Diaphragmatic Paralysis After Interscalene Brachial Plexus Block: A Randomized, Double-blinded, Unicenter and Controlled Clinical Trial to Reduce the Dose of Levobupivacaine 0,25% 20 ml to 10 ml Undergoing Arthroscopic Shoulder Surgery
Phase: PHASE3
Conditions: Diaphragmatic Paralysis, Brachial Plexus Block
Sponsor: Instituto de Investigación Sanitaria Aragón

 
 
 
 
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1 
 
1 COVER PAGE  
 
1.1 Official title: 
Study Protocol  (ID: NCT04385966) entitled “Diaphragmatic paralysis after interscalene 
brachial plexus block: a randomized, double-blinded, unicenter and controlled clinical 
trial to reduce the dose of levobupivacaine 0,25% 20 ml to 10 ml undergoing 
arthroscopic shoulder surgery”. 
 
1.2 NCT number: 
NCT04385966. 
 
1.3 Document date: 
February 10th, 2021. 

 
 
 
 
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CLINICAL TRIAL PROTOCOL 
 
 
 
OFFICIAL TITLE 
Diaphragmatic paralysis after interscalene brachial plexus block: a randomized, 
double-blinded, unicenter and controlled clinical trial to reduce the dose of 
levobupivacaine 0,25% 20 ml to 10 ml undergoing arthroscopic shoulder surgery. 
 
1.4 NCT NUMBER 
ClinicalTrials.gov register number: NCT04385966. 
 
1.5 DOCUMENT DATE 
ClinicalTrials.gov 
register 
date: 
08 
May 
2020.

Administrative Information 
Version 1.0. 17 October 2019 
 
3 
2 ADMINISTRATIVE INFORMATION 
 
2.1 TITLE 
Diaphragmatic paralysis after interscalene brachial plexus block: a randomized, 
double-blinded, unicenter and controlled clinical trial to reduce the dose of 
levobupivacaine 0,25% 20 ml to 10 ml undergoing arthroscopic shoulder surgery. 
2.2 TRIAL REGISTRATION 
EudraCT register number (register date): 2019-003855-12 (07 January 2020). 
Spanish Trial Register (REec) (register date): 2019-003855-12 (07 January 2020).  
Ethics Committee approval (approval date; responsible): EC19/093 (18 December 
2019; Maria Gonzalez Hinjos [Ethics Committee Secretariat]). 
Phase: III. 
 
 
 
 
 
 
Protocol code: REDOLEV-2019. 
Version (date): 1.0 (17 October 2019). 
2.3 SPONSOR 
Aragon Institute for Health Research (IISAragon). Address: Avenida San Juan 
Bosco 13, Edificio CIBA, Planta baja. Phone: +34 976 71 68 18 . 
2.4 FUNDING 
The institution where the study is enrolling is: Anestesia and Intensive care 
Departament. Hospital Universitario Miguel Servet (HUMS). Paseo Isabel la Católica, 
1-3, 50009 Zaragoza, Spain. Phone: +34 976 76 55 00. 

Administrative Information 
 
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Aragon Health Sciences Institute (IACS)  Instituto Aragonés de Ciencias de la Salud 
(IACS). Address: Calle de San Juan Bosco, 13, 50009 Zaragoza, Spain. Phone: +34 
976 71 58 95. Email: dbordonaba.iacs@aragon.es. 
In this clinical trial, the sponsor and the Principal Investigator (PI) state that no funding 
sources, no potential conflicts of interest, and no institutional affiliations of the 
researcher are available.  
In accordance with the posterior defined methodology of this study and with the 
resources available in the HUMS, the development of the research project does not 
need any additional economic expenditure.  

Abbreviations 
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5 
3 ABBREVIATIONS 
- 
ADR  
Adverse Drug Reaction. 
- 
AE 
 
Adverse Event 
- 
AEMPS 
Spanish Agency of Medicines and Medical Devices 
- 
ARP   
Assessment research physician 
- 
CI 
 
Collaborator Investigator 
- 
DCF 
 
Data Collection Forms. 
- 
DMC   
Data Monitoring Committee 
- 
DTR 
 
Diaphragmatic Thickness Ratio 
- 
EDT 
 
Expiratory Diaphragmatic Thickness. 
- 
GA 
 
General Anaesthesia 
- 
HDPA  
HemiDiaphragmatic Paralysis Acute 
- 
HUMS  
Hospital Universitario Miguel Servet 
- 
IBPB   
Interscalene Brachial Plexus Block. 
- 
IC 
 
Informed Consent. 
- 
ICU 
 
Intensice Care Unit 
- 
IDT 
 
Inspiratory Diaphragmatic Thickness.  
- 
IRP  
 
IBPB research physicians 
- 
LA 
 
Local anesthetic 
- 
LBP 
 
Levobupivacaine 
- 
NRS   
Numerical Rating Scale 
- 
NSAID  
Non-steroidal anti-inflammatory drugs 
- 
PACU  
Post-Anesthesia Care Unit 
- 
PCA 
 
Patient-Controlled Analgesia 
- 
PI 
 
Principal Investigator. 
- 
PMR  
Participant Medical Record. 
- 
RCT 
 
Randomized Controlled Trial 
- 
RP 
 
Research Physician 
- 
RRP   
Recruitment research physicians 
- 
SADR  
Serious Adverse Drug Reaction. 
- 
SAE   
Serious Adverse Event. 
- 
SS  
 
Statistical staff 
- 
ToF 
 
Train of Four 
- 
UADR  
Unexpected Adverse Drug Reaction. 

Abbreviations 
 
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- 
US 
 
Ultrasound 
 

Introduction 
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4 INTRODUCTION 
 
4.1 RESEARCH DRUG: NAME AND DESCRIPTION 
Research Drug: Levobupivacaine (Chirocane®). FDA approval: NDA-20997 (1999). 
Description: Levobupivacaine (LBP) is the S(-) enantiomer of the amide-type local 
anaesthetic Bupivacaine with a pharmacodynamic and an equivalent potency. 
However, LBP presents less neurological and cardiac toxicity with less prolongation of 
the QT segment and less negative inotropic effect Its onset of action is less than fifteen 
minutes and causes a sensory block of approximately 6 hours after intradural 
administration, 9 hours after epidural administration and 17 hours after peripheral nerve 
block with a dose of 2 mg/kg(1). 
4.2 BACKGROUND AND RATIONALE 
Shoulder surgery is a surgical procedure that involves dynamic pain, moderate or 
severe, in the postoperative period that can compromise the patient's early 
rehabilitation (2,3). 
Brachial plexus blockade by interscalene approach (IBPB ) is one of the most effective 
anaesthetic and analgesic techniques used in this type of surgery (4,5). According to 
the 10th International Classification of Diseases (ICD-10), it has the procedure code: 
3E0T3CZ (3,6). 
The main indications for IBPB are surgery of the shoulder joint, the two lateral thirds of 
the clavicle, the proximal part of the humerus, and as an anaesthetic complement in 
surgeries of the pectoral and dorsal areas of the thorax (2,3,7,8). In these cases, 
locoregional anaesthesia offers a better postoperative analgesic control, lower 
consumption of opioids, a lower economic cost, a lower incidence of nausea and 
vomiting and a shorter hospital stay (9). 
On the other hand, the IBPB associates a series of complications such as phrenic 
nerve block, neuroaxial diffusion, total spinal block, vascular puncture, Bezold-Jarisch 
reflex, stellate ganglion block, recurrent nerve block, etc (7). 

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The absolute contraindications of IBPB are exceptional: patient rejection, allergy to 
local anaesthetics, local infection at the puncture site, or hemodynamic instability. 
However, relative contraindications are more common such as chronic obstructive 
pulmonary disease (COPD), contralateral phrenic nerve or recurrent paresis and a 
previous neurological deficit of the arm (2,8). 
The diaphragm is the main inspiratory muscle when constrained it causes a caudal 
movement of the chest which results in inspiratory movement. It is responsible for the 
75% increase in lung volume in normal breathing, compared to the remaining 25% that 
is the responsibility of the intercostal, scalene and sternocleidomastoid muscles. Its 
insertion at an inferolateral level of the thoracic cage is called the apposition zone. The 
ultrasound (US) visualization of the apposition zone in inspiration and expiration 
presents high rates of sensitivity and diagnostic specificity of hemidiaphragmatic 
paralysis acute (HDPA). The diaphragmatic paralysis can be categorized as: complete 
in case of a >75% decrease of the diaphragmatic excursion (DE) or a paradoxical DE, 
partial if there is a 25% to 75% decrease of the DE or null in case of a variation lower 
than 25% (10,11). 
The diaphragm is innervated by the phrenic nerve, which originates from the C3-C5 
nerve roots. This nerve can be blocked by the IBPB due to the rostral migration, 
volume dependent, of the local anaesthetic that will originate an ipsilateral 
diaphragmatic paralysis (4,9). Classically, Urmey et al. (1991) established that IBPB 
caused a 100% incidence of phrenic nerve block with subsequent ipsilateral 
diaphragmatic paralysis defined according to ICD-10 with code J98.6 (6,12). 
Nowadays, thanks to the advances in the techniques of nervous localization by US and 
the reduction of the dose of local anaesthetic required in these techniques of 
locoregional anaesthesia, the incidence of diaphragmatic paralysis has been reduced 
up to an interval of 13-47% according to recent publications. This literature provides 
very variable results so the contraindications of IBPB are still in force (4,13–16). 
For the diagnostic evaluation of phrenic blockade, lung US is a non-invasive, 
reproducible, non-radiant and reliable tool (9,11). Recently, the measurement of 
diaphragmatic thickness has been published as a diagnostic tool for phrenic paralysis 
(15,17). By visualizing the apposition area with US, during inspiration and expiration, 
the inspiratory diaphragmatic thickness (IDT) and the expiratory diaphragmatic 
thickness (EDT) can be quantified. A normal EDT can range from 2.2-2.8 mm and a 
normal IDT can reach more than 4 mm. While IDT or EDT values below 2 mm indicate 

Introduction 
 
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PDA (17). Thus, from this US measurement, the IDT and EDT are obtained and then 
the ratio of inspiratory/ expiratory diaphragmatic thickness ratio (DTR) is calculated by 
the ratio of IDT/EDT. The DTR has a sensitivity of 93% and a specificity of 100% for 
the diagnosis of diaphragmatic dysfunction if it is lower than 1.2 (15,18). 
Likewise, forced spirometry is a first-line diagnostic tool in the diagnosis of 
neuromuscular pathology such as diaphragmatic paralysis (19). Phrenic nerve block 
has been associated with a decrease of about 25% in respiratory parameters such as 
Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV1), and 
15% in the Peak Expiratory Flow (PEF) Rate (4,11). This side effect is usually well 
tolerated by most patients, but in those with a history of COPD, restrictive diseases, or 
obstructive sleep apnea-hypopnea syndrome or compromised breathing capacity may 
be a contraindication. Also, such respiratory compromise and the corresponding 
hypoxemia caused to have an impact on the patient's post-surgical comorbidity. 
For this reason, this technique of locoregional anaesthesia is contraindicated in those 
patients with a history of severe respiratory pathology in whom this diaphragmatic 
paralysis cannot be assumed (8). Therefore, this type of patient is forced to undergo 
general anaesthesia, as the only possible anaesthetic option with the side effects that 
general anaesthesia and mechanical ventilation equally entails for this type of patient. 
However, 
locoregional 
anaesthesia 
offers 
numerous 
clinical 
and 
economic 
perioperative benefits over general anaesthesia (9). 
To date, there are no published data in the literature about the respiratory impact of 
US-guided IBPB with local anaesthetic volume and objectified by respiratory and 
imaging functional diagnostic tests during the usual clinical practise of an 
anesthesiologist in Spain (15). 
This study will try to objectify the diaphragmatic paralysis caused by the IBPB 
technique performed on patients undergoing scheduled arthroscopic shoulder surgery 
during the usual clinical practice of an Anesthesia Service in a third level hospital in our 
country. The aim is to describe the real respiratory and functional repercussion caused 
by this side effect of BPBHA at present, to assess the benefit-risk ratio and the relative 
contraindications of this anaesthetic technique in the future. 
The evaluation of the benefit-risk of the intervention in this clinical trial (CD) is very 
satisfactory because there are two diagnostic tests available (diaphragmatic US and 
forced spirometry) that are non-invasive, bloodless, painless, and assistive that could 

Introduction 
 
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also be performed according to normal clinical practice. In the same way, the invasive 
technique that is carried out consists of the practice of the IBPB according to the usual 
clinical practice of the anesthesiologist so it does not involve more risk than usual. 
Therefore, there is no added risk for the patient-derived from the intervention proposed 
in this study.  
However, the benefit that we seek to obtain is to know the incidence and the real 
clinical repercussion of the IBPB to evaluate in the future the contraindications of this 
locoregional technique used in our daily anaesthesia practice. Thus, patients with 
respiratory or nerve pathology who, to date, are forced to undergo general anaesthesia 
without locoregional support in shoulder surgery could be accepted and benefit from 
locoregional anaesthesia and analgesia in shoulder surgery, supported by evidence of 
the expected results. 
In case we can objectify an incidence of diaphragmatic paralysis lower than the classic 
estimate of 100% as other scientific works are already recording, shortly, the 
contraindications of this anaesthetic technique could be reconsidered and the usual 
clinical practice of the anesthesiologist modified based on the evidence (15,20–22). 
4.3 RISK-BENEFITS BRIEF 
In this study, the intervention to be performed (IBPB with LBP) is an anaesthetic 
invasive technique carried out in the current practice at the Regional Anaesthesia 
Division of the Department of Anesthesia, Intensive care and Pain management in the 
Hospital Universitario Miguel Servet (HUMS).  
This anaesthetic technique entails a series of risks and complications such as vascular 
puncture, peripheral nerve damage or systemic poisoning by local anaesthetics, risks 
that would also be assumed if the patient did not participate in this clinical trial, since 
the concentration, volume and dose of the intervention drug are the same as those 
used by normal clinical practice for carrying out this type of surgery. 
The two diagnostic techniques used (US scan and spirometry) are assistive, non-
invasive, painless and could be performed equally, even if the patient are not been 
enrolled. 

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This study does not include any invasive procedures added to the usual current 
practice for performing anaesthesia in patients scheduled for arthroscopic shoulder 
surgery. 
 
4.4 ROUTE, DOSE AND TIME OF ADMINISTRATION: DESCRIPTION 
AND JUSTIFICATION 
The medication for this study is Chirocane® 2.5 mg/ml Injectable and Infusion Solution. 
Its administration will be carried out following the technical datasheet of the Spanish 
Agency for Medicines and Healthcare Products (AEMPS) with the therapeutic 
indication in adults of surgical anaesthesia by peripheral nerve block (23). 
In this study, the medication will be administered by an attending anesthesiologist 
specialized in the management of regional anaesthesia.  
Chirocane® 2.5 mg/ml will be administered around the nerve while the attending 
anesthesiologist performs the peripheral nerve block needle (IBPB).  
During the administration of the dose, the patient's vital functions will be monitored and 
measures will be taken to prevent blood puncture according to normal clinical practise 
(23). 
10 ml and 20 ml of Chirocane® 0.25%, equivalent to a dose of 25 and 50 mg, 
respectively, will be administered. Thus, it will be administered according to its AEMPS 
datasheet. The 0.25% (2.5 mg/ml) concentration, the 10-20 ml volume and the 25-50 
mg dose used are within the intervals allowed by the AEMPS datasheet. The amount of 
medicine allowed by AEMPS is a concentration of 2.5-5 mg/ml, a volume of 1-40 ml 
and a dose of 2.5-150 mg. Therefore, the maximum single dose of 150 mg allowed by 
AEMPS will never be exceeded (23). 
The dosage pattern will be standardized by protocol, in a single dose, administered in 
bolus with a period of punctual treatment prior to surgery in the immediate preoperative 
where the surgical anesthesia of the peripheral nerve will be performed by means of a 
IBPB. 
 

Introduction 
 
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4.5 STUDY POPULATION: DESCRIPTION 
The source of our population sample is all the patients undergoing an arthroscopic 
shoulder surgery at the Division of Shoulder Surgery attached to the Orthopaedics 
Department in the HUMS. 
4.6 RESEARCH HYPOTHESES 
- 
Ho: There is no statistically significant decrease in the incidence of acute 
diaphragmatic paralysis, quantified by the Diaphragmatic Thickness Ratio, after 
Interscalene Brachial Plexus Block with ultrasound-guided interscalenic 
approach in scheduled arthroscopic shoulder surgery after administration of a 
volume of 10 ml of Levobupivacaine 0.25% (dose 25 mg) compared to 20 ml of 
Levobupivacaine 0.25% (dose 50 mg). 
- 
Ha: There is a statistically significant decrease in the incidence of acute 
diaphragmatic paralysis, quantified by the Diaphragmatic Thickness Ratio, after 
Interscalene Brachial Plexus Block with ultrasound-guided interscalenic 
approach in scheduled arthroscopic shoulder surgery after administration of a 
volume of 10 ml of Levobupivacaine 0.25% (dose 25 mg) compared to 20 ml of 
Levobupivacaine 0.25% (dose 50 mg). 

Objectives 
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5 OBJECTIVES  
 
5.1 PRIMARY OBJECTIVE 
The primary study objective is to determine the HDPA diagnosed by using 
diaphragmatic thickness index in US after Low Volume (10 mL) versus Standard 
Volume (20 mL) of Levobupivacaine 0,25% for IBPB.  
5.2 SECUNDARY OBJECTIVES 
Secondary end-points are: 1) HDPA diagnosed by using FVC and FEV1 in spirometry, 
2) HDPA diagnosed by using diaphragmatic excursion in US, 3) postoperative pain 
regarding time to first analgesic consumption and 24-hour cumulative total 
consumption of Patient-controlled analgesia (PCA) pump of Morphine IV; (4) 
postoperative harms between two trial-arms; and (5) to perform a cost-analysis of the 
intervention of the study. 

Methods 
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6 METHODS 
The protocol of this clinical trial is conducted in concordance with the Consolidated 
Standards of Reporting Trials (CONSORT) statement and the recommendations for 
Interventional Trials (SPIRIT) guidelines (24–26).  This protocol is published elsewhere 
(27). 
6.1 TRIAL SETTING 
Patients will be recruited for the study only from Shoulder Surgery Unit and 
Orthopaedics Anaesthesia Division of the Hospital Universitario Miguel Servet (HUMS) 
in Zaragoza, Spain. HUMS provides health care to a population size of about 400000 
inhabitants and about 80 arthroscopic shoulder surgery are performed every year. 
Enrollment began in 2020 and is anticipated to continue through 2021. 
6.2 TRIAL DESIGN 
The REDOLEV trial is designed as a randomized, comparative, prospective, phase III, 
unicenter, double-blind, two-arm and controlled Clinical trial (RCT). 48 patients 
scheduled for arthroscopic shoulder surgery under general anesthesia (GA) with 
interscalene brachial plexus block (IBPB) for postoperative analgesia will be included. 
Eligible patients will be randomly assigned to 2 groups: G1 (Control arm: Standard 
volumen dose will be 20 mL of 0,25% Levobupivacaine) or G2 (Treatment arm: Low 
volumen 
dose 
will 
be 
10 
mL 
of 
0,25%Levobupivacaine). 

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6.2.1 VARIABLE TABLE 
 
TIMING 
Pre IBPB 
Surgery 
4-hour Post IBPB 
24-hour Post IBPB 
PRIMARY VARIABLES  
1. 
Inspiratory 
Diaphragmatic 
Thickness. 
2. 
Expiratory 
Diaphragmatic 
Thickness. 
3. 
Diaphragmantic 
Thickness 
Ratio. 
 
1. Inspiratory Diaphragmatic 
Thickness. 
2. Expiratory Diaphragmatic 
Thickness. 
3. Diaphragmantic Thickness 
Ratio. 
 
SECONDARY 
VARIABLES  
1. Informed consent date.  
2. Randomization date. 
3. Participant data. 
4. Ultrasound data. 
5. Spirometry data. 
1. Surgery data. 
1. PACU data. 
2. Ultrasound data. 
3. Spirometry data. 
4. Pain data. 
1. Hospital data. 
2. Spirometry data. 
3. Pain data. 
4. Safety data. 
Tabla 1: Study Variables 

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6.3 ELEGIBILITY CRITERIA  
6.3.1 INCLUSION CRITERIA 
1. Patients aged 18 to 80 years. 
2. ASA I-III. 
3. Scheduled for shoulder arthroscopic shoulder surgery and interscalene 
brachial plexus block. 
6.3.2 EXCLUSION CRITERIA 
1. Age <18 and >80 years. 
2. Pregnancy. 
3. Exclusión to perform IBPB or spirometry. 
4. Allergy to amide group local anaesthetics, opioids or nonsteroidal anti-inflammatory 
drugs. 
5. Background of Pulmonary diseases (chronic obstructive pulmonary disease (COPD) 
and moderate, severe or not well-controlled asthma), diaphragmatic paralysis or 
neurological disease with diaphragmatic dysfunction, brachial plexus neuropathy or 
chronic opioid consumption (more than 3-months consumption or more than oral 
Morphine 1 mg 1-month). 
6. Coagulation disorders (INR>3, TTPA > 35 y AP <50%). 
6.3.3 WITHDRAWAL CRITERIA 
Patients may be withdrawn from treatment and trial evaluations at any time. The 
specific reasons for a patient's withdrawal from this trial are : 
1. Voluntary withdrawal at any time they wish, without this representing any type 
of harm to the subject in the subsequent treatments that may be required. 
2. Safety reasons at the discretion of the investigator.  
3. Significant non-compliance with the protocol, at the discretion of the investigator 
and coordinator. 
4. Incorrect recruitment (the patient does not meet the inclusion/exclusion criteria) 
or incorrect randomization (the patient is not assigned trial medication 
according to the protocol). 

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Participants who withdraw their IC will be automatically withdrawn from the study, 
cannot be re-enrolled and the assigned patient number will not be reused. They will be 
asked the reason for their withdrawal, the presence of an adverse event (AE), and will 
be asked for their IC for their follow-up. These data will be recorded in the DCF.  
Patients incorrectly included will be withdrawn from treatment if the BPBAI and other 
assessments (chest ultrasound and spirometry) have not been performed. 
Post-treatment losses have been foreseen a priori in the statistical calculation of the 
sample size by means of an estimated 10% of the patient. Patients lost after being 
included and randomized in this CD will not be replaced and patient recruitment will 
continue until the sample size (n=48) established a priori is achieved. 
The follow-up after the administration of the medication and the performance of the 
BPBAI lasts 24 hours post-operatively. It is performed in the hospital ward by means of 
clinical and spirometry evaluation. 
6.4 INTERVENTIONS 
Eligible patients will be randomised in equal proportions between low volumen dose 
(10 mL of 0,25% Levobupivacaine) group and standard volume dose (20 mL of 0,25% 
Levobupivacaine) group, receiving either only once as a single-shot IBPB in surgery 
theatre before arthroscopic shoulder surgery.  
The two study-arm drugs will be provided and relabeled by Pharmacy Department of 
HUMS. After the trial recruitment, they will be checked and destroyed as current 
practice according to CEICA guidelines. 
During the hospital stay, there will be four visits to the participants. Spirometry and US 
will be performed as baseline and post-intervention assessments. After surgery, 
Morphine IV PCA system will be administered to control postoperative analgesia. Every 
research physician in charge of US and spirometry assessments will be blinded to the 
IBPB intervention. 
The interventions will be entirely integrated within routine clinical practice. 
1. 
Interscalene Brachial Plexus Block (IBPB: MeSH Unique ID: D065527 and CIE-
10 code 3E0T3CZ) will be performed with ultrasound-guidance using a variable 
frequency, linear transducer (GE Medical, Milwaukee, WI, USA). After sterile skin 

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preparation with chlorhexidine, an in-plane posterior approach with a 22-gauge 50 mm 
Stimuplex Ultra 360º needle will be used to deposit the study drug in the interscalene 
space, between the middle scalene and anterior scalene muscles and the brachial 
plexus, at the level of the sixth cervical vertebra. Before surgery commenced, IBPB 
success will be determined using sensory loss in the thumb and index fingers. Patients 
without evidence of brachial plexus block within 10 minutes of local anesthetic injection 
were excluded from analysis. 
Hence the resulting 2 study groups will be as follows:  
- 
Group Control: (Group 1) Standard Volume dose IBPB: 20 mL of 0,25% 
Levobupivacaine. 
- 
Group Treatment: (Group 2) Low Volume dose IBPB: 10 mL of 0,25% 
Levobupivacaine. 
2. 
Diaphragmatic US will be performed before (baseline) and 4-hour (1 hour 
minimum after extubation) after IBPB in a sitting and supinus position. Ipsilateral and 
contralateral hemidiaphragm of each patient will be imaged using a lineal ultrasound 
transducer (GE Medical, Milwaukee, WI, USA). Ultrasound apposition zone will be 
assessed in anterior axillary line and the diaphragmatic thickness will be recorded in 
maximal inspiration and espiratory. They will be expressed by Inspiratory 
Diaphragmatic Thickness (IDT) and Expiratory Diaphragmatic Thickness (EDT). ED will 
be evaluated on inspiration and expiration as number of intercostal spaces and motion 
type, expressed by normal/caudal, nule or cephalad/paradoxical motion of the 
diaphragm with inspiration. 
3. 
Spirometry will be performed using a bedside spirometer (Air-Smart Spirometer; 
NuvoAir AB © 2020, Riddargatan 17D, SE-11457 Stockholm, Sweden) before 
(baseline) and 4 (1 hour minimum after extubation) and 24 hours after IBPB in sitting 
and supinus position. It will be performed in accordance with the standards of lung 
function testing of the American Thoracic Society (ATS) and the Spanish Society 
of Pulmonology and Thoracic Surgery (SEPAR) (28–30). Forced vital capacity (FVC), 
forced expiratory volume at 1 second (FEV1), FEV1/FVC ratio and peak expiratory flow 
(PEF) will be measured three times every assessment to obtain acceptable and 
reproducible criteria. Best FVC and FEV1 effort will be recorded. 
Assessments will occur in 3 times, no depending on whether participants are assigned 
to the intervention group, as follows: 

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1. Assessment 1: After consent and randomization, baseline US and 
spirometry will be performed in hospital room. 
2. Assessment 2: 4 hours post IBPB and 1 hour minimum post extubation 
US and spirometry will be performed in PACU. 
3. Assessment 3: 24 hours post IBPB. Spirometry will be perform in hospital 
room. 
4. 
Combined Locorregional-General Anaesthesia (GA): Before induction, the IBPB 
will be developed in surgery theatre. 2 g cefazoline will be given IV. All patients will 
receive an intravenously GA with Fentanyl 2 ug/kg, Propofol 2 mg/kg and Rocuronium 
0,6 mg/kg. Patient will be orotracheally intubated and mechanical ventilation will be 
applied. Respiratory rate and tidal volume will be adjusted to keep the patient 
normocapnic. Bispectral index (BIS) and Train of Four (ToF) will be monitored. 
Anaesthesia will be maintained with Sevoflurane (0.7-1 MAC) to get a 40-60 BIS 
monitor. Intraoperative analgesia with Remifentanil IV (0.05–0.2 μg/kg/min) will be 
administered at the discretion of the attending anesthesiologist. Every patient will 
receive Paracetamol 1 g and Enantyum 50 mg IV. Dexametasone 8 mg and 
Ondansetron 4 mg IV as anti-emetic prophylaxis will be given. The fluid management 
with balanced crystalloids is aiming for normovolemia. Before extubation, if ToF 4/4 
<90% Sugammadex 2 mg/kg will be used. After leaving surgery theatre, the patient will 
attend to PACU. 
5. 
Arthroscopic shoulder surgery will be routinely performed arthroscopically by 
the same two surgeons with the patient in the beach chair position. No concurrent open 
repairs will be included.  
6. 
Postoperative Patient-controlled analgesia pump (CADD®-Solis Infusion 
System, Smiths Medical, Minneapolis; USA) of Morphine IV will be administered in 
PACU. PCA will be delivered a 1 mg bolus (2 mL) with 10 minutes time-close without 
basal IV administration for 24-hour postoperative follow-up. Patient numeric rating 
scale (NRS) pain score (0-10) will be recorded after entry and discharge PACU and at 
24 hours. 
7. 
PACU Interventions: Room air oxygen saturation, US and spirometry will be 
assessed using the procedure described above. Patients will be discharged from the 
PACU after achieving an Aldrete score greater than 8 (of 10 possible points).  
8. 
Hospital Interventions: During hospitalization, all the patients will receive 1 g 
Paracetamol and 50 mg Enantyum IV alternatively every 4 hours. 2 g Metamizol IV will 
be given in Participants with NSAID drugs allergic background. 4 mg Ondansetron IV 

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every 12 hours will be given as nausea and vomiting prophylaxis. After post IBPB, 24 
hours Spirometry and an EVA score will be recorded for each patient. The follow-up will 
finish in postoperative 30 days with incidence, frequency and severity of Serious 
Adverse Events (SAE) and hospital admission reviews. 
LA or other trial drugs allergic reactions could be observed in rare cases. If this is 
suspected withdraw the trial medication from the patient. This should be reported as an 
adverse event.  
As active comparator, 24 patients will be enrolled in the Standard Volume Dose arm.  
20 ml Levobupivacaine Hydrochloride 2.5 MG/ML will be administered in the IBPB 
before the arthroscopic shoulder surgery. As Experimental study arm, 24 patients will 
be included in the Low Volume Dose group. 10 ml Levobupivacaine Hydrochloride 2.5 
MG/ML will be administered in the IBPB before the arthroscopic shoulder surgery. 
6.5 OUTCOMES 
The primary outcome of REDOLEV trial is 1) difference in the proportion of patients 
with HDPA according to DTR in US between the treatment and control groups. DTR 
will be the result of Inspiratory Diaphragmatic Thickness and Expiratory Diaphragmatic 
Thickness. The ratio will be defined by DTR=IDT/EDT. HDPA after IBPB at 4 hours will 
be diagnosed with a DTR<1.2 (15,18,31). The time frame will be between the baseline 
data and 4-hour after interscalene brachial plexus block. 
Secondary study outcomes are the difference between the intervention and control 
groups: (1) in the proportion of patients with HDPA diagnosed in spirometry by using a 
diminution of ≥20% of baseline, 4-hour and 24-hour postoperative FCV and (2) FEV1, 
(3) in the proportion of patients with HDPA according to DE in US expressed by 
number of intercostal spaces (reduction ≥25%) and motion type (positive to paradoxal 
or nule diaphragmatic motion), (4) in postoperative 24-hour cumulative IV morphine 
consumption (mg) and (5) in time to first analgesic consumption (min) of Patient 
controlled analgesia (PCA) pump and (6) in the incidence, frequency and severity of 
(Serious) Adverse Events as assessed by CTCAE v4.0 (15,32–34). Every secondary 
outcome will be compared in each study group. 
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For the cost-analysis, secondary outcomes will be the use of services and sick leave 
will be evaluated using the economic variables described above for the 12 months 
before and 1 month and 12 months after the study intervention. The cost of anesthetic 
management medications will be obtained from the hospital pharmacy department. 
Service use (medications, medical and laboratory tests, admissions, etc.) and sick 
leave of the patients evaluated will be obtained telematically from the hospital 
database. The average monetary costs (in €) of each of the interventions will be 
calculated after multiplying the use of health services or sick leave by the unit cost. The 
unit cost for the use of health resources and productivity losses will be confined to the 
context of the study intervention, i.e. the Aragonese Health System (SALUD) and the 
National Health System. The unit costs of the use of services will be extracted from the 
tariffs published in the Official Bulletin of Aragon of the Government of Aragon (35) and 
will be expressed in euros (€). Since not all tariffs are published in the same year, they 
will be updated using the sanitary retail price indexto the year 2021. To estimate the 
unit cost of sick leave, the average wage in Aragon and the minimum wage in Spain in 
2020 will be used. Productivity losses will be calculated from the perspective of human 
capital (36,37). For the cost analysis, the health system perspective and the limited 
company perspective (health system perspective and sick leave) will be taken into 
account. A sensitivity analysis will be performed by varying the unit cost of sick leave. 
This is a per Intention-To-Treat study. 
6.6 SAMPLE SIZE 
The sample size was calculated according to HDPA incidence after IBPB. Previous 
studies determined HDPA incidence after IBPB was always 100%(12,32). However, 
locorregional blocks have been improved for years thanks to US development. Recent 
studies have already referred that using low volume and concentration doses of LA in 
IBPB decreases the HDPA incidence (4,20,38,39).  
This trial assumed a HDPA after IBPB rate of 90% in the control group, and 33% in the 
treatment group according to previous studies with similar LA Volumen and doses for 
IBPB (4,20,38). These findings suggest that after decreasing the IBPB LA dose hence 
(10 ml, 0,25% or 25 mg) we expect to find less HDPA after IBPB.  
Therefore, in order to power this trial to detect a mean difference in HDPA after IBPB 
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power of 90% with equal allocation to two arms would require 21 patients in each arm 
of the trial. To allow for 10% drop out, 24 will be recruited per arm, ie, 48 participants 
will be the total sample size using Epidat® software (40,41). 
6.7 RECRUITMENT 
Prospective participants of surgery waiting list will be screened through reviewing of 
health records by research physicians to determine eligibility in one study site. They will 
be recruited after hospital admission hours before surgery. Inclusion and exclusion 
criteria will be assessed for purposes of adhering to the Consolidated Standards of 
Reporting Trials (CONSORT) standards. Informed consent will be provided and the 
baseline evaluation that includes Common Assessment Battery, baseline spirometry 
and baseline US will be completed. Individuals who decline to participate will be asked 
to provide a reason as well as basic demographic information to facilitate comparison 
between study participants and those who are eligible but decline to participate.  
An average of three adult patients consults per week for arthroscopic shoulder surgery. 
Through the REDOLEV trial, we will expect to successfully recruit and interview 48 
patients in 12 months. 
6.8 ASSIGMENT OF INTERVENTIONS 
In this trial, four independent research physician teams will be part of: IBPB research 
physicians (IRP), Assessment research physician (ARP), Recruitment research 
physicians (RRP) and Statistical staff (SS).  
All patients who give consent for participation and meet all the inclusion criteria and 
none of the exclusion criteria will be consecutively included by RRP. Participants will be 
randomly allocated with equal probabilities to both two study arms (control or treatment 
group) by IRP. IBPB performance and the administration of study drug will be carried 
out only by IRP. IRP will be a group of three anesthesiologists experienced in 
locorregional blocks. Spirometry and US assessments will be conducted by ARP, only 
one blinded anesthesiologist. This will decrease inter-operator variability.  
The allocation sequence as per a random number table will have been generated using 
Epidat® software by SS. SS will conduct the study analyses. 

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6.9 RANDOMIZATION 
An a priori randomized treatment assignment will be made using the Epidat computer 
software. The computer algorithm requires the number of treatments (2 treatments), 
types of groups to be created (groups of equal size) and a number of participants (48 
cases) (40,42). The randomization table will be defined by the Epidat software before 
the start of Clinical trial recruitment.  
During this study, two figures are involved: the PI and the Collaborator Investigators 
(CI). The PI will be responsible for recruiting the patient and verifying that the inclusion 
and exclusion criteria are met. A single CI will have access to the treatment 
randomization list and will be the only non-blind person in the CI. This non-blind CI will 
have the functions of verifying the treatment group corresponding to each participant 
recruited and preparing the medication attributed to each patient that will later be 
administered. 
The PI and the other blind CIs will not have access to the treatment randomization list 
or the patient's medical history until after 24 hours post-operative. By that time, all US 
and spirometry measurements will have been made. At this point, the patient's 
perioperative data will be collected and the assigned randomization group will be 
unmasked. 
The maintenance of the randomization codes will be achieved thanks to the 
independence of the non-blind CI from the IP and the rest of the CIs, operators of the 
measurements. 
In case it is necessary to open the blind before performing the last follow-up 
measurement, the unblinded CI will reveal the treatment group assigned to the 
corresponding patient and the process, as well as its causes will be documented and 
explained in the Patient Medical Record (PMR).  
One of the conditions under which the treatment codes may be opened is the 
appearance of a Serious and Unexpected Adverse Reaction (SAR), in which it is 
required to know the dose of medication administered for the clinical management of 
the patient. Some examples of pathologies that would require opening the 
randomization codes are systemic intoxication by local anaesthetics or serious 
respiratory complications. 

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Cases will be recruited according to their chronological order of surgical intervention 
according to which they will be randomly assigned to one of the two treatment groups 
according to the protocol (40,42). 
6.9.1 BLINDING 
A double-blind masking will be performed where neither the PI nor the operator 
performing the ultrasound and spirometry measurements will know the intervention 
group assigned to the patient until the end of the follow-up period 24 hours after all the 
measurements have been collected.  
The highest quality ultrasound machine available in the hospital and a portable 
spirometer with European quality and validation certificates will be available. 
6.10 DATA 
The source data of this trial are the data from the perioperative US and spirometry 
measurements performed on each participant. The source data will be contained in the 
original files or certified copies of the source documents kept in the Departament of 
Anaesthesia in the HUMS.  
The Data Collection Form (DCF), the test reports and PMR shall be considered source 
documents. 
All measurements will be collected in the DCF by RRP and ARP. 
As the primary outcome, HDPA will be observed by using DTR in US which provides a 
93% Sensibility, 100% Specificity (15,17,18,31,43). US images will be interpreted in 
real-time and assessment data will be entered into the DCF. Every participant will be 
evaluated baseline and after-IBPB his block diaphragm and non-block side to have 
their own control in every assessment. Spirometry will be evaluated by using a 
certificated portable spirometer with a 79% Sensibility and 90% Specificity 
(15,32,33,44–48). It will be performed in supine and sitting position to increase the 
sensitivity and specificity (48). Postoperative pain will be measured and collected by 
using PCA pump record. PCA is decrease analgesic consumption, increases the 
patient satisfaction score and duration of effective analgesia (49–51). The incidence, 
frequency and severity of AE/SAE as assessed by CTCAE v4.0 will be recorded (34). 

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Every research personnel will be trained in the study requirements. ARP 
anesthesiologist has been training in diaphragmatic US for six months in advance.  
Participants may withdraw from the study for any reason at any time. The PI also may 
withdraw participants from the study in order to protect their safety or if they are 
unwilling or unable to comply with required study procedures. Withdrawal reason will 
be asked, measured and figure in the DCF. 
All write measurements will be duplicated in the DCF and in the Participant Medical 
Record (PMR). Spirometer and PCA assessments will have an additional electronic 
record in Spirometer phone app and PCA system. All data will be entered electronically 
to the database at the participating site. Statistical analysis will manage range checks 
for data values.  
All study data will be hosted securely on the HUMS network, protected by several 
firewalls. A complete back up of the database will be performed monthly. Participant 
study files will be kept on file in storage for 25 years at the participating site.  
6.11 STATISTICAL METHODS 
Excell (Redmont, USA), IBM SPSS v.22 (Chicago, USA) and Open Epi v3.0.1 
(Santiago, Spain) will be used to collect data and conduct analyses. For all analyses, a 
statistically significant result is assumed if p<0.02. We will use the Bonferroni method 
to appropriately adjust the overall level of significance for multiple primary outcomes, 
and secondary outcomes. 
A descriptive analysis of the data will be performed: the qualitative variables (Sex, 
Surgical side, BPBAI complications, etc.) will be presented using the frequency 
distribution of the percentages of each category and the quantitative variables studied 
(Ultrasound and spirometer variables, etc.) will be explored with the Kolmogorov - 
Smirnov compliance test (Goodness-of-fit test to a normal distribution). Central 
tendency (mean or median) and dispersion (standard deviation or percentiles) 
indicators will also be given. 
To respond to the main hypotheses raised in this study, the degree of association 
between the variables involved will be examined using graphical (scatter diagram) and 
analytical (simple correlation coefficient) methods. The interpretation of the intensity of 

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the relationship was carried out following the criteria established by Gerstman (2015) 
and Martínez-González et al (52,53). 
Concerning bivariate analysis or comparison between two variables (factors), the 
association between the factors will be investigated using hypothesis contrasting tests. 
In the case that both variables compared were qualitative, a comparison of proportions 
with chi-square or Fisher's exact test will be used. In the case that one of them is 
quantitative, a comparison of means will be made using the Student t-test, ANOVA, 
and if they do not follow normal distribution the Mann-Whitney U-test or the Krustal-
Wallis test. Likewise, a bivariate correlation (Pearson's Correlation) will be carried out 
when both variables are quantitative or, if the conditions of application are not fulfilled, 
a Spearman's correlation. 
In some of the catalogued variables, where the case also serves as a control (before-
after relationship): comparisons of means will be made for related samples when one 
of them is quantitative (t of Student, ANOVA for repeated measurements), and if they 
do not follow a normal distribution the Wilcoxon test or the Friedman test. 
As for multivariate analysis, to study the relationship of each variable controlling for the 
possible effect caused by third variables, the analysis will be completed using 
regression models. 
As an interim analysis will be performed, confidence intervals and hypothesis tests will 
be calculated according to the O'Brien-Fleming method. 
The study drug will be provided by the Pharmacy Service of the HUMS as current 
practice. 
6.11.1 
Statistical analysis for the cost-analysis 
The difference in healthcare use and costs between groups was assessed 1 month and 
1 year after the intervention.  
Due to the variable distribution and the high proportion of zeros in the sample, mean 
differences in healthcare use and days on sick leave between groups were estimated 
using two-part models. A preliminary logistic regression was applied to obtain the 
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generalised linear models with Poisson distribution performed conditional on the 
positive outcome of the first part. The models were controlled for baseline healthcare 
resource use (those incurred in the 12 months preceding the intervention).  
The cost analysis was performed using generalised linear models (GLM) with gamma 
distribution with a logistic link and costs as the dependent variable. The models were 
controlled for baseline costs (those incurred in the 12 months preceding the 
intervention). Differences in time in the operating room and PACU between intervention 
and control groups were assessed through a t-test. Sample size estimation is in detail 
elsewhere.(54) For all analyses, a statistically significant result was assumed if p<0.05. 
Analyses were performed with Stata MP (version 17.0). 
6.12 MONITORING   
The Data Monitoring Committee (DMC) will carry out monthly scheduling monitoring 
visits, at least every ten participants. Participant rights and well-being protection, trial 
data accuracy and trial conduction will be verified to be in compliance with the currently 
approved protocol. An interim-analysis will be performed by SS when 50% of patients 
(n=24) have been randomised and have completed the follow-up. Promotor and PI 
agreement will end the trial only if there will be participant harm proof, prematured 
statistical significance, futility, logistical issues.   
All medicines will be administered according to the usual clinical practice of the ARTD 
Service, TOC Service and the AEMPS technical sheet (28,29,38–41,30–37). 
In this clinical trial, there is no medication that is not allowed. 
The container of the research drug will be labeled, and at the time of use the patient 
number and date of use will be indicated on the label, and it will be kept for later 
accounting. In this way, the traceability of the medication and therapeutic compliance 
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In addition, each participant will be provided with an Anesthesia Assessment Sheet 
where all medication administered during the perioperative period will be listed. This 
document is individualized and stored in the PMR.  
The PI and sponsor of this clinical trial will not make any deviation or modification to the 
protocol without the permission, prior review and written opinion in favour of the 
modification from the AEMPS and CEICA.  
All deviations from the original statistical plan will be described and duly justified in 
writing in the new version of the protocol and/or in the final report of the clinical trial, if 
necessary. 
6.13 HARMS  
Adverse Events (AE), Serious Adverse Events (SAE), Adverse Drug Reactions (ADR), 
Serious Adverse Drug Reactions (SADR) and Unexpected Adverse Drug Reactions 
(UADR) will be defined according to Guideline for good clinical practice of European 
Medicines Agency (55). According to AEMPS Levobupivacaine label, common adverse 
reactions (AR) are hypotension, nausea, vomiting, anemia, dizziness, cephalea, fever, 
etc (23). IRP will determine relatedness of an event to drug based on a temporal 
relationship, unexpected or unexplained nature, previous medical conditions or 
concomitant medications. Every AE, SAE, ADR, SADR and UADR will be recorded in 
the DCF and the PMC. They will be notified, in a specific record form, to sponsor and 
health authorities within 24 hours of first knowledge by PI. They will be followed until 
they will be cronic or cured. 
For secondary outcomes, harm variables will be recorded at operating room, 4-hour, 
24-hour and 30-day after intervention eg IBPB, anesthetics, PACU and hospital 
complications and mortality. 30-day after review will consider potential long-term 
intervention complications.  

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7 ETHICS AND DISSEMINATION 
This study has been approved by the Ethics Committee of Clinical Research of Aragon 
(CEICA; Approval registration: EC19/093), the Institutional review board of HUMS 
(Spain) and the study sponsor (Aragon Institute for Health Research [IISAragon]). This 
trial will be conducted in compliance with the European Union Clinical Trials Directive 
(2001/20/EC), the principles of the Declaration of Helsinki (2013) and Spanish 
Organic Law of 3/2018 on Personal data protection and guarantee of digital rights (56–
58). Ethics Committee of Clinical Research of Aragon (CEICA; Approval registration: 
EC19/093) approved the non-substacial modification of the study protocol to include a 
secondary cost-analysis on 10th February 2021 (Ethics approval document is uploaded 
at the end of this file). 
A written informed consent (IC) with impartial witness will be obtained from all subjects 
by PI and RRP after hospital admission. By signing IC, participants agree with the 
storage of data and publication of the study result. 
All the material used is obtained thanks to the HUMS (Zaragoza, Spain). The 
knowledge derived from this study can generate future commercial benefits that will 
belong to the research team. Participants will not be entitled to claim part of that 
benefit. No economic compensation will be made to the patients included in the 
research work. 
The diagnostic tests derived from this research project have no relevance for the health 
of the participants or their families. No genetic analysis is performed in this work. 
In this research work, the participation of students is not required. 
The outcomes of this clinical trial will become a property of the Department of 
Anesthesia who will decide the publication policy. The conclusions will lead to a PhD 
research work from the Doctoral School of the University of Zaragoza, will be 
presented at congresses and in scientific publications but will always be done with 
grouped data and no participant could be identified. As the article 42 of the Spanish 
Law RD 1090/2015 defines, the results obtained in the clinical trial will be published, 
whatever their result, in scientific journals with mention to the Ethics Committee that 
approved the study. Likewise, the promoter will publish the report of results once the 
clinical trial will be concluded, according to article 47 of the mentioned law. 

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The study civil responsibility insurance (Berkley, Assurance number: 2034180) is 
available in accordance with current Spanish legislation (Royal Decree 1090/2015). 
The 
authors 
declare 
that 
they 
have 
no 
competing 
interests. 

References 
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9 ANEXO: Additional analysis of the study 
REDOLEV-2019 
After a narrative review of the literature on the cost analysis of brachial plexus block 
with interscalene approach (BPBAI), we obtained only three results. Gonano et al 
(2009) concluded that BPBAI is a more efficient technique compared to general 
anesthesia for arthroscopic shoulder surgery (59). However, no cost studies comparing 
different regional anesthesia techniques in this type of surgery have been reported. 
Therefore, we proposed a non-substantial modification to the Protocol v1.0 of the 
REDOLEV-2019 Study, approved on December 18, 2019 (EC19/093) by the Spanish 
Agency of Medicines and Health Products (AEMPS) and the Research Ethics 
Committee of the Autonomous Community of Aragon (CEICA). Thus, Ethics 
Committee of Clinical Research of Aragon (CEICA) approved the non-substacial 
modification of the study protocol to include a secondary cost-analysis on 10th February 
2021 (Ethics approval document is uploaded at the Clinicaltrials.gov).