Incidence of Postoperative Residual Neuromuscular Blockade - A Multicenter, Observational Study in Portugal
Conditions: Residual Neuromuscular Blockade, Residual Paralysis, Post-Anesthesia, Observational Study, Complication of Anesthesia, Neuromuscular Blockade
Sponsor: Centro Hospitalar do Porto

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Incidence of Postoperative Residual Neuromuscular Blockade - A Multicenter, Observational 
Study in Portugal 
 
Study Protocol with Statistical Analysis Plan 
Version 1.0; 15/September 2017 
Sponsor: Centro Hospitalar do Porto (CHPorto); Largo do Prof. Abel Salazar 4099-001 Porto, Portugal 
 
Principal Investigator: Simao Esteves; simao.esteves@me.com 
 
ClinicalTrials.gov Identifier: NCT03417804 
 
 

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1. SYNOPSIS 
 
Title 
Incidence of Postoperative Residual Neuromuscular Blockade - A Multicenter, 
Observational Study in Portugal. 
Study Design 
Epidemiological multicenter, observational, prospective study. 
Primary 
Objective 
To determine   the   incidence   of   postoperative   residual   neuromuscular blockade - 
defined by a TOF ratio < 0.9 - at PACU arrival. 
Secondary 
Objectives 
To determine the incidence of severe postoperative residual neuromuscular blockade 
– defined by a TOF ratio < 0.7 at PACU arrival 
To evaluate the association of postoperative residual blockade and the use of reversal 
agents (neostigmine, sugammadex or none) 
To evaluate the association of postoperative residual blockade and the use of intra-
operative monitoring of neuromuscular blockade 
Target 
Population 
Subjects aged at least 18 years old (n=360) admitted for different types of elective 
surgical procedures requiring general anesthesia with neuromuscular blocking agents. 
Sample Size 
Calculation 
Sample size was calculated according to the following assumptions: 
 
Portuguese population to be submitted to surgery with general anesthesia 
in the next year is approximately 100.000 cases 
 
incidence of patients that arrive at the PACU with objective evidence of 
incomplete neuromuscular recovery is 26% 
 
Discontinuation rate of 20% 
Assuming a margin of error of 5% and a confidence interval of 95%, it is 
expected that approximately 360 patients are required to achieve primary 
endpoint 
Statistical 
Analysis 
Patients will be stratified as follows: patients with TOF ratio ≥ 0.9, patients with TOF ratio < 
0.9, patients with TOF ratio < 0.7 
Absolute and relative frequencies will be calculated for each category of TOF ratios. 
95% confidence intervals will be estimated and presented. 
Statistical significance of the comparisons with TOF ratio <0.9 and TOF ratio <0.7 at 
PACU will be performed through Chi-square test or Fisher’s Exact Test. In addition, 
relative risks and 95% CI for TOF ratio <0.7 and TOF ratio <0.9 at PACU will be performed 
for the comparisons. 

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A descriptive analysis will be performed for all demographic and clinical data. 
 
 

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1.1. 
Study Flow Chart 
 
 
Pre-
surgery 
Post-surgery 
 
Procedures 
 
At 
Anesthetic 
visit 
Period 1 
At PACU arrival 
Period 2 
At hospital discharge 
Written informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
 
Patient number 
 
X 
 
Vital signs: arterial blood, pressure, 
heart rate, temperature and oxygen 
saturation 
 
X 
 
Neuromuscular blockade assessment 
(TOF ratio measurements) 
 
 
X 
 
Demographic data (gender, age, 
weight, height) 
 
X 
 
Clinical history 
 
X 
 
Co-morbidities 
 
X 
 
Information about operating room 
 
X 
 
Surgical diagnostic 
 
X 
 
ASA status 
 
X 
 
Medication: NMBA, NMBA reversal 
agents, volatile anesthetics, hypnotics, 
opioids 
 
X 
 
Dates: discharge/death 
 
X 
 
Adverse events 
 
 
X 
Final outcome: discharge/death 
 
 
X 
 
 
 
 

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2. TABLE OF CONTENTS 
 
INVESTIGATOR SIGNATURE PAGE .................................................... ERRO! MARCADOR NÃO DEFINIDO. 
1. 
SYNOPSIS ........................................................................................................................................ 1 
1.1. 
Study Flow Chart .................................................................................................................... 4 
2. 
TABLE OF CONTENTS ....................................................................................................................... 5 
3. 
LIST OF ABBREVIATIONS ................................................................................................................. 6 
4. 
RATIONALE ...................................................................................................................................... 7 
5. 
OBJECTIVES..................................................................................................................................... 8 
5.1. 
Primary Objective .................................................................................................................. 8 
5.2. 
Secondary Objective ........................................................................................................... 8 
5.3. 
Exploratory Objective ........................................................................................................... 8 
6. 
INVESTIGATIONAL AND ANALYSIS PLAN ....................................................................................... 9 
6.1. 
Overall Study Design ............................................................................................................. 9 
6.2. 
Beginning and End of the Study ......................................................................................... 9 
6.3. 
Study Procedures .................................................................................................................. 9 
6.3.1. Period 1 - data collection at PACU arrival ......................................................... 10 
6.3.2. Period 2 - Discharge data collection .................................................................. 11 
6.3.3. Other considerations .............................................................................................. 11 
6.3.4. Study Schedule ........................................................................................................ 11 
6.4. 
Target Population ................................................................................................................ 12 
6.4.1. Subject Inclusion Criteria ....................................................................................... 12 
6.4.2. Subject Exclusion Criteria ....................................................................................... 12 
6.4.3. Subject Discontinuation Criteria ........................................................................... 12 
6.5. 
Participating Centers .......................................................................................................... 12 
7. 
STATISTICAL ANALYSIS .................................................................................................................. 13 
7.1. 
Sample size determination ................................................................................................. 13 
7.2. 
Primary Endpoint.................................................................................................................. 13 
7.3. 
Secondary Endpoints .......................................................................................................... 13 
7.4. 
Exploratory Endpoints ......................................................................................................... 13 
7.5. 
Missing data ......................................................................................................................... 13 
7.6. 
Interim Analyses ................................................................................................................... 13 
7.7. 
Statistical and Analytical Methods .................................................................................. 14 
7.6.1. Definition of Analysis Population .......................................................................... 14 
7.6.2. Variables and Statistical Methods ....................................................................... 14 
8. 
PHARMACOVIGILANCE .............................................................................................................. 15 
9. 
ETHICAL, REGULATORY, AND ADMINISTRATIVE CONSIDERATIONS ......................................... 17 
9.1. 
Ethical Conduct of the Study ............................................................................................ 17 
9.1.1. Subject Information and Consent ........................................................................ 18 
9.2. 
Publications ........................................................................................................................... 19 
9.3. 
Study Documents and Records Retention ..................................................................... 20 
10. 
REFERENCES ................................................................................................................................... 21 
 
 
 
 

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3. LIST OF ABBREVIATIONS 
 
 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ASA 
American Society of Anesthesiologists 
CNPD 
National Data Protection Committee 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
FAS 
Full Analysis Set 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
NA, N/A 
Not Applicable 
NMB 
Neuromuscular Blockade 
NMBA 
Neuromuscular Blocking Agent 
OR 
Operating Room 
PACU 
Post Anesthesia Care Unit 
SAE 
Serious Adverse Event 
TOF 
Train-of-four 
 
 
 

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4. RATIONALE 
 
General anesthesia is usually achieved through the balance of three components: analgesic, 
hypnotic and neuromuscular blocking agents (NMBAs). NMBAs optimize surgical conditions and 
tracheal intubation. Nevertheless, one of the problems associated is the residual neuromuscular 
blockade, secondary to the remaining effect of these agents at a moment that complete 
reversal of their effect would be desirable.1-3  
Residual neuromuscular blockade is frequently described in surgical patients at the post 
anesthesia care units (PACUs) when non-depolarizing NMBAs are administered in the operating 
room (OR).4-9 Incidence values range from 16% to more than 70% with a definition of residual 
neuromuscular blockade in presence of train-of-four (TOF) ratio < 0.7-0.9.9-12 The use of NMBAs of 
intermediate action, intraoperative  neuromuscular  monitoring  and  reversal  of  NMBAs  have  
been described as factors that contribute to the reduction, but not the elimination, of residual 
neuromuscular blockade.5,12-14  
Quantitative neuromuscular monitoring methods, such as acceleromyography, are the most 
reliable to assess neuromuscular blockade.8,15 Quantitative neuromuscular monitoring provides 
a more objective data on neuromuscular transmission and improves detection of residual 
neuromuscular blockade in comparison with visual or tactile evaluation of the TOF response.8,16-
18 
For many years, the standard criterion of adequate recovery of neuromuscular function was a 
TOF ratio of at least 0.7. However, evidences have been provided that considerable signs and 
symptoms of residual neuromuscular blockade may persist until a TOF ratio of 0.9. Therefore, 
presently, the criterion for adequate reversal of residual neuromuscular blockade is a TOF ratio ≥ 
0.9 at the thumb adductor.17,19-21 
Clinical consequences of residual neuromuscular blockade in PACUs have been documented 
since 1979.22 Impaired airway protective reflexes and increased risk for  aspiration,  a  reduced  
hypoxic  ventilator  response,  pharyngeal  dysfunction, hypoxemia,   diplopia   and   
unpleasant   symptoms   of   muscle   weakness   are complications of residual neuromuscular 
blockade that may increase postoperative morbidity.5,11,16,20,23-25 
A first study was conducted in eight Portuguese hospitals between July and November 2010 
reported a global incidence of 26% of TOF ratio < 0.9 at arrival at the PACU highlighting the 
dimension of the problem in Portugal.26 

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Since 2010 neuromuscular blockade management had considerably changed. This previous 
study promoted a growing conscience of the real importance of residual blockade in our 
surgical patients and convinced us that changes must be done to improve these results. Clinical 
sessions on neuromuscular blockade management and monitoring were held in various 
Portuguese hospitals. At the same time, a novel neuromuscular reversal agent (sugammadex) 
was available and experience with this new drug has been increasing each year replacing in 
many cases the conventional anticholinesterasic drugs. Based on these two facts we propose 
to reassess the incidence of residual neuromuscular blockade six years after the first study 
keeping a similar study design to confirm the paradigm shift that we believe might have 
happened. 
 
5. OBJECTIVES 
 
5.1. 
Primary Objective 
 
o 
To determine   the   incidence   of   postoperative   residual   neuromuscular blockade - 
defined by a TOF ratio < 0.9 - at PACU arrival. 
 
5.2. 
Secondary Objective 
 
o 
To determine the incidence of severe postoperative residual neuromuscular blockade 
– defined by a TOF ratio < 0.7 at PACU arrival 
 
o 
To evaluate the association of postoperative residual blockade and the use of reversal 
agents (neostigmine, sugammadex or none) 
 
o 
To evaluate the association of postoperative residual blockade and the use of intra-
operative monitoring of neuromuscular blockade 
 
5.3. 
Exploratory Objective 
 
o 
To evaluate  the  association  of  postoperative  residual  blockade  with  co- 
morbidities and ASA status 
 
 
 

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6. INVESTIGATIONAL AND ANALYSIS PLAN 
 
6.1. 
Overall Study Design 
 
This 
is 
a 
multicenter, 
observational/non-interventional 
study 
involving 
adult 
patients 
undergoing different types of elective surgical procedures requiring general anesthesia with 
neuromuscular blocking agents. 
 
The study will have two periods: 
 
Period 1 – Evaluation at PACU arrival. 
 
Period 2 - Collection of hospital patient discharge data. 
 
A total of 360 patients will be included from approximately 10 centers in Portugal, where the 
PACU is adjacent to the Operating Room (OR). Each center should recruit between 30 and 40 
patients. 
 
6.2. 
Beginning and End of the Study 
 
Each subject is considered to be enrolled in the study when the subject has provided 
written informed consent. 
 
Enrolment will be stopped when approximately 360 patients are recruited. 
 
A subject is considered to have completed the trial after all of the protocol specified 
activities are completed. 
 
A subject is considered to have discontinued after he/she has withdrawn consent or has 
been discontinued under the conditions specified in Section 6.4.3. 
 
Overall, study start is when the first site is initiated and study ends at database lock. 
 
 
 
6.3. 
Study Procedures 
 

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During the routine preoperative anesthesia visit the patient will be asked to participate in the 
study. A description of the study will be provided to the patient by the investigator or qualified 
designee and any questions will be properly answered. If the patient agrees to participate in 
the study an informed consent form (ICF) will be signed. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. A copy of the signed and dated consent form 
should be given to the subject before participation in the study. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study. 
All consented subjects will be given a unique patient number that will be used to identify the 
subject for all procedures. Each subject will be assigned only one patient number. 
 
6.3.1. Period 1 - data collection at PACU arrival 
 
Immediately after patient arrival in the PACU and as soon as clinically adequate (basic 
monitoring and oxygen therapy in place) the anesthesiologist assigned to the PACU (who was 
not involved in the anesthetic procedure) will collect demographic data (gender, age, weight, 
height), vital signs (heart rate, blood pressure, oxygen saturation and temperature). 
Neuromuscular blockade (TOF Ratio) will be measured. Clinical history, co-morbidities, surgical 
diagnosis, ASA classification and perioperative medication data (dosage and last 
administration time) will be collected as well. 
As this is an observational study, intra-operative monitoring of neuromuscular blockade will not 
be mandatory by protocol and will be left at the discretion of the anesthesiologist as according 
to the clinical practice. Only information about whether this evaluation was performed or not, 
and if yes if it was used quantitative or qualitative methods, will be collected in the CRF. 
 
Neuromuscular blockade evaluation 
Neuromuscular blockade will be evaluated using a quantitative method.  Three consecutive 
TOF stimulations will be applied. In case these 3 measures differ more than 20%, another 

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sequence of 3 consecutive TOF measurements will be considered. If after the 2nd sequence 
the 3 consecutive TOF measurements still differ more  than  20%  between  the  maximum  and  
the  minimum  the  patient  will  be excluded. 
 
Residual neuromuscular blockade definition 
Residual neuromuscular blockade will be defined by a TOF ratio < 0.9. 
 
Patients will be stratified as follow: 
TOF ratio ≥ 0.9 – Absence of Residual Neuromuscular Blockade  
TOF ratio < 0.9 – Presence of Residual Neuromuscular Blockade 
TOF ratio < 0.7 – Presence of severe Residual Neuromuscular Blockade 
 
6.3.2. Period 2 - Discharge data collection 
 
Hospital Patient Discharge Data will be collected for each subject. The occurrence of SAEs 
and AEs will be recorded as well as the final outcome. 
 
6.3.3. Other considerations 
 
This study will reflect real life clinical practice. The anesthetic technique in terms of drugs and 
type of monitoring used will be of entire responsibility of the anesthesiologist. 
 
All  study  activities  will  be  consistent  with  EU  directive  2001/20/EC  section  for  non- 
interventional studies : 
o NMBAs and reversal agents’ (as well as all drugs which will be used during the 
anesthesia) administration will be done in accordance with routine anesthesiology 
practice and labeling of these medicine products; 
o No further interventional means, methods or procedures, are scheduled for subjects, 
which would otherwise not be applied; 
o Furthermore, there will be no additional visits to the hospital or a mandatory visit 
schedule, deviating from daily clinical practice. 
 
6.3.4. Study Schedule 
 
The study schedule and activities are provided in the Study Flow Chart in Section 1.1. 
 
 

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6.4. Target Population 
 
6.4.1. Subject Inclusion Criteria 
 
To participate in this study subjects must meet the following criteria: 
 
o 
18 years of age or older; 
o 
Informed consent signed; 
o 
Admission for elective surgery; 
o 
Administration of non-depolarizing NMBAs during surgery. 
 
6.4.2. Subject Exclusion Criteria 
 
Subjects will be excluded from this study if they do not fulfill the inclusion criteria or in case of: 
o 
Admission for emergency surgery; 
o 
Reoperation on the same hospital admission; 
o 
More than 10 minutes elapsed between extubation and neuromuscular block 
monitoring at PACU. 
 
6.4.3. Subject Discontinuation Criteria 
 
A subject may discontinue the study at any time without having to state the reason. As this is 
an observational study, discontinuation from the study does not mean any change to the 
surgical, anesthesia or medical care procedures. 
 
Additionally subject participation must be terminated during the study for any of the following 
reasons: 
o 
Impossibility to obtain 3 measures of TOF ratio at PACU; 
 
If a patient withdraws from the study for any reason before its completion, the reason and 
the date of withdrawal should be recorded on the CRF. 
 
6.5. Participating Centers 
 
The study will be carried out in public hospitals with a relevant number of surgeries with 
general anesthesia. Centers will also be selected based on the distance between OR and 

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PACU which should not exceed 10 min walking distance. 
About 10 hospitals will be invited to participate in the study. 
7. STATISTICAL ANALYSIS 
 
7.1. Sample size determination 
 
Sample size determination was calculated by assuming that the Portuguese population to be 
submitted to elective surgery with general anesthesia is approximately 100.000 cases/year.26 
From the previous study of Esteves et al26, the incidence of patients that arrive at the post 
anesthesia care unit with objective evidence of incomplete neuromuscular recovery was 26%. 
When considering this incidence of 26%, a margin of error of 5% (acceptable maximum 
deviation) and a confidence interval of 95%, we obtained a minimum sample size of 295 
patients (StatsDirect 3 Statistical Software). 
Considering conservative estimation for the discontinuation rate of 20%, it is expected that 
approximately 360 patients are required to achieve the primary endpoint. 
 
7.2. Primary Endpoint 
 
o 
TOF ratio < 0.9 at PACU 
 
7.3. Secondary Endpoints 
 
o 
TOF ratio < 0.7 at PACU 
o 
TOF ratio <0.9, TOF ratio <0.7 at PACU by reversal agents administered (neostigmine, 
sugammadex or none) 
o 
TOF  ratio  <0.9,  TOF  ratio  <0.7  at  PACU  by  NMB  monitoring  used intraoperatively 
 
7.4. Exploratory Endpoints 
 
o 
TOF ratio <0.9, TOF ratio <0.7 at PACU by co-morbidities and ASA status 
 
7.5. Missing data 
 
Missing data will not be imputed. 
 
 
7.6. Interim Analyses 
 

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Not applicable. 
 
 
7.7. Statistical and Analytical Methods 
 
7.6.1. Definition of Analysis Population 
 
Full analysis set population (FAS) will include all treated patient if the patient meets the all 
criteria. 
 
TOF result will be defined as the average of 3 measures. If the 3 measures have a 
difference above 20%, another sequence of 3 TOF measurements should be assessed. 
 
7.6.2. Variables and Statistical Methods 
 
Variables/Time Points of Interest 
o 
Demographic/anthropometric information (i.e: age, sex, height and weight) 
o 
Clinical history 
o 
Co-morbidities 
o 
Vital signs (i.e.temperature, oxygen saturation, heart rate and arterial blood pressure) 
o 
ASA classification 
o 
Surgical diagnostic 
o 
Anesthesia duration (time) 
o 
Perioperative medication, its’ dosages and last administration time (used during 
surgical procedure, including neuromuscular blocker and reversal agents) 
o 
Time between date of surgery and date of discharge 
o 
TOF ratio at PACU 
o 
Adverse events 
o 
Assessment if NMB monitoring in the OR during surgery was performed 
o 
Final outcome (discharge or death). 
 
Statistical Methods 
 
All subjects that meet the study criteria will be included in the statistical analysis. The TOF result 
is defined as the average of 3 measures as described in the study procedures. 
 
A descriptive statistical analysis will be performed on all demographic and clinical data. 
Considering the continuous variables distributions, data will be presented as mean and 
standard deviation or as median, minimum and maximum, as appropriate. Categorical 

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variables will be presented as absolute and relative frequencies. 
 
Patients will be stratified as follows: 
o 
patients with TOF ratio ≥ 0.9 
o 
patients with TOF ratio < 0.9 
o 
patients with TOF ratio < 0.7. 
 
Primary Variable 
The primary variable of  the study is the TOF ratio <0.9. Absolute and relative frequencies will be 
calculated. 95% confidence intervals will be estimated and presented. 
 
Secondary Variables and Exploratory Variables 
Comparisons will be performed between TOF ratio <0.9, TOF ratio <0.7 at PACU, and the 
following variables: 
o 
the use of reversal agents (neostigmine, sugammadex or none) 
o 
NMB monitoring used intraoperatively and type of monitoring used 
o 
co-morbidities and ASA status 
 
Statistical significance of the comparisons with TOF ratio <0.9 and TOF ratio <0.7 at PACU will 
be performed through Chi-square test or Fisher’s Exact Test. In addition, relative risks and 95% 
CI for TOF ratio <0.7 and TOF ratio <0.9 at PACU will be performed for the comparisons. All tests 
will be performed considering a significance level of 0.05 (5%). Analysis will be performed using 
IBM SPSS Statistics. 
 
8. PHARMACOVIGILANCE 
This is a non-interventional study. No individual administration of any therapeutic or prophylactic 
agent is assigned in this protocol, and there are no additional procedures required as part of 
this protocol. 
Reporting will be in compliance with the International Conference on Harmonization (ICH) 
definitions of adverse events (AEs) and serious adverse events (SAEs) (ICH Guideline E2A: 
Definitions and Standards for Expedited Reporting) procedures and any applicable local 
laws and regulations. 
 

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Only Serious Adverse Events will be collected and sent to the Sponsor within 24 hours of 
becoming aware of the event. Non-serious adverse events as well as any safety information 
that is clinically significant in the opinion of the investigator will be collected and recorded in 
the CRF.  
 
Definitions 
 
Adverse Event 
In accordance with the ICH E2A guideline, an adverse event is any untoward medical 
occurrence in a patient administered a medicinal product and which does not necessarily 
have to have a causal relationship with this treatment. An AE can, therefore, be any 
unfavorable and unintended sign (for example, an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to this medicinal product. 
 
Serious Adverse Event 
In accordance with the ICH E2A guideline, a serious adverse event or reaction is any adverse 
drug, biologic, or device experience occurring at any dose that results in any of the following 
outcomes: 
1. Death; 
2. Life-threatening adverse study drug experience; "life-threatening" in the context of 
serious adverse event, refers to an event in which the subject was at immediate risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe; 
3. New or prolongation of an in-patient hospitalization; 
4. Persistent or significant disability/incapacity; or 
5. Congenital anomaly/birth defect. 
 
In addition, an important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, it may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
Severity 

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Where the determination of AE severity rests on medical judgment, the determination of 
severity must be made with the appropriate involvement of a medically qualified investigator. 
The severity of AEs will be graded according to the following definitions:  
Mild: awareness of sign, symptom, or event, but easily tolerated. 
Moderate: discomfort enough to cause interference with usual activity and may warrant 
intervention. 
Severe: incapacitating with inability to do normal daily living activities or significantly affects 
clinical status, and warrants intervention. 
 
Causality 
A causality assessment (attribution) must be performed and recorded for each SAE/non-
serious AE in relationship to the use of the study drug or device. Causality will be determined by 
an investigator who is a qualified physician according to his/her best clinical judgment. Use 
the following criteria as guidance (not all criteria must be present to be indicative of causality 
to a product: There is evidence of exposure to a product; the temporal sequence of the AE 
onset relative to the administration of the product is reasonable; and the AE is more likely 
explained by the a determined product than by another cause. 
 
9. ETHICAL, REGULATORY, AND ADMINISTRATIVE CONSIDERATIONS 
 
By signing this protocol, the investigator agrees to conduct the study in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good 
Pharmacoepidemiology Practice; and all applicable local laws, rules and regulations relating 
to the conduct of the clinical study. 
 
This project will be carried out in accordance with prevailing ethical principles: 
o 
Subject’s written agreement to participate 
o 
Ethical Committee review (to safeguard subjects’ interests, rights and privacy) 
o 
Approval by applicable Hospital Administrations 
 
 
9.1. 
Ethical Conduct of the Study 
 
Prior to initiation of the study at any center, the study, including the protocol, informed 

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consent, and other study documents must be approved by an appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) if this is a local requirement. 
Approval by the National Private Data Protection Committee (CNPD) will also be required. 
 
The IRB/IEC must be constituted according to applicable regulatory requirements. As 
appropriate, amendments to the protocol must also be approved by the IRBs/IECs before 
implementation at the centers, unless warranted to eliminate an immediate hazard. The 
IRB/IEC approval should be obtained in writing, clearly identifying the study, the documents 
reviewed (including informed consent), and the date of the review. The study as described in 
the protocol (or amendment), informed consent, and other study documentation may be 
implemented only after all the necessary approvals have been obtained as applicable and 
the sponsor has confirmed that it is acceptable for the investigator to do so. 
In the event that the IRB/IEC requires changes in the protocol, the sponsor shall be 
advised and must approve the changes prior to implementation. The investigator shall not 
modify the study described in the protocol once finalized and after approval by the IRB/IEC 
without the prior written approval of sponsor. 
 
9.1.1. Subject Information and Consent 
 
Since this is a non-interventional study, the consent needed from the patient is for the 
collection of his/her data that are or become available during routine care. Subjects will also 
be asked to consent that the information collected about their surgery and their health 
may be used for further analysis and publication.  
 
The informed consent form (ICF) will stipulate that all applicable regulations to protect the 
privacy of his/her data will be respected. Only anonymous data and sample results will be 
collected. All subjects included must sign the ICF in the subject’s native language before any 
information is collected for the study. The investigator will co-sign the ICF. The ICF must be 
approved (e.g., by an Ethics Committee) as per local regulatory requirements before study 
initiation. 
 
The following will be applied to subject informed consent: 
o 
The details of the protocol must be discussed with each potential subject, and 
written informed consent must be obtained for all subjects before any study- 
related procedure is performed; 

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o 
In obtaining informed consent, the information must be provided in language and 
terms understandable to the subject; 
o 
The subject, or the subject's legal representative, must give written consent to 
participate in the study; 
o 
The signed and dated consent form itself must be retained by the investigator as part 
of the study records; 
o 
A copy of the signed and dated consent form must be given to the subject; 
o 
The consent form must include all of the required elements of informed consent in 
accordance with ICH Guidelines E6 and local laws, which do apply for non- 
interventional trials; 
o 
The consent form must be approved by the appropriate IRB/IEC and sponsor before 
study initiation at a study site; 
o 
Any subsequent changes to the approved ICF must be reviewed and approved by the 
appropriate IRB/IEC and sponsor before implementation. 
 
9.2. 
Publications  
 
This study is intended for publication, even if terminated prematurely.  Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript. 
For multicenter trials, subsequent to the multicenter publication, an investigator and his/her 
colleagues may publish their data independently.  In most cases, publication of individual study 
site data does not add value to complete multicenter results, due to statistical concerns.  
Limitations of single study site observations in a multicenter trial should always be described in 
such a manuscript. In such cases the Sponsor must have the opportunity to review all proposed 
abstracts, manuscripts or presentations regarding this study 45 days prior to submission for 
publication/presentation.  
Authorship credit should be in accordance with International Committee of Medical Journal 
Editors (ICMJE) guidelines criteria for authorship of Publications: 
1. 
Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2. 
Drafting the article or revising it critically for important intellectual content; AND 
3. 
Final approval of the version to be published; AND 
4. 
Agreement to be accountable for all aspects of the work in ensuring that questions 

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related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
Authors must meet conditions 1, 2, 3 and 4.  All significant contributions to study execution may 
also be taken into account to determine authorship, provided that contributions have also 
been made to all four of the preceding authorship criteria. 
All significant collaborators at site level should be determined by the Principal Investigator at 
each site and should not exceed 6.   
Appearance of the name of authors in the publications will follow the following order: the first 
author is the investigator sponsor, the second author is the person responsible for the data 
analysis and statistics, followed by the list of names of the principal investigators of the centers 
according to their contribution to the study, and the last author is the investigator coordinator. 
 
9.3. 
Study Documents and Records Retention 
 
During the study and after termination of the study the investigator must maintain copies of all 
documents and records relating to the conduct of the study. This documentation includes, 
but is not limited to, protocols, CRFs and other data collection forms, advertising for subject 
participation, adverse event reports, subject source data, correspondence with health 
authorities and IRBs/IECs, consent forms and investigator’s curriculum vitae. 
 
Subject files and other source data must be kept for the maximum period of time permitted by 
the hospital. The sponsor must be consulted if the investigator wishes to assign the files to 
someone else, remove them to another location, or is unable to retain them for the specified 
period. 
 
All study documents shall be made available if required by relevant health authorities. The 
investigator should consult with the sponsor prior to discarding study and/or subject files. 
 
 
 

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10. REFERENCES 
 
1. 
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3. 
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4. 
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meta-analysis. British Journal of Anaesthesia 2007;98:302-16. 
5. 
Murphy GS. Residual neuromuscular blockade: incidence, assessment and relevance in the 
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6. 
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pulmonary complications. A prospective, randomized, and blinded study of postoperative pulmonary 
complications after atracurium, vecuronium and pancuronium. 
Acta 
Anaesthesiol Scand 
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9. 
Murphy GS, et  al. Residual neuromuscular blockade and critical  respiratory  events in the 
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10. Kopman, AF. Neuromuscular monitoring: Old issues, new controversies.  Journal  of critical Care 
2009;24:11-20. 
11. Murphy GS, Szokol JW, Marymont JH, et al. Residual paralysis at the time of tracheal extubation. 
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