
if there is sufficient ground that continuation of the study will jeopardise subject health 
or safety. The investigator will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed. 
 
8.2 AEs, SAEs and SUSARs 
 
8.2.1 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 ESPB using ropivacaine, 
or ESPB with placebo (normal saline). All adverse events reported spontaneously by 
the subject or observed by the investigator or his staff will be recorded up to 30 days 
after surgery. 
 
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that 
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes 
listed above due to medical or surgical intervention but could have been based 
upon appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 
8 days to complete the initial preliminary report. All other SAEs will be reported 

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within a period of maximum 15 days after the investigator has first knowledge of 
the serious adverse events. 
 
8.2.3 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 investigator 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 investigator 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 (CA). 
 
The expedited reporting will occur not later than 15 days after the investigator 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. 

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Method for breaking the code 
When a serious AE comes in and if it might be a SUSAR on which additional treatment 
is necessary, the pharmacist responsible for preparation of the study medication, 
who is already deblinded, is informed. The attending anesthesiologist, operating 
orthopedic surgeon, patient and the coordinating researcher are deblinded. 
 
8.3 Annual safety report 
 
In addition to the expedited reporting of SUSARs, the investigator will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, CAs, and CAs 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. 
 
8.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol 
 
8.5 Data Safety Monitoring Board (DSMB) 
A data safety monitoring board will not be established. 

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9. STATISTICAL ANALYSIS 
All statistical analysis will be done after consultation with a senior statistician. 
Intention to treat analysis will be performed. Continuous data will be described and 
presented as mean and standard deviation or as median an interquartile range. 
Normality of distributions of continuous variables will be assessed with skewness and 
kurtosis measures. 
Missing observations will be reported as missing (not replaced). 
 
 
9.1 Primary study parameter 
The null hypothesis states there is no difference in effectiveness of the ESPB compared 
to placebo on early postoperative pain intensity measured with NRS in patients that 
underwent lumbar spine fusion surgery. This hypothesis will be tested two-sided, with 
α=0.05. A clinically relevant minimal difference in NRS would be 1.5 points.9 Regression 
analysis will be used for statistical analysis, with experimental status and pre-operative 
NRS as independent variables. 
 
9.2 Secondary study parameters 
Analysis for 24-hour morphine consumption is conducted as described for the primary 
study parameter; regression analysis will be used for statistical analysis, with 
experimental status and pre-operative morphine consumption as independent variables. 
Other continuous data (escape medication consumption, length of hospital stay, anti- 
emetics consumption, time to first opioid use/request, quality of recovery) will be 
assessed using a Student’s t-test if the data are normally distributed. Non-parametric 
Mann-Whitney U test will be used in case data is not sufficiently normally distributed. 
Categorical variables (acceptability of pain and opioid use 30 days after surgery) will be 
compared between the intervention and control group using the Fisher Exact Test. The 
mean difference between groups will be presented together with the 95% confidence 
interval. 
 
9.3 Other study parameters 
Baseline data of the two groups (age, weight, height, duration of surgery, blood loss 
during surgery, as well as gender, ASA classification and type of surgery) will be 
described. 
Preoperative use of analgesics (type, dose, route of administration) will not be 
analysed but merely described. 

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9.4 Analysis of covariates 
It is hypothesized that there could be a difference in the primary outcome variable 
(NRS for pain) and the secondary outcome variable (24-hour morphine consumption) 
between the subgroups defined by factors among which daily preoperative opioid use is 
most important.19 Therefore, as secondary analysis the regression for the analysis of the 
effect of an ESPB on NRS and morphine consumption will be extended with an 
interaction term between the experimental condition and preoperative opioid use. 
To investigate if there is a difference in outcome parameters, an additional analysis 
will be performed classifying the patients in single- or multilevel fusion surgery. In 
previous research by Gerbershagen et al., describing pain intensity on the first day 
after surgery, pain intensity was equal in single and multilevel fusion surgery.[1] As yet, 
no multilevel ESPB study was conducted. 
 
9.5 Interim analysis 
An interim analysis will not be performed in this study.  
A safety analysis will be performed yearly, with the formulation of the annual safety 
report. 

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10. ETHICAL CONSIDERATIONS 
 
10.1 Regulation statement 
This study will be conducted at the Sint Maartenskliniek Nijmegen, according to this 
protocol, the guidelines in the declaration of Helsinki and later revisions thereof, the 
ICH guidelines for Good Clinical Practice, in accordance with the Medical Research 
Involving Human Subjects Act (WMO) and applicable regulatory requirements. No 
patients will be recruited before written approval has been obtained from the local 
Medical Ethics Review Committee as well as from the Board of Directors of the Sint 
Maartenskliniek Nijmegen. 
 
10.2 Recruitment and consent 
Patients will be recruited from the list of patients visiting the preoperative screening. 
The attending anaesthesiologist will screen these patients for eligibility. All candidate- 
participants will be asked consent for sharing contact data with the investigator. All 
candidate-participants receive standardized information about the operation. The 
investigator contacts candidate-participants, will check for eligibility, and, if eligible, 
the patients will be informed about the study verbally (by telephone by the 
investigator) and in writing. The terminology in the information sheet is chosen so that 
the layman can fully understand the content. The patient will be given ample time for 
consideration and if patients agrees to participate, signed informed consent forms are 
returned to the researcher (patient receives return envelope). 
 
10.3 Compensation for injury 
The investigator has a liability insurance which is in accordance with article 7 of the 
WMO. 
 
The investigator (also) has an insurance which is in accordance with the legal 
requirements in the Netherlands (Article 7 WMO). This insurance provides cover for 
damage to research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 
4 years after the end of the study. 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
The research data will be managed in accordance with the FAIR principles. Procedures 
of the Sint Maartenskliniek will be followed for data handling, collection, management, 
analyses, archiving and reporting. Any calculated data and all digital data will be filed 
under a study number at the Sint Maartenskliniek Nijmegen, department of Research. 
The data will be kept for 15 years. A record of the full addresses and names of the study 
subjects and a copy of the signed informed consent form, which must be able to uniquely 
identify a study subject, and the corresponding study number will be kept separately. 
These records are to be retained for 15 years following the completion of the trial. 
 
Baseline patient characteristics and outcome variables will be collected from the spine 
registry (WKR) database of the Sint Maartenskliniek and enriched with the perioperative 
anesthetic and surgical procedure characteristics derived from electronic medical 
records (EMR) as the core set is integrated in the EMR of the Sint Maartenskliniek (HiX). 
All data entries will be made directly in (electronic) case report forms (eCRFs) using 
CastorSMS. 
 
Research data will be retrieved from eCRFs, inserted into a SPSS or STATA for statistical 
analyses and archived in CastorSMS. 
 
Backups of all digital files kept by the Sint Maartenskliniek Nijmegen are updated and 
stored separately every night. Paper versions of files are stored in an archive in the Sint 
Maartenskliniek which is only accessible by the Principal Investigator (also doctoral thesis 
co-supervisor) and the current investigators of the Sint Maartenskliniek. 
 
DANS EASY will be the data repository for open access. 
 
 
11.2 Monitoring and Quality Assurance 
Monitoring and quality assurance will be established according to the advice of the NFU 
(Dutch Federation of University Medical Centres (NFU)). The classification for risk is 
estimated at negligible risk. Therefore, the monitoring will consist of the following; 
- 
Frequency of one visit per year; 
- 
Check of rate of inclusion and dropout; 
- 
Check if the investigator file is complete (see ICH E6 (R2) Good Clinical 
Practice guidelines)20; 

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- 
Check for written informed consent in 1% of participants; 
- 
Check for in- and exclusion criteria of the first 3 participants and 1% of the 
following participants; 
- 
Verification of source data of 1% of the participants; 
- 
Check for missed SAE’s in 1% of the participants and verify reported SAE’s; 
- 
Monitoring will be executed by a qualified monitor of the department of 
Research of the Sint Maartenskliniek Nijmegen, who has successfully 
attended the BROK-course. 
 
11.3 Amendments 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the CA. 
 
Non-substantial amendments will not be notified to the accredited METC and the CA, but 
will be recorded and filed by the investigator. 
 
11.4 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. 
 
11.5 Temporary halt and (prematurely) end of study report 
The investigator will notify the accredited METC and the CA of the end of the study within 
a period of 90 days. The end of the study is defined as the last patient’s last visit. 
 
The investigator will notify the METC immediately of a temporary halt of the study, 
including the reason of such an action. 

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In case the study is ended prematurely, the investigator will notify the accredited METC 
and the CA 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 and the CA. 
11.6 Public disclosure and publication policy 
 
Any publication of the results, either partial or complete, in the form of articles 
appearing in journals or the verbal presentation by the investigators, or their 
representatives, requires the agreement of the principal investigator. All participating 
investigators can use the results of the study for their presentations at conferences, 
only after contact with the principal investigator (Dr. M. Fenten) and the project leader 
(drs. I. van de Wijgert). All participating investigators will be acknowledged in the 
publication(s), and if possible be co-author. 

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12. STRUCTURED RISK ANALYSIS 
12.1 Synthesis 
Ropivacaine is used globally and is known as a safe, effective analgesic. A structured risk 
analysis exists for the application of Ropivacaine HCl and NaCl 0.9% in the Summary of 
Product Characteristics (SPCs).14,15 The risks of local anesthetic systemic toxicity (LAST) 
is extremely uncommon. A prospective clinical registry study performed by Sites et al. 
(2012) analyzing 12,668 ultra-sound guided nerve blocks showed no cardiac arrests. Other 
adverse events across all peripheral local anesthetics are postoperative neurologic 
symptoms, seizure, pneumothorax, unintended venous puncture, unintended arterial 
puncture and unintended paresthesia during block placement. The total incidence of this 
adverse events (per 1000 nerve blocks) was 1.8 (95% confidence interval 1.1-2.7).21 
 
Bupivacaine is a well-established long-acting regional anesthetic, which like all amide 
anesthetics has been associated with cardiotoxicity when used in high concentration or 
when accidentally administered intravascularly. Ropivacaine is a long-acting regional 
anesthetic that is structurally related to Bupivacaine. It is a pure S(-)enantiomer, unlike 
Bupivacaine, which is a racemate, developed for the purpose of reducing potential 
toxicity and improving relative sensory and motor block profiles.11 This toxic dose is 
established to be max 300 mg/dose and 700 mg/24h. The choice for ropivacaine as 
regional anesthetic in this study is due to this reduced potential toxicity and therefore 
safer drug profile. 
 
Although extensive experience with ropivacaine, few studies on administration of sodium- 
channel blockers via ESPB exist. No adverse events related to ESPB were found in the 11 
included studies with data from 171 patients in a recent systematic review.4 The 
procedure of administering ESPB has a very low risk of complications.The structures are 
easily identifiable via sonography. No critical structures are present nearby the target 
point.8,13 The transverse process acts as an anatomical barrier and avoids needle insertion 
into the pleura or vessels, thus preventing a pneumothorax or hematoma. Moreover, the 
needle is relatively far from the vertebral canal, which means the risk of spinal cord injury 
is very low. In a pooled review, which yielded 242 reported cases between 2016 and 2018, 
only one adverse event (a pneumothorax) was reported.22 Locoregional anesthesia via an 
ESPB preserves bladder function and motor neuron function enabling early mobilization. 
Since motor function is unaltered, immediate postoperative neurological evaluation of 
spinal cord function is possible.23 

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The Sint Maartenskliniek has a long history of applying locoregional analgesia and our 
anesthesiologists are very experienced using sonography. This will lower the risk of 
complications even more. 
 
Receiving placebo is in our opinion justifiable, because this group will not be withhold 
standard treatment. The administration of ESPB with ropivacaine is an add-on therapy to 
our standard care. The risks of receiving placebo are negligible. 
 
 

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13. REFERENCES 
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