High Flow Oxygen Therapy Versus Conventional Oxygen Therapy in Cardiac Surgery Patients-OPTICAR Study
Phase: NA
Conditions: Hypoxemic Respiratory Failure
Sponsor: National and Kapodistrian University of Athens

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OFFICIAL STUDY TITLE: HIGH FLOW OXYGEN THERAPY VERSUS 
CONVENTIONAL OXYGEN THERAPY IN CARDIAC SURGERY PATIENTS-
OPTICAR STUDY  
 
PROTOCOL SUBMITTED FOR IRB APPROVAL: Evaggelismos General Hospital, 
Athens, Greece, Date: March 3, 2017 [Protocol ID: NKU ATHENS; OPTICAR 
47/03/03/2017]  
 
ClinicalTrials.gov Identifier: NCT03282552 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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High Flow Oxygen therapy versus Conventional Oxygen Therapy in Cardiac Surgery 
Patients-OPTICAR study  
 
Applying Investigators 
1. Stavros Theologou, RΝ, MSc, PhD(c), Cardiothoracic Intensive Care  
2. Eleni Ischaki, MD, PhD, Consultant in Intensive Care Medicine 
3. Spyros G. Zakynthinos, MD, PhD, Professor in Intensive Care Medicine 
4. Christos Charitos, MD, PhD, Lead Consultant in Cardiac Surgery 
5. Spyros D. Mentzelopoulos, MD, PhD, Associate Professor in Intensive Care Medicine 
 
 
Brief summary 
    High flow oxygen therapy has been applied after extubation in cardiac surgery patients 
with uncertain efficacy. The current authors plan to conduct a prospective, randomized, 
controlled study of nasal high flow therapy (NHF) application with higher (60 L/min) or 
lower flow (40 L/min) oxygen mixture administration versus standard oxygen treatment 
(Venturi mask) after extubation of patients undergoing elective or non-elective cardiac 
surgery. 
 
Detailed description 
    Over the past decade, nasal high flow (NHF) has been introduced for oxygen therapy in 
adults. Its indications have been expanded, especially in cases of acute hypoxemic respiratory 
failure.  
    The device consists of an air/oxygen blender connected via an active heated humidifier to 
a nasal cannula, through a single limb, heated inspiratory circuit. It delivers a fraction of 
inspired oxygen (FiO2) from 21% to 100% with a flow rate up to 60 L/min. FiO2 adjustments 
are independent of the set flow rate so that the patient is given heated, humidified high-flow 
oxygen, with a flow that can be adjusted above the patient’s maximum inspiratory flow rate, 
thereby increasing confidence about the actual FiO2 being delivered to the patient.1 These 
device characteristics make it more promising in comparison with conventional low- and 
high-flow oxygen devices (e.g., nasal cannula, non-rebreathing masks, Venturi masks), 
especially in patients with high inspiratory flow rates, such as patients with acute respiratory 
failure (ARF).1,2 
    The benefits arising from application of oxygen with high flow rates via NHF are 1) 
reduction in the entrainment of room air and thus ensuring higher and more stable FiO2 
values,3,4 2) generation of positive airway pressures during expiration as a result of the 
expiratory resistance imposed to the patient’s exhalation against the continuous high flow of 
incoming oxygen gas,5-8 3) improving mucociliary function and clearance of secretion  by 
continuous heating and humidifying of the administered gas,9,10 4)  reducing dead space 
ventilation11,12 and 5) reducing work of breathing13. 
    All the aforementioned NHF mechanisms of actions exert various effects on the respiratory 
system, including improved gas exchange, lower respiratory rate and effort and improved 
lung mechanics which are correlated with more comfort and less subjective dyspnea.13-15 
    Respiratory complications after cardiac surgery can affect morbidity and mortality, and 
increase the healthcare cost.16,17 Advanced age, duration of extracorporeal circulation, history 
of significant underlying cardiac or pulmonary disease and phrenic nerve injury are the main 

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prognostic factors for post cardiac surgery respiratory complications.18,19 Traditionally, low- 
and high-flow oxygen systems are used to reverse postsurgical respiratory complications with 
or without addition of continuous (CPAP) or bi-level (NIV) positive airway pressure.20-22 
NHF might be superior for the prevention or treatment of those respiratory complications, 
since it can provide high-flow of heated and hydrated oxygen while the positive airway 
pressure created by the high gas flow can recruit alveoli and increase the end-expiratory lung 
volume.23,24                                                      
     Studies applying NHF immediately after extubation in cardiac surgery patients revealed 
better oxygenation and less need for advanced methods of respiratory support compared to 
conventional oxygen devices25,26 , and similar results compared to noninvasive ventilation27. 
However, Zochios et al,28 summarized all the available up to date data of NHF compared to 
conventional oxygen devices and non-invasive ventilation in patients undergoing 
cardiothoracic surgery and they did not find any further benefit by NHF use. The 
aforementioned discordant results could be explained by the differences in the studied 
populations and NHF flow settings. The proposed initial flow rate differs among the studies, 
with some authors2,4 suggesting initial lower flows (35-40 L/min) that will be better tolerated 
by the patients and others suggesting initial maximal flows (60 L/min) to rapidly relieve 
dyspnea and prevent muscle fatigue. 29,30 
 
Aim 
    The primary goal of the study is to evaluate the efficacy of NHF versus conventional 
oxygen systems as regards treatment failure (as defined below) and respiratory parameters 
[respiratory rate, PaO2 / (fraction of inspired oxygen) FiO2, peripheral oxygen saturation 
(SpO2), use of accessory muscles, and dyspnea and comfort as regards the technique of 
respiratory support by using a visual analogue scale (VAS) after the extubation of cardiac 
surgery patients. An additional major goal of the study is to compare two different initial 
NHF flows of 60 L/min and 40 L/min, intensive care unit (ICU) Length of Stay, Hospital 
Length of Stay, rates of ICU re-admission and re-intubation and any other respiratory / non-
respiratory complications and adverse events.  The rate of failure of the initial treatment will 
be determined as the primary study outcome. 
 
Methods 
    This is a prospective, non-blinded, randomized study in post-extubated cardiac surgery 
patients. The study population will consist of three patient groups: The first group (Study 
Group 1) will include patients on NHF with initial settings of FiO2=0.6 and gas 
flow=60L/min. The second group (Study Group 2) will include patients on NHF with initial 
settings of FiO2=0.6 and gas flow=40L/min. In the third group (control group) all patients 
will receive oxygen therapy according to the standard practice of our cardiac ICU department, 
i.e., Venturi mask with FiO2=0.6 and flow of 15 L/min. 
    Treatment failure will be defined as any crossover from one treatment to another due to 
patient’s respiratory distress and discomfort. To be more specific, switch of gas flow from 
40L/min to 60L/min, crossover from either NHF group to standard practice (Venturi mask) 
or need for more advanced respiratory support such as non-invasive ventilation or invasive 
mechanical ventilation. inability to reverse FiO2 and/or gas flow escalation above initial 
settings within 48 hours of its initiation. Escalation reversal will be defined as return to initial 
(or lower) FiO2 and/or gas flow for ≥4 hours. 

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    Inclusion criteria will be: Cardiac ICU adult patients > 18 years after elective or urgent 
cardiac surgery having passed a successful Spontaneous Breathing Trial (SBT) with T-piece 
and FiO2=0.6. A successful SBT will have to fulfil the following criteria31, 32, 33 respiratory 
rate: 12-29 breaths/min, SpO2> 92%, PaCO2 <45mmHg, heart rate <120/min, and systolic 
arterial pressure of 90-160 mmHg while receiving norepinephrine at a rate of 0.00 μg/kg/min 
to 0.15 μg/kg/min. The most important inclusion criterion is residual respiratory impairment 
at the end of SBT defined as PaO2/FiO2 <200 mmHg while receiving FiO2=0.6. The decision 
to extubate under these specific conditions will be made by the attending physicians. 
    The exclusion criteria will comprise: 1) Obstructive Sleep Apnea Syndrome supported by 
a continuous positive airways pressure device, 2) preoperative diagnosis of Chronic 
Obstructive Pulmonary disease, 3) patients already tracheostomized, 4) do not resuscitate 
status, 5) Glasgow Coma Scale score <13, 6) Insufficient knowledge of Greek Language , 
and 7) any visual or hearing impairment. 
    In the preoperative period, the investigators will have to provide detailed information about 
the nature of the study to cardiac surgery patients and their next-of-kin. A study information 
sheet will be provided and the study will also be verbally explained during a preoperative 
investigator visit. Postoperatively, written, informed next of kin consent will be requested. 
Patient consent for continued study participation will also be requested as soon as allowed 
by their clinical condition. Pertinent criteria will include absence of any acute physiological 
derangement (e.g. hypoxemia or hemodynamic instability) necessitating therapeutic 
intervention; patients will have to be alert and oriented, and without any concurrent 
symptoms such as shortness of breath or moderate-to-severe postoperative pain.       
 
Study protocol 
    Postoperative cardiac surgery patients will be assessed for SBT trial after having been 
weaned off sedation.  According to routine practice criteria of the cardiothoracic ICU, before 
SBT initiation, patients will have to be deemed as clinically stable by their attending 
physicians as regards their underlying cardiovascular disease and afebrile (body temperature 
<38 °C); their a hemoglobin concentration should normally exceed 8 g/dL. The SBT will be 
conducted using a T-piece with 0.6 FiO2 for a period of 60 min. Before extubation, an arterial 
blood gas sample will be obtained to determine whether PaO2/FiO2 is <200 mmHg. Patients 
will be included in the study as long as they fulfill all the inclusion criteria and none of the 
exclusion criteria. They will then be randomized to any of the three study groups and oxygen 
therapy will commence immediately after extubation.  
     
    The 3 study groups will be the following; 
Study group 1) NHF with FiO2=0.6, T=37°C, gas flow 60L/min,  
Study group 2) NHF with FiO2=0.6, T=37 FiO2=0.4C, gas flow 40L/min,  
Control group 3) Venturi mask with FiO2=0.6, oxygen flow 15 L/min.  
 
Randomization procedure 
    Following extubation, patients will be randomly assigned to Study group 1 or 2, or to 
Control group at 1:1:1 ratio. Blocks of 3 numbers will be consecutively drawn from a 
sequence of 99 unique random numbers (range, 1-99). Random numbers will be  generated 
by using Research Randomizer version 4.0 (www.randomizer.org). Upon patient enrollment, 
attending investigators will receive text message on their mobile phone devices. The text 
message will display the patient’s code number and group.   

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  Patient monitoring and data collection 
   Continuous patient monitoring will include electrocardiographic lead II, intra-arterial 
pressure, SpO2, and respiratory rate.  
   Data on patient characteristics, including the European System for Cardiac Operative Risk 
Evaluation (EUROSCORE) II will be collected at baseline. Data collection time points for 
SpO2, respiratory rate, PaO2/FiO2, comfort with respect to dyspnea and respiratory support 
modality (VAS score34,35,36), accessory muscles’ use, arterial pressure and heart rate, 
vasopressor support, and core body temperature will be as follows: within 30 min of 
extubation (baseline) and at 1, 2, and 4 hours, and every 4 hours onwards until 48 hours 
postextubation. Fluid balance of the first 24 and 48 hours postextubation will be recorded as 
well.  
    Adverse events/clinical course complications (e.g. hypoxemia and/or need for re-
intubation, arrhythmias such as atrial fibrillation, occurrence of delirium,37,38,39,40,41 epileptic 
seizures, surgical re-exploration due to bleeding, ICU readmission, chest wound infection), 
and any patient discomfort/intolerance related to HFNC will also be recorded. 
Management of respiratory support 
    Patients will be assessed for gradual reduction in the intensity of respiratory support or 
need for support escalation every 4 hours postextubation. Gradual weaning from NHF will 
be accomplished by FiO2 decrease to 0.5, followed by gas flow decrease to 30 L/min NHF 
weaning target will include an FiO2 of 0.4 and a gas flow of 20 L/min.8,42 If at an NHF FiO2 
of 0.4 and a flow rate of 20 L/min, SpO2 can be maintained at >92% and respiratory rate 
remains within 12-20 breaths/min for ≥2 hours, patients will be switched to a Venturi mask 
providing an FiO2 of 0.4). In the Control group, a reduction of FiO2 to 0.4 (via a Venturi 
mask) will be sought. Patients of all groups fulfilling the aforementioned SpO2/respiratory 
rate criteria for at least 4 hours while receiving an  FiO2 of 0.4 via a Venturi mask will be 
considered for ICU discharge. As part of standard practice, patients will be scheduled for 
twice-daily physiotherapy.    
   Regarding treatment escalation in Study groups, if SpO2 drops to ≤92% for at least 5 min 
at a gas flow of less than 60 L/min, gas flow will first be increased by 5-10 L/min.4 Next, if 
SpO2 remains at or below 92%, FiO2 will be increased43 to achieve an SpO2 of >92%. In the 
Control group, an SpO2 of 92% or less for at least 5 min will be initially treated with FiO2 
increase. In all groups, persistent and/or worsening hypoxemia will be ultimately treated with 
non-invasive mechanical ventilation and/or reintubation and initiation of invasive mechanical 
ventilation.  
Treatment decisions and premature discontinuation of physiological data collection  
    Changes in the intensity and/or modality of respiratory support will ultimately be decided 
by the primary attending physicians of the patients. Initiation of mechanical ventilation or 
ICU discharge within 48 hours of extubation will result in discontinuation of the pre-specified 
4-hourly patient data collection. 
 

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Outcome measures 
Primary: Occurrence of treatment failure; regarding the NHF groups, this will be further 
specified as inability of weaning from NHF (i.e. inability of achieving successful weaning 
from NHF) according to study protocol.   
Secondary: 1] Successful maintenance of an SpO2 of >92% and a respiratory rate of 12-29 
breaths/min at the specified time points of follow-up; the term ʺsuccessfulʺ corresponds to 
the absence of any escalation of respiratory support above its initially specified level for each 
one of the Study groups and the Control group; 2] PaO2/FiO2 at the specified time points of 
follow-up; 3] Any use of accessory respiratory muscles at the specified time points of follow-
up; and 4] Patient comfort as regards dyspnea, and patient tolerance of NHF support 
according to a VAS score. 
Additional: 1] Length of cardiothoracic ICU stay; 2] Length of hospital stay; 3] ICU and in-
hospital mortality; and 4] Adverse events (e.g. hypoxemia and/or need for re-intubation, 
arrhythmias such as atrial fibrillation, occurrence of delirium, epileptic seizures, surgical re-
exploration due to bleeding, ICU readmission, chest wound infection), and any patient 
discomfort/intolerance related to NHF.   
 
Sample Size and Power Analysis 
    The proposed sample size is based on a formal power calculation, i.e. an apriori power 
analysis, which is an efficient method of controlling statistical power before a study is 
actually conducted; for power analysis, G*Power 3 software was used.44 We predict a 
treatment failure rate of 15% in the 2 Study groups (10% in Study group 1 and 20% in Study 
group 2) and a failure rate of 51% in the Control group. The predicted NHF-to-control 
treatment failure ratio of 0.29 corresponds to the lower limit of the 95% confidence interval 
(CI) of a previously determined ″NHF vs. Control″ odds ratio for support escalation.25 For 
alpha=0.05 and power=0.80, 63 patients (n=21 per group) will be required. However, we 
cannot exclude a potential risk for dropouts and/or missing data. To compensate for such a 
risk, we propose the ultimate enrolment of 99 patients  (i.e. n=33 per group), in order to 
achieve an alpha value of 0.05, a power of 0.96, and a ″safety margin″ of 57% as regards 
possible dropouts and/or missing data. The predicted study enrollment rate is 40-50 patients 
per year. 
Interim Analysis and Data Monitoring 
 
    At 1 year following study start, an interim analysis will be conducted by Drs. Sotirios 
Malachias (Senior Consultant in Intensive Care Medicine, First Department of Intensive 
Care Medicine, University National and Kapodistrian University of Athens Medical School, 
Evaggelismos General Hospital, Athens, Greece) and Michail Argyriou (Senior Consultant, 
Department of Cardiac Surgery, Evaggelismos General Hospital, Athens, Greece). The 
analysis will be focused at evaluating and confirming 1) the safety of the study protocol 
(including any reported adverse events); 2) the applicability of the study protocol (including 
an assessment of the achieved level of adherence to the specified investigational 
interventions); 3) the completion of the attached study forms as mandated by the study 
protocol; and 4) the safety of the electronically stored patient data. Actions related to the 

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aforementioned points 1-4 may be undertaken at the discretion of the aforementioned study-
independent Colleagues at any time point throughout the conduct of the current study. Data 
quality and completeness will also be evaluated by the aforementioned study-independent 
Colleagues after the completion of the study. 
 
Statistical Analysis Plan 
 
    Analyses will be performed according to intention-to-treat principle. Distribution 
normality will be determined by Kolmogorov Smirnov test. Continuous variables will be 
presented as mean±SD or median (IQR). Qualitative variables will be presented as number 
(percentage). Percentages will be compared by Fisher’s exact test. 
    The effect of group on treatment failure will be assessed using multivariable Cox 
regression. Hazard ratios and respective 95% confidence intervals will be determined for 
group, EUROSCORE II (which includes age and gender as risk factors), body mass index, 
cardiopulmonary bypass time, and duration of postoperative sedation and pre-extubation 
assisted and spontaneous breathing. 
    SpO2 >92%, and respiratory rate within 12- 20 breaths/min will be assessed as binary 
outcomes (i.e. maintenance vs. no maintenance of SpO2/respiratory rate above/within the 
aforementioned limits without escalation of support above initial level) Logistic regression 
models will be fitted using group, time, and group*time interaction as explanatory variables. 
Changes in oxygenation, VAS comfort scale score, and non-outcome follow-up variables 
(i.e. PaCO2, arterial blood lactate, hemoglobin concentration, hemodynamic variables, 
temperature, and vasopressor support) will be analysed by using linear mixed models 
analyses with group, time, and group*time,  as fixed factors, and ʺpatientsʺ as random factor. 
Dependent variables with skewed distributions will be log-transformed. The Bonferroni 
correction will be applied on the P values of pairwise comparisons.  
    Two-tailed P values will be reported. Statistical significance will be accepted at 0.05. 
Analyses will be conducted using SPSS version 21 or any subsequent version (IBM 
corporation, Armonk NY).  
 
Importance of the study   
     
    The early use of NHF in post-extubated cardiac surgery patients may potentially assist 
them in achieving a faster recovery by providing higher and more stable levels of humidified 
and warmed oxygen while supporting the respiratory effort through positive airway 
pressures. This could also be associated with a reduction in the risk for postoperative 
pulmonary complications. This study may also help in determining the best level of initial 
NHF support in cardiac surgery patients with postoperative hypoxemia.    
 
Study Funding Statement 
     
    The AIRVOTM 2 (Fisher & Paykel Healthcare, Auckland New Zealand) device (with built 
in flow generator) is already available at our institution. Regarding disposables, we estimate 
a total cost of 90 Euro per patient (heated humidifier, 60 Euro; Nasal prongs, 15 Euro; 
compatible opti flow circuit, 15 Euro. The maximum cost of disposables is estimated at 5940 

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Euro (+24% value added tax). This cost will be covered by the Special Account for Research 
Funds, University of Athens Medical School, Athens, Greece. The current study will not 
cause any financial burden to Evaggelismos Hospital.  
 
Doctoral Thesis 
 
This study corresponds to the Doctoral Thesis of Mr. Stavros Theologou.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Pun BT, Devlin JW. Delirium monitoring in the ICU: strategies for initiating and sustaining 
screening efforts. Semin Respir Crit Care Med. 2013;34:179-188.   
42. 
Fernandez R, Subira C, Frutos-Vivar F, Rialp G, Laborda C, Masclans JR, Lesmes A, 
Panadero L, Hernandez G. High-flow nasal cannula to prevent postextubation respiratory 
failure in high-risk non-hypercapnic patients: a randomized multicenter trial. Ann Intensive 
Care. 2017;7:47.    
43. 
Corley A, Rickard CM, Aitken LM, Johnston A, Barnett A, Fraser JF, Lewis SR, Smith AF. 
High-flow nasal cannulae for respiratory support in adult intensive care patients. Cochrane 
Database Syst Rev. 2017;5:CD010172.   
44. 
Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis 
program for the social, behavioral, and biomedical sciences. Behav Res Methods. 
2007;39:175-191.  . 
 
 
 
 
 
 
 
 
 
 

12 
 
 
 
STUDY INFORMATION SHEET [ClinicalTrials.gov ID: NCT03282552] 
PATIENT INITIALS (if applicable): 
 
PATIENT CODE (if applicable): 
 
Main Investigators: Stavros Theologou, Eleni Ischaki, Spyros G. Zakynthinos, 
Christos Charitos, Spyros D. Mentzelopoulos  
 
STUDY TITLE:  High Flow Oxygen therapy versus Conventional Oxygen Therapy in 
Cardiac Surgery Patients-OPTICAR study  
 
Introduction 
    We request your consent for your family member’s participation in this scientific study. 
The study has been approved by our Institutional Review Board (IRB – Scientific & Ethics 
Committee). To decide whether you agree (or disagree) with your relative’s participation in 
this study you should fully understand the pertinent risks and benefits. You are asked to read 
this text and discuss anything you do not understand with the study investigators, or other 
clinicians of the Department of Cardiac Surgery, or any other competent healthcare 
professional who enjoys your confidence. If you understand the study, you may be asked to 
sign and date the consent form in the postoperative period. If you choose your relative’s 
participation in the study, you will be given a copy of the signed consent form. Please note 
that as soon as your relative regains decision making capacity, they will be asked 
whether they agree to their continued study participation, and may validate your signed 
consent form by signing on it next to their name.  
 
CONSENTING FOR YOUR RELATIVE’S PARTICIPATION CONSTITUTES A 
FREE AND RESPONSIBLE CHOICE OF YOURS. 
 

13 
 
 
 
    Your relative may participate or discontinue his/her participation in the study at any time, 
according to your decision, without in any way losing the advantages of scientifically sound 
medical care based international guidelines and available medical literature evidence. 
    If desired, the principal investigators of the study or your relative’s attending physician 
will contact your relative’s family physician to inform him/her about the study. 
 
Study Scientific Background 
    Weaning (liberation) from mechanical ventilation and extubation after major surgery occur 
when certain criteria are met.1-3 Post-extubation respiratory failure after cardiothoracic 
surgery is a common and significant complication predisposing to increased intensive care 
unit (ICU) and hospital length of stay, and ultimately, poor in-hospital outcome.4,5 Its etiology 
is multifactorial and may include pleural effusions, impaired airway mucociliary function, 
ineffective cough due to pain, atelectasis, reduced lung/chest wall compliance, ventilator-
associated and extracorporeal circulation-associated lung injury, dysfunction of the 
respiratory muscles and abnormal ventilatory responses to gas exchange disturbances.5,6  
    Standard oxygen delivery devices include the Venturi mask and the nasal catheter. The 
Venturi mask is most commonly used in clinical practice and can provide an inspired oxygen 
fraction (FiO2) of 24%-60% with oxygen-in-air mixture outflows of 30-50 L/min.8 At a 
delivered oxygen concentration of 60%, inspired gas outflow is approximately 27-30 L/min.8 
The Venturi mask delivers a dry oxygen-in-air mixture that may cause dehydration of 
secretions, and disturbance of the mucociliary function of the upper airways. This might  
increase the risk of postoperative atelectasis and infection.4-6   
    High flow nasal cannula oxygen therapy (Nasal High Flow, NHF) is an oxygen delivery 
technique that seems to be gaining ground in recent years. The device consists of an 
oxygen/air mixer connected through an efficient heated humidifier and a heated circuit to a 
nasal cannula. NHF delivers an FiO2 of 21% to 100% with a gas flow rate of  up to 60 
L/min.7,8 FiO2 adjustments are independent of flow settings, and patients can receive heated, 
humidified and oxygen-rich gas mixtures at flow rates exceeding their own maximum 
inspiratory flow rates.7-9 NHF physiological benefits include more predictable FiO2 values 

14 
 
 
 
due to reduced dilution of oxygen,10,11 flow-dependent positive airway pressure,15,16 reduced 
anatomical dead-space ventilation,14,15 improved mucociliary function and clearance of 
secretions16,17 and reduced work of breathing.18 Therefore, NHF may improve gas-exchange 
and lung mechanics, reduce respiratory rate and effort, and ameliorate dyspnea.18-20 
    Despite these overall, encouraging results, it is still uncertain whether NHF can confer a 
clinical outcome benefit compared to conventional oxygen devices in postoperative cardiac 
surgery patients.21,22 Discordant results among relevant studies could be explained by 
differences in the studied populations and NHF flow settings.21,22  The proposed initial flow 
rate differs among the studies, with some authors7,8 suggesting initial lower flows (35-40 
L/min) that will be better tolerated by the patients and others suggesting initial maximal flows 
(60 L/min) to rapidly relieve dyspnea and prevent muscle fatigue. 22,23 
Study Objective 
    We aim to evaluate to evaluate the efficacy of NHF (with initial flows of 60 L/min or 40 
L/min) versus conventional oxygen therapy with respect to the adequacy of postoperative 
respiratory support (i.e. occurrence or no occurrence of treatment failure) and respiratory 
function (respiratory rate, oxygenation, use of accessory muscles, dyspnea, comfort, and 
immediately after the extubation of cardiac surgery patients with postoperative hypoxemia. 
Additional study outcomes will include ICU length of stay, hospital length of stay, rates of 
ICU re-admission and re-intubation and any other respiratory/non-respiratory complications 
and adverse events. 
Study protocol 
    This is a prospective, non-blinded, randomized study in postoperative cardiac surgery 
patients. The study population will consist of three patient groups:  
    The first group (Study Group 1) will include patients on NHF with initial settings of 
FiO2=60% and gas flow=60L/min.  
    The second group (Study Group 2) will include patients on NHF with initial settings of 
FiO2=60% and gas flow=40L/min  

15 
 
 
 
     In the third group (Control group), all patients will receive oxygen therapy according to 
the standard practice of our cardiac ICU department, i.e., Venturi mask delivering an FiO2 of 
60% and a flow of 15 L/min. 
    Baseline measurements will be undertaken within 30 min after extubation. Subsequently, 
all patients will be assessed for downward titration of respiratory support at 1, 2 hours, and 
then, every 4 hours after extubation. Respiratory physiological follow-up will extend up to 
48 hours after extubation. At the aforementioned follow-up time points, data collection will 
include SpO2, respiratory rate, PaO2/FiO2, comfort as regards dyspnea and respiratory 
support modality [visual analogue scale (VAS) score24], accessory muscles’ use, arterial 
pressure and heart rate, vasopressor support, and core body temperature Fluid balance of the 
first 24 and 48 hours postextubation will also be recorded. 
    Gradual weaning from NHF support will include FiO2 downward titration to 50%, 
followed by downward titration of gas flow to 30 L/min, aiming at a final wean-off goal of 
FiO2=0.4 and gas flow=20 L/min (unless the attending physician decides to turn the patient 
to a Venturi mask from a gas flow of 25 to 30 L/min).12 If at NHF FiO2=0.4 and flow rate=20 
L/min, pulse oximeter-measured, peripheral oxygen saturation (SpO2) and respiratory rate 
can be respectively maintained above 92% and within 12 to 20 breaths/min for at least 2 
hours, patients will be switched to conventional oxygen therapy with a Venturi mask 
(FiO2=0.4). In the control group, downward titration of support will be aimed at Venturi mask 
FiO2=0.4. Patients of all groups fulfilling the aforementioned SpO2/respiratory rate criteria 
for at least 4 hours while receiving an FiO2 of 0.4 via a Venturi mask will be considered for 
cardiothoracic ICU discharge.  
    During the postoperative/postextubation period, respiratory support may be escalated to 
maintain an SpO2 of >92% and a respiratory rate of 12-29 breaths/min. Changes in respiratory 
support level and/or modality will ultimately made and/or approved by the patients’ primary 
attending physicians.   
 
Study Eligibility Criteria 
• Adult Cardiac ICU patients. 

16 
 
 
 
• Age of more than 18 years. 
• After elective or urgent cardiac surgery. 
• Successful spontaneous breathing trial with T-piece and an FiO2 of 60% (eligibility criterion 
for extubation). 
• PaO2/FiO2 of less than 200 mmHg (moderate hypoxemia – normal value ~500 mmHg) 
• Hemodynamically stable, defined as systolic arterial pressure within 90 to 160 mmHg with 
or without low-to-moderate vasopressor support. 
Exclusion Criteria: 
• Obstructive sleep apnea syndrome supported by continuous positive airways pressure.  
• Diagnosis of exacerbation of chronic obstructive pulmonary disease.  
• Patients with tracheostomy.  
• Do-not-attempt resuscitation status.  
• Glasgow Coma Scale score below 13 (inability of satisfactory communication). 
• Insufficient knowledge of Greek language. 
• Visual or hearing impairment.  
Possible intervention-related risks:  
    We do not expect any NHF-associated increase in the risk of any clinically important 
adverse event. We cannot however exclude the possibility of subjective poor tolerance to the 
NHF device. This may occasionally be related to mucus dryness, or an episode of nasal 
bleeding.25  
Possible intervention-related benefits 
    For the participating patient: Improvement of postoperative respiratory function and 
subjective breathing comfort και της υποκειμενικής άνεσης, and possible reduction in the 
risk of postoperative pulmonary complications and length of cardiothoracic ICU/hospital 

17 
 
 
 
stay. 
    For medical science: Improvement in the clinical management of cardiac surgery patients 
with moderate postextubation hypoxemia. 
Discontinuation of study participation 
    The attending or principal investigator and the attending physician have the right (and 
obligation) to terminate your relative’s participation in this study without your consent, in 
case 
of 
any 
unexpected 
and 
potentially 
harmful 
(to 
your 
relative) 
event. 
The participation of your relative in this study is completely voluntary and you may 
discontinue it at any time. You will be timely informed about the time of study termination. 
You will be timely informed about the clinical course of your relative throughout the study’s 
follow-up period. 
Compensation in case of injury related to the investigational interventions 
    In case of a study protocol-related complication, the responsible researchers will inform 
you about the complication, the potential for complication reversal, and about your relative’s 
compensation. 
Use of medical information privacy and authorization 
    All data collected will be safe-guarded for the protection of medical confidentiality. Your 
relative will be referred to only by initials and a code number. The study information may be 
used in study reports or scientific presentations. 
    Additional scientific information of the study (eg, values of variables resulting from 
measurements of the protocol) will not be recorded in the patient's file. This information will 
be entered electronically by researchers and will be protected by a password and antiviral 
computer programs. If desired, the researchers will provide you with a pertinent study 
information note. 
    By signing the consent form you permit the aforementioned persons to take the above 
actions. There will be no publication or communication of the data that reveal your relative’s 
identity. The withdrawal of your relative from the study does not automatically cancel the 

18 
 
 
 
use of his-her personal information. If you wish to cancel the use of your relative’s data you 
should provide a written request to the responsible investigators, who will then be obliged to 
respond (to your request). 
YOU UNDERSTAND THAT YOU HAVE THE RIGHT OF ACCESS TO THE 
MEDICAL RESEARCH RECORDS OF YOUR RELATIVE IN ACCORDANCE 
WITH THE LAW. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

19 
 
 
 
 
References (updated 14/09/2018) 
1. Takaki S, Kadiman SB, Tahir SS, Ariff MH, Kurahashi K, Goto T. Modified rapid shallow 
breathing index adjusted with anthropometric parameters increases predictive power for 
extubation failure compared with the unmodified index in postcardiac surgery patients. J 
Cardiothorac Vasc Anesth. 2015;29(1):64-8.  
2. Thille AW, Cortés-Puch I, Esteban A. Weaning from the ventilator and extubation in ICU. 
Curr Opin Crit Care. 2013;19(1):57-64.  
3. BouAkl I, Bou-Khalil P, Kanazi G, Ayoub C, El-Khatib M. Weaning from mechanical 
ventilation. Curr Opin Anaesthesiol. 2012;25(1):42-7.  
4. Miskovic A, Lumb AB. Postoperative pulmonary complications. Br J Anaesth. 
2017;118(3):317-334.   
5. Badenes R, Lozano A, Belda FJ. Postoperative pulmonary dysfunction and mechanical 
ventilation in cardiac surgery. Crit Care Res Pract. 2015;2015:420513.  
6. Weissman C. Pulmonary complications after cardiac surgery. Semin Cardiothorac Vasc 
Anesth. 2004;8(3):185-211.  
7. Spoletini G, Alotaibi M, Blasi F, Hill NS. Heated Humidified High-Flow Nasal Oxygen in 
Adults: Mechanisms of Action and Clinical Implications. Chest. 2015;148(1):253-261.  
8. Gotera C, Díaz Lobato S, Pinto T, Winck JC. Clinical evidence on high flow oxygen therapy 
and active humidification in adults. Rev Port Pneumol. 2013;19(5):217-227.  
9. Ischaki E, Pantazopoulos I, Zakynthinos S. Nasal high flow therapy: a novel treatment rather 
than a more expensive oxygen device. Eur Respir Rev. 2017;26(145):170028.  
10. Chanques G, Riboulet F, Molinari N, Carr J, Jung B, Prades A, Galia F, Futier E, Constantin 
JM, Jaber S. Comparison of three high flow oxygen therapy delivery devices: a clinical 
physiological cross-over study. Minerva Anestesiol. 2013;79(12):1344-1355.  
11. Ritchie JE, Williams AB, Gerard C, Hockey H. Evaluation of a humidified nasal high-flow 
oxygen system, using oxygraphy, capnography and measurement of upper airway pressures. 
Anaesth Intensive Care. 2011;39(6):1103-1110.  
12. Parke RL, Eccleston ML, McGuinness SP. The effects of flow on airway pressure during 
nasal high-flow oxygen therapy. Respir Care. 2011;56(8):1151-1155.  

20 
 
 
 
13. Parke RL, McGuinness SP. Pressures delivered by nasal high flow oxygen during all phases 
of the respiratory cycle. Respir Care. 2013;58(10):1621-1624.  
14. Möller W, Celik G, Feng S, Bartenstein P, Meyer G, Oliver E, Schmid O, Tatkov S. Nasal 
high flow clears anatomical dead space in upper airway models. J Appl Physiol (1985). 
2015;118(12):1525-1532.  
15. Möller W, Feng S, Domanski U, Franke KJ, Celik G, Bartenstein P, Becker S, Meyer G, 
Schmid O, Eickelberg O, Tatkov S, Nilius G. Nasal high flow reduces dead space. J Appl 
Physiol (1985). 2017;122(1):191-197.  
16. Chikata Y, Izawa M, Okuda N, Itagaki T, Nakataki E, Onodera M, Imanaka H, Nishimura 
M. Humidification performance of two high-flow nasal cannula devices: a bench study. 
Respir Care. 2014;59(8):1186-1190.  
17. Hasani A, Chapman TH, McCool D, Smith RE, Dilworth JP, Agnew JE. Domiciliary 
humidification improves lung mucociliary clearance in patients with bronchiectasis. Chron 
Respir Dis. 2008;5(2):81-86.  
18. Mauri T, Turrini C, Eronia N, Grasselli G, Volta CA, Bellani G, Pesenti A. Physiologic 
Effects of High-Flow Nasal Cannula in Acute Hypoxemic Respiratory Failure. Am J Respir 
Crit Care Med. 2017;195(9):1207-1215  
19. Mauri T, Alban L, Turrini C, Cambiaghi B, Carlesso E, Taccone P, Bottino N, Lissoni A, 
Spadaro S, Volta CA, Gattinoni L, Pesenti A, Grasselli G. Optimum support by high-flow 
nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates. 
Intensive Care Med. 2017;43(10):1453-1463..     
20. Vargas F, Saint-Leger M, Boyer A, Bui NH, Hilbert G. Physiologic Effects of High-Flow 
Nasal Cannula Oxygen in Critical Care Subjects. Respir Care. 2015;60(10):1369-1376.  
21.  Zochios V, Klein AA, Jones N, Kriz T. Effect of high-flow nasal oxygen on pulmonary 
complications and outcomes after adult cardiothoracic surgery: A qualitative review. J 
Cardiothorac Vasc Anesth 2016;30:1379-1385.  
22. Corley A, Bull T, Spooner AJ, Barnett AG, Fraser JF. Direct extubation onto high-flow nasal 
cannulae post-cardiac surgery versus standard treatment in patients with a BMI ≥30: a 
randomised controlled trial. Intensive Care Med. 2015;41(5):887-894.   
23. Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, Prat G, Boulain T, Morawiec E, 
Cottereau A, Devaquet J, Nseir S, Razazi K, Mira JP, Argaud L, Chakarian JC, Ricard JD, 
Wittebole X, Chevalier S, Herbland A, Fartoukh M, Constantin JM, Tonnelier JM, Pierrot 

21 
 
 
 
M, Mathonnet A, Béduneau G, Delétage-Métreau C, Richard JC, Brochard L, Robert R; 
FLORALI Study Group; REVA Network. High-flow oxygen through nasal cannula in acute 
hypoxemic respiratory failure. N Engl J Med 2015;372:2185-2196. 
24. Maggiore SM, Idone FA, Vaschetto R, Festa R, Cataldo A, Antonicelli F, Montini L, De 
Gaetano A, Navalesi P, Antonelli M. Nasal high-flow vs Venturi mask oxygen therapy after 
extubation: effects on oxygenation, comfort and clinical outcome. Am J Respir Crit Care 
Med 2014;190:282–288. 
25. Campbell EJ, Baker MD, Crites-Silver P. Subjective effects of humidification of oxygen for 
delivery by nasal cannula. A prospective study. Chest. 1988;93(2):289-293.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

22 
 
 
 
 
Patient Initials:__________________ 
Patient Number:_________________ 
 
CONSENT DECLARATION OF THE PATIENT’S LEGAL REPRESENTATIVE 
ʺHigh Flow Oxygen therapy versus Conventional Oxygen Therapy in Cardiac Surgery 
Patients-OPTICAR studyʺ ClinicalTrials.gov Identifier: NCT03282552 
Note in the following blank the name of the clinician who informed you about the research and 
cycle the following answers. 
1. I have read the study information leaflet. 
YES / NO 
2. I was given the opportunity to ask questions and discuss the issues related to the study with 
the researcher: ------------------------------------------------------------------------------------------------------ 
YES / NO 
3. I was given satisfactory answers and information to all my questions. 
YES / NO 
4. I am aware of the fact that I reserve the right to withdraw my consent to the participation 
of my relative in the study at any time and without any obligation to explain the underlying 
reasons. 
YES / NO 
5. I understand that by my signature, I authorize access to and release of my relative's personal 
and medical data to competent persons authorized by the study investigator, to the competent 
authorities, and to the Independent Ethics Committee as necessary. I understand that I can 
withdraw my authorization at any time for the use or disclosure of my relative’s personal and 
medical data. I agree to give my permission to these individuals to access my relative's files. 
YES / NO 
6. Have you had adequate time to make your decision? 
YES / NO 
7. Do you accept your relative’s participation in this clinical trial? 
YES / NO 
PATIENT NAME [CAPITAL LETTERS]:                                                         [SIGNATURE & DATE] 
NAME OF THE PATIENT’S LEGAL REPRESENTATIVE [CAPITAL LETTERS]: 
 
ADDRESS: 
SIGNATURE & DATE 
PHONE: 
 
INVESTIGATOR NAME (CAPITAL LETTERS): 
ADDRESS: 
SIGNATURE & DATE 
PHONE: 
 
 

23 
 
 
 
 

24 
 
 
 

25 
 
 
 
DIAGRAMMATIC STANDARD OPERATING PROCEDURE (SOP) FOR THE 
ALGORITHMIC 
PERFORMANCE 
OF 
INVESTIGATIONAL 
INTERVENTIONS 
SpO2: peripheral oxygen saturation; ABG: arterial blood gas; VAS, visual analogue 
scale; PaO2: arterial oxygen tension; FiO2: inspired oxygen fraction; SG: study group; 
CG: control group. 
*, Patient consent for continued study participation may be obtained verbally provided 
that: 1) Informed, written consent has already been obtained from the patient’s next-of-
kin; 2) The patient is deemed competent for decision making by the primary attending 
physician; and 3) A study-independent healthcare professional is present as a witness 
to the consent procedure. Written patient consent for continued study participation may 
also be obtained by the patient’s signing on (and thereby ʺratifyingʺ) the existent next-
of-kin consent form; the patient may sign next to his/her name. If the patient refuses 
to continue his/her participation in the study, the protocol must stop and the 
attending physician must be accordingly notified; high-standard patient 
management must be smoothly continued.   
†, Weaning criteria (including SpO2 exceeding 92% AND respiratory rate within 
12-20 breaths/min) are detailed in the current protocol’s Methods section; 
IMPORTANT NOTE: preceding steps restart from the step that includes 
consideration to further reduce FiO2 by 0.1 if SpO2 exceeds 92%. 
‡, In SG 2, support escalation should be initially accomplished by gas flow increase of 
5-10 L/min; this can be followed by FiO2 titration to an SpO2 of more than 92%. 
§, Regarding CG patients on nonrebreathing mask due to respiratory support escalation, 
an FiO2 reduction from 0.9 to 0.6 via a Venturi mask should be performed for escalation 
reversal. 
**, Reversal of respiratory support escalation is defined as return to initial (or lower) 
FiO2 and/or gas flow for at least 4 hours.  
Applicable definition of hypoxemia: SpO2 drop to 92% or less for at least 5 min. 
 
 
 
 
 

26 
 
 
 
SOP FOR THE RATING OF THE LEVEL OF BREATHING COMFORT 
At the specified time points of patient follow-up: Investigators should use the below-
displayed comfort/discomfort visual analogue scale to help patients rate the level of 
their breathing comfort. The following simple question should be asked: How would 
you rate the level of your breathing comfort starting from 0 (maximum discomfort – 
feeling unable to breathe) to 10 (maximum comfort – feeling capable of smooth and 
steady breathing, without having even the slightest difficulty).  
 
 
 
 
 
 
 
 
 
 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
Contents 
1.PURPOSE 
2. BACKGROUND 
2.1. DEFINITIONS 
2.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN 
THE CLINICAL TRIAL. 
2.3 SEVERE ADVERSE EVENT OR REACTION 
2.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR 
3. SCOPE OF THIS SOP 
4. RESPONSIBLE PERSONNEL 
5. PROCEDURE 
5.1 Duration of AE Recording 
5.2 Which AE to record and which Forms to use 
5.3 Which AE to report to the SEC 
5.4 Evaluation of AE/Rs during the trial 
5.5. Evaluation of causality 
5.6. Evaluation of expectedness 
 
6. REFERENCES 
4 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
1. PURPOSE 
This Standard Operating Procedure (SOP) describes the procedure to be 
used by the investigator for the recording, management and reporting of 
Adverse Events (AEs), Adverse Reactions (ARs), Serious Adverse Events 
(SAEs), Suspected Serious Adverse Reactions (SSARs) and Suspected 
Unexpected Serious Adverse Reactions (SUSARs) which occur in subjects 
participating in the non-commercial, academic, investigator-initiated, 
prospective, parallel-group, randomized, unblinded OPTICAR study. 
2. BACKGROUND 
This SOP is written in accordance with Good Clinical Practice (GCP) 
requirements as previously outlined in Directives 2001/20/EC and 
2005/28/EC, and currently supported by the CLINICAL TRIALS 
REGULATION (EU) No 536/2014. 
2.1. DEFINITIONS 
The following definitions have been adapted: 
Adverse Event 
Any untoward medical occurrence in a patient or clinical trial subject 
administered an intervention ( INT) and which does not necessarily have 
a causal relationship with this treatment. 
Therefore, an AE can be any unfavorable or unintended change in the 
structure (signs), function (symptoms) or chemistry (laboratory data) in 
a subject to whom an INT has been administered, including occurrences 
which are not necessarily caused by or related to the INT. 
Adverse Reaction 
All untoward and unintended responses to the use of an INT related. 
This definition also covers errors and uses outside what is foreseen in 
the protocol, including misuse and abuse of the INT device. 
The definition implies a reasonable possibility of a causal relationship 
between the event and the INT. This means that there are facts (evidence) 
or arguments to suggest a causal relationship. 
Serious Adverse Event and Serious Adverse Reaction 
Any adverse event or reaction in a trial subject that: 
(a) results in death; or 
(b) is life threatening; places the subject, in the view of the investigator, 
at immediate risk of death from the experience as it occurred (this does 
not include an adverse experience that, had it occurred in a more severe 
form, might have caused death); or 
(c) requires hospitalization or prolongation of existing hospitalization; 
(d) results in persistent or significant disability or incapacity  
Important Safety Issues 
5 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
Important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may 
require intervention (medical or surgical) to prevent one of the other 
outcomes listed in the definition above should also be considered serious. 
Such events might include: 
1. An alarming adverse experience 
2. Specific Adverse events and/or laboratory abnormalities which are 
listed in the trial protocol as critical to safety evaluations and requiring 
reporting. 
Suspected Serious Adverse Reaction 
An adverse reaction that is classed in nature as serious and which is 
consistent with the information about the INT device listed in the relevant 
reference documentation in the case of a licensed device being used 
within its licensed indication or in the Investigator’s Brochure (IB) in the 
case of a licensed device being used outside its licensed indication. 
Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with 
the applicable product information. 
Suspected Unexpected Serious Adverse Reaction 
An adverse reaction that is classified in nature as both serious and 
unexpected. 
2.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN THE 
CLINICAL TRIAL. 
Events which may materially alter the current benefit-risk assessment of 
an investigational INT or which could be sufficient to consider changes in 
INT administration or in the overall conduct of the trial may fall into the 
category of ‘Other Safety Issues’ and be considered as serious events 
which will require reporting to the sponsor in a letter headed Safety 
Report: 
a. An increase in the rate of occurrence or a qualitative change of an 
expected serious adverse reaction, which is judged to be clinically 
important, 
b. Post-study Suspected Unexpected Serious Adverse Reactions 
(SUSARs) that occur after the patient has completed a clinical trial and are 
reported by the investigator to SEC, 
c. New events related to the conduct of the trial or the development of the 
IMPs and likely to affect the safety of the subjects, such as: 
1) A Serious Adverse Event (SAE) which could be associated with the trial 
procedures and which could modify the conduct of the trial, 
2) A significant hazard to the subject population such as lack of efficacy of 
an IMT  used for the treatment of a life-threatening disease, 
Recommendations of the Data Monitoring Committee (DMC), if any, 
where relevant to the safety of the subjects. 
6 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
An "Other Safety Issue" can also fall into the category of Urgent Safety 
Measures. Please refer to the Standard Operating Procedure for the 
Recording and Reporting of Deviations, Violations, Potential Serious 
Breaches, Serious Breaches and Urgent Safety Measures. 
2.3 SEVERE ADVERSE EVENT OR REACTION 
The term “severe” is often used to describe the intensity of an event or 
reaction (e.g. mild, moderate or severe) and should not be confused or 
interchanged with the term “serious”. 
2.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR 
This section describes the key responsibilities of the investigator, further 
delegation of these responsibilities to other team members must be 
documented on the trial delegation log. 
1. The principal investigator (PI) must further ensure that the team are all 
familiar with the appropriate use of the INT, as described in the protocol. 
2. Adverse Event (AE) Recording: All AEs must be recorded in the medical 
records (if source data) and/or the patient case report form (CRF), 
Serious Adverse Event (SAE) forms and AE logs as described in the 
protocol. 
3. AE Assessment: The PI / investigator(s) must assess each event for 
seriousness, expectedness and causality using the appropriate 
documentation (protocol and safety reference document). 
4. Trend/signal analysis: The PI must ensure the AE log is reviewed 
regularly. This can be performed by the PI alone or reviewed collectively 
at trial meetings. These reviews need to be documented. 
5. SAE Reports: The PI must ensure that initial and follow-up SAE reports 
are sent to the Scientific and Ethics Committee (SEC), according to the 
protocol. 
6. Confidentiality: The PI must always maintain subject confidentiality. 
7. Urgent Safety Measure: The PI / investigator(s) may take appropriate 
urgent safety measures to protect clinical trial subjects from any 
immediate hazard to their health and safety. This may be taken 
immediately. However, following the measure the PI / investigator must 
follow the SOP on “Deviations, serious breaches and urgent safety 
measures” . 
3. SCOPE OF THIS SOP 
This SOP covers the procedures for the recording, management and 
reporting of all AEs, ARs, SAEs, SSARs and SUSARs that occur in subjects 
participating in the OPTICAR Study. This document further details, 
safety alerts, safety reference document updates, and highlights the key 
responsibilities of the PI (if applicable). All pertinent documentation 
must always be readily accessible by the DMC. 
7 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
4. RESPONSIBLE PERSONNEL 
The PI and the individual investigators within a trial team are responsible 
for keeping records of all adverse events that occur in trial subjects as per 
protocol. 
5. PROCEDURE 
Please ensure that you are using the most recent SOP version. 
5.1 Duration of AE Recording 
The protocol must clearly define the duration of AE recording. 
5.2 Which AE to record and which Forms to use? 
The table below provides guidelines for where to record AE information: 
The PI may further designate who within the trial team is qualified to 
perform the delegated task. This must be authorized in the delegation 
log. 
Type of Adverse Events 
Format of Recording Information 
All Adverse events 
Medical Records 
All AEs and SAEs (as per protocol) 
AE section of CRF 
All SAEs (as per protocol) 
AE log 
All SAEs (as per protocol) 
SAE report form 
5.3 Which AE to report to the SEC? 
All AEs/ARs that fulfill the criteria for the definition of serious, whether 
expected or not, need to be reported to the SEC. 
5.4 Evaluation of AEs/ARs during the trial 
The following documents need to be referred to when assessing any AE in 
the trial: 
 Protocol 
 Trial specific Procedure for unblinding (if applicable) 
Each AE must be evaluated for seriousness, causality, severity and 
expectedness. The PI must assess the AE as serious as per the definition 
of an SAE in section 2. 
5.5. Evaluation of causality 
The PI’s / investigator's causality assessment is vital information since 
the PI / investigator(s) is / are best placed to review how the subject has 
changed since baseline (before treatment is administered). Every effort 
must be made by the PI to obtain all the required information to 
determine whether the AE is related to the trial intervention. 
The PI is asked to consider the following before reaching a decision: 
 Medical History 
 Lack of efficacy/worsening of existing condition 
 Study treatment(s) 
 Other treatments-concomitant or previous 
8 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 Withdrawal of study treatment-especially following study 
discontinuation/end of study 
 If applicable, erroneous treatment with study INT  
 Protocol related process 
 The PI’s / investigator’s evaluation of severity 
5.6. Evaluation of expectedness 
The PI must evaluate whether the event is expected or unexpected 
against the protocol and the safety reference documents for the trial. An 
event can be considered as “unexpected” if it adds significant information 
on the specificity or severity of an expected event. 
 
9 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
6. REFERENCES 
1. DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 4 April 2001 on the approximation of the laws, regulations 
and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use. Official Journal of the European 
Communities. 2002; L121/34-L121/43. 
2. COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down 
principles and detailed guidelines for good clinical practice as regards 
investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of 
such products (Text with EEA relevance). Official Journal of the European 
Union. 2005; L91/13-L91/19. 
3. INFORMATION FROM EUROPEAN UNION INSTITUTIONS, BODIES, AND 
AGENCIES. EUROPEAN COMMISSION. Communication from the 
Commission — Detailed guidance on the collection, verification and 
presentation of adverse event/reaction reports arising from clinical trials 
on medicinal products for human use (‘CT-3’) Official Journal of the 
European Union 2011; C172/1–C172/13. 
4. World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects. World Medical Association. 
JAMA. 2013; 310:2191-2194. 
5. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND 
OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products 
for human use, and repealing Directive 2001/20/EC. Official Journal of 
the European Union 2014; L158/1-L158/76. 
10 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
 
 
 
 
Adverse Events Recording and Reporting Log 
 
 
All events should continue to be recorded in source data and CRF as per protocol. This log must 1) be kept on site; 2) be readily 
accessible by the DMC; and 3) be sent to SEC upon request 
The PI CANNOT DOWNGRADE THE ASSESSMENT. 
Patient 
trial no 
Adverse 
Event 
term 
INT Name 
Is 
Event 
Serious 
Y/N 
Serious 
‘Type’1 
Start date - 
stop date 
Causal 
relationship2 
Severity 
Grade* 
Expected 
(Y/N) 
Outcome³ 
Date 
site 
aware 
of SAE 
Date SAE 
1st 
reported 
to the SEC 
 
 
KEY: 
 
1 
 1=resulted in Death, 2=life Threatening, 3=required inpatient or prolonged existing hospitalization, 4=resulted 
in persistent or significant disability/incapacity, 5=resulted in congenital anomaly/birth defect, 6= Important 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
Medical Event. 
2 
a= definitely, b=probably, c=possibly, d=unlikely, e= not related, f=not assessable 
* 
as per approved protocol or as per trial CRF definition 
³ 
1= Resolved, 2 = Resolved with sequelae, 3 = Unresolved, 4= Worsening, 5 = Fatal, 6= not assessable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
Serious Adverse Event 
Reporting Form 
Protocol No: 
Name of PI: 
Name of Site: 
Initial Report 
Follow-up Report 
12 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
FOR THE ATTENTION OF: 
DMC / SEC / Pharmacovigilance Manager / Regulatory Advisor 
Please complete 
Name of Person sending report: 
Job title of Person sending report: 
Email of Person sending report: 
Contact Phone number of Person sending report: 
THIS IS AN URGENT REPORT THAT REQUIRES IMMEDIATE ATTENTION 

13 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
1. 
SAE Onset Date:  
(dd/mm/yyyy) 
2. 
SAE Stop Date:  
(dd/mm/yyyy) 
3. 
Location of serious adverse event:   
 
4. 
Was this an unexpected adverse event? 
Yes 
No 
5. 
Brief description of participant(s) with no personal identifiers: 
Sex:  F 
M 
Age:   
 
6. 
Brief description of the nature of the serious adverse event (attach description if more 
space needed):   
 
 
7. 
Category of the serious adverse event: 
death – date   /  /  (dd/mmm/yyyy) 
congenital anomaly / birth defect 
life-threatening  
 
required intervention to prevent 
hospitalization-initial or prolonged 
permanent impairment 
disability / incapacity 
other:  
 
8. 
Intervention type: 
Medication or Nutritional Supplement: specify  
       
Device: Specify:   
 
Surgery: Specify:   
                      
Behavioral: Specify:   
  
9. 
Relationship of event to intervention: 
Unrelated (clearly not related to the intervention) 
Possible (may be related to intervention) 
Definite (clearly related to intervention) 
14 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
 
10. Was study intervention discontinued due to event? 
Yes
No 
 
11. What medications or other steps were taken to treat the serious 
adverse event? 
 
 
 
 
12. List any relevant tests, laboratory data, 
history, including preexisting medical 
conditions 
 
 
 
13. 
Type of report: 
 
 
 
 
 
 
14. Full list of medications the patients was receiving at the time of the 
SAE 
-------------------------- 
-------------------------- 
-------------------------- 
--------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
 
Signature of PI / investigator:  
Date:   
 
 
 
Initial 
Follow-up 
Final 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
      
 
 
Standard Operating Procedure 
for the Recording and Reporting of 
Deviations, Violations, Potential Serious breaches, Serious breaches and 
Urgent Safety Measures 
 
 
Template Reference: 
Version Number: 
Author: 
Implementation date of current 
version: 
1.0 
Approved by: 
Name/Position: 
Signature: 
Date: 
Name/Position: 
Signature: 
Date: 
This Template will normally be reviewed every year unless changes to the 
legislation require otherwise 
 
 
 
 
 
 
ACRONYMS: 
GCP 
Good Clinical Practice 
INT 
Intervention in the context of a Clinical Trial 
DMC 
Data Monitoring Committee 
SOP 
Standard Operating Procedure 
ISF 
Investigator Site File 
PI 
Principal Investigator 
CI 
Chief Investigator (Study Chair) 
CRF 
Case Report Form 
SEC 
Scientific and Research Ethics Committee 
USM 
Urgent safety measures 
TMF 
Trial Master File 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
 
Standard Operating Procedure for the Recording and Reporting of (protocol 
and /or GCP) Deviations, Violations, Potential Serious breaches, Serious 
Breaches and Urgent Safety Measures 
 
1. PURPOSE 
 
This Standard Operating Procedure (SOP) specifies the overall process and 
procedure for investigators to follow for the OPTICAR study in the event of a 
protocol and/or Good Clinical Practice (GCP) deviation. Criteria to follow are 
outlined to assess the impact of the deviation in light of the definition of a potential 
serious breach and / or an urgent safety measure. 
 
This SOP describes the procedure for the principal investigator (PI) / investigator 
to record the event and notify the Scientific and Research Ethics Committee (SEC). 
 
2. RESEARCH POLICY 
All OPTICAR SOPs will be reviewed and approved by the SEC of Evaggelismos 
Hospital, Athens, Greece; This SEC is directly linked to the National Research Ethics 
Committee. 
 
3. BACKGROUND 
 
In concordance with the currently applicable European Union Clinical Trials 
Regulation 536/2014, the Investigator/Institution should only conduct the trial in 
accordance with the approved protocol unless an urgent safety measure must be 
taken. 
 
The PI / investigator, or a person designated by the PI (in the trial delegation log), 
should document and explain any deviation from the approved protocol. 
 
Definitions used throughout this document 
 
3.1 Protocol Deviation: A deviation is usually an un-intended departure from the 
expected conduct of the trial (protocol, SOPs), e.g. a protocol visits date deviation (a 
common deviation in clinical trials). These events will be identified by the trial team 
during trial conduct and must be continually monitored by the chief investigator 
(CI)/PI and site team. 
 
It is recognized that minor deviations from approved clinical trial protocols and 
GCP occur commonly in Clinical Trials. Not every deviation from the protocol will 
result in a serious breach. Many of these instances are technical deviations that do 
not result in harm to the trial subjects or significantly affect the scientific value of 
the reported results of the trial. These cases should be documented in the case 
report form (CRF) and appropriate corrective and preventative action taken to 
ensure they do not recur. Please use the CRF and the PI’s Log of (Protocol and/or 
GCP) Deviations / Violations / Potential Serious breaches / Serious 
breaches / Urgent Safety Measures. 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
3.2 Violations: A violation can occur when there is a consistent variation 
in practice from trial protocol, SOPs. A violation can be classified as major 
if there is a significant occurrence which affects participant safety 
or integrity of the research. You are required to report to the PI any 
violation that may impact on the subjects’ safety or affects the integrity of the 
study data. 
 
Examples of this include but are not limited to; 
 
o Failure to obtain informed consent (i.e. no documentation in source data or an 
Informed Consent form). 
o Enrolment of subjects that do not meet the inclusion/exclusion criteria. 
o Undertaking a trial procedure not approved by the SEC (unless for immediate safety 
reasons). 
o Failure to report a Serious Adverse Event/Reaction. 
o Incorrect use of an Intervention Device. 
 
Minor Violation - a violation that does not impact on subjects’ safety or 
compromise the integrity of study data. Examples of this maybe; 
 
Missing original signed consent form (but clearly legible photocopy present) 
 
3.3 Serious Breaches of the protocol and/or GCP 
 
Please consider whether the violation that has occurred on site meets the following 
definitions. These cases must be reported to the SEC as soon as the PI / investigator 
has become aware of the event. 
 
(1) The PI of OPTICAR  shall notify the SEC in writing of any serious breach of - 
(a) the conditions and principles of GCP in connection with OPTICAR  ; or 
(b) the protocol relating to OPTICAR, as amended from time to time. 
 
A “serious breach” is a breach which is likely to affect to a significant degree – 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial. 
 
 
 
3.4 Urgent Safety Measures (Implementing a Protocol Deviation under an 
emergency) 
 
The PI / investigator may implement a deviation from, or a change of the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior approval from 
the SEC. This is defined as an Urgent Safety Measure: 
The PI / investigator may take appropriate urgent safety measure(s) to protect 
clinical trial subjects from any immediate hazard to their health and safety. The 
measures should be taken immediately. However, to meet the legal timelines, the 
PI / investigator must inform the SEC in writing immediately and within 24 
hours. 
See section 6.13 below for the REPORTING procedures. 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
 
4. SCOPE OF THIS SOP 
 
This SOP details the process (for PI / investigators) to follow for the recording and 
reporting of OPTICAR protocol deviations and violations. It describes what 
consideration must be considered to assess whether the deviations and violations 
also meet the definition of a potential serious breach or urgent safety measure 
and the reporting requirements. 
 
 
5. RESPONSIBLE PERSONNEL 
 
The site PI has the responsibility to record and report any violations to the SEC 
within the agreed timeframes and in accordance with this SOP if these are deemed a 
potential serious breach/urgent safety measure. Deviations need only be 
documented on site, in the case report form (CRF) and on the PI’s Log of (Protocol 
and/or 
GCP) 
Deviations/Violations/Potential 
Serious 
breaches/Serious 
breaches/Urgent Safety Measures and file noted where required. Any corrective 
and preventative action should also be documented and retained in the site file. 
 
              The SEC must consider the following actions: 
Receipt and Assessment (i.e. assessment of deviations/violations, 
isolated/systematic incident, patient(s) harmed or put at risk/data credibility etc.) 
 Investigation 
 Corrective and Preventative Action (CAPA) 
 Reporting to the National Research Ethics Committee 
 Trial suspension or Trial termination 
 Compliance with a 7-day reporting timescale 
 
If the PI is unsure whether a deviation or violation is a potential serious 
breach, then please notify the Data Monitoring Committee (DMC) and the SEC 
as soon as possible and provide as much information as possible. 
 
The DMC and SEC should assess the impact of the breach on the scientific value of 
the trial; this can be carried out in conjunction with the PI/ chief investigator (CI). If 
a potential serious breach is identified by a member of the DMC, the DMC should 
further discuss with the CI/PI in order to clarify the situation and recommend 
appropriate corrective and preventative action. Furthermore, The DMC must report 
the serious breach to the SEC. 
 
The regulatory timeline will only commence once the DMC has been notified of an 
event and has assessed the event as being a serious breach. 
 
6. PROCEDURE 
 
6.1 Identification of deviations, violations and potential serious breaches 
 
The judgment on whether a breach is likely to have a significant impact on the 
scientific value of the trial depends on a variety of factors e.g. the design of the trial, 
the type and extent of the data affected by the breach, the overall contribution of 
the data to key analysis parameters, the impact of excluding the data from the 
analysis etc. 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
In addition, it is important that the PI notifies the SEC of what corrective and 
preventative action has been taken (CAPA) to devise a formal plan of corrective 
and preventative action. 
 
6.1.1 Deviations 
 
Recording: In the CRF and the deviations and violations log and file noted if 
necessary. 
 
Reporting: Where a deviation is reoccurring and may result in identification of a 
serious breach, this should be notified to the PI / CI and the DMC. 
 
Escalation: Corrective and preventative actions should be implemented for 
deviations. It is recommended that reoccurring deviations be discussed at trial 
meetings, trigger protocol amendments, and if required, detailed in the clinical 
study report. 
 
6.1.2 Violations 
 
Recording: In the CRF and the deviations and violations log and file noted if 
necessary. 
 
Reporting: Violations of GCP, protocol and regulations must be notified to the PI / 
and the DMC within 2 calendar days of becoming aware of that violation. 
 
Escalation: Corrective and preventative actions (including protocol amendments as 
appropriate) should be implemented for violations. If the violation is determined to 
be a potential serious breach, then this would be reported to the SEC within 
regulatory timelines. 
It is recommended that reoccurring violations be discussed at trial meetings and 
detailed in the clinical study report. Violations may result in trial suspension by 
Oversight Authorities. 
 
A violation may constitute the DMC / SEC to undertake a triggered monitoring visit. 
All major violations must be resolved to conclusion. Depending on the nature of 
the violation it may constitute a Serious Breach of GCP and further follow up and 
reporting may be required by the DMC in line with current regulations. 
 
6.2 Procedure for notifying Oversight Authorities of a serious breach 
 
6.2.1. Site team to complete the “Notification of Serious Breaches of GCP or Trial 
Protocol form (see Appendix 1) all available details pertaining to the breach should 
be documented on the form. 
 
6.2.2. Completed Notification of Serious Breaches of GCP form to be sent to the DMC 
and the SEC. 
 
 
6.2.3. Violation / serious breach to be noted on the Log of (Protocol and/ or GCP) 
Deviations/Violations/Potential Serious breaches/Serious breaches/Urgent Safety 
Measures 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
 
In addition, the PI must log the Potential serious breach in the PI’s Log of (Protocol 
and/ 
or 
GCP) 
Deviations/Violations/Potential 
Serious 
breaches/Serious 
breaches/Urgent Safety Measures. 
 
6.3 Assessment by the DMC / SEC 
 
DMC / SEC to discuss potential serious breach internally through: 
 
Discussion with appropriate team members (e.g. regulatory advisor) 
 
Assess which relevant GCP, regulatory or protocol section the breach was identified 
in. 
 
 
6.4 Corrective and Preventative Actions (CAPA): 
 
The DMC, SEC, and the CI/PI must agree on the appropriate corrective and 
preventative action to be taken and this should be documented and detailed within 
the body of the notification report. 
 
 
6.5 Follow up reports: 
 
Follow up reports should be made in writing; the serious breaches form can also be 
used for this, provided that the "follow-up" nature of the report is clearly identified. 
 
6.6 Escalation and dissemination process: 
Internally: 
The institutional manager(s) of the PI / investigator must be informed of what 
CAPA is in place. The manager(s) may have to inform their quality assurance and 
senior management if necessary. 
 
 
6.7 Urgent Safety Measure and pertinent notification by a site 
 
Where unexpected events require an urgent modification of a clinical trial, the PI 
may take urgent safety measures without awaiting prior authorization. If such 
measures justify a temporary halt of the trial, the PI should apply for a substantial 
modification before restarting the trial. 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
REFERENCES 
 
1. DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 4 April 2001 on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use. Official Journal of the European 
Communities. 2002; L121/34-L121/43. 
2. COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down 
principles and detailed guidelines for good clinical practice as regards 
investigational medicinal products for human use, as well as the 
requirements for authorization of the manufacturing or importation of such 
products (Text with EEA relevance). Official Journal of the European Union. 
2005; L91/13-L91/19. 
3. INFORMATION FROM EUROPEAN UNION INSTITUTIONS, BODIES, AND 
AGENCIES. EUROPEAN COMMISSION. Communication from the Commission 
— Detailed guidance on the collection, verification and presentation of 
adverse event/reaction reports arising from clinical trials on medicinal 
products for human use (‘CT-3’) Official Journal of the European Union 2011; 
C172/1–C172/13. 
4. World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects. World Medical Association. 
JAMA. 2013; 310:2191-2194. 
5. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for 
human use, and repealing Directive 2001/20/EC. Official Journal of the 
European Union 2014; L158/1-L158/76. 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
8. APPENDICES 
 
Appendix 1 Notification of a Serious Breach form  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
 
 
Appendix 1: Notification of a Serious Breach form 
Notification of Serious Breach of Good Clinical Practice or Trial Protocol 
 
 
Your Name: 
Your Organization: 
Your Contact Details: 
Date Breach Identified by PI: 
Date Breach Notified to Scientifc 
and Research Ethics Committee: 
Details of Individual 
committing breach: 
OPTICAR; ClinicalTrials.gov 
Identifier: NCT03282552 
Report: 
Tick 
appropriately 
Initial 
Report 
Follow-up 
Report 
Please give details of the breach 
Potential impact to patient safety and/or data credibility: 
Patient safety 
Patient confidentiality 
Approval Issues 
Scientific value / data credibility 
NA/None 
Other Non-compliances (specify) 
INT 
Background: 
(continue on additional sheets if required) 
Other relevant information: 
(i.e. study status, site(s), SEC, PI details etc.) 
(continue on additional sheets if required) 
Please give details of the action taken: 
This should include: Any investigations by your institution, the results and outcomes 
of the investigations (if known or details of when they will be available/submitted), 
how it will be reported in the final report/publication, the corrective & preventative 
action implemented to ensure the breach does not occur again. 
(continue on additional sheets if required) 
Actual impact to patient safety and/or data credibility: 
Patient safety 
Patient confidentiality 
Approval Issues 
Scientific value / data credibility 
NA/None 
Other Non-compliances (specify) 
INT 

1st Department Of Intensive Care Medicine 
 Evaggelismos General Hospital 
OPTICAR Study 
 
SIGNATURE PAGE 
 
Author and Job Title: 
Signature: 
Date: 
Authorized by: 
Name and Job Title 
Signature: 
Date: