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Trial registered on ANZCTR


Registration number
ACTRN12616001564448
Ethics application status
Approved
Date submitted
21/10/2016
Date registered
11/11/2016
Date last updated
12/03/2019
Date data sharing statement initially provided
17/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Sigh35 and end-expiratory occlusion test assess fluid responsiveness in critically ill patients undergoing pressure support ventilation: a validation study.
Scientific title
Sigh35 and end-expiratory occlusion test to assess fluid responsiveness in critically ill patients undergoing pressure support ventilation: a validation study.
Secondary ID [1] 290367 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record
Main trial following pilot: ACTRN12615001232527.

Health condition
Health condition(s) or problem(s) studied:
Hemodinamically unstable ICU patients requiring fluid administration 300656 0
Critically ill patients showing signs of tissue hypoperfusion 300657 0
Hypotensive ICU patients 300660 0
Condition category
Condition code
Anaesthesiology 300512 300512 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Sigh35 is a hemodynamic test allowing the prediction of fluid responsiveness in critically ill patients showing spontaneous breathing activity. Sigh35 consists in the application of 35cmH20 for 4 seconds by a mechanical ventilator. The rise of the intrathoracic pressure causes a drop in pulse pressure (PP) and stroke volume index (SVI) which are proportional to preload dependency of the right ventricle (i.e. a patient who needs fluid will have a more consistent drop than a patient who does not need fluid). Sigh35 has been tested in a pilot study (ACTRN12615001232527).
2)End expiratory occlusion test (EEO) is another hemodynamic test allowing the prediction of fluid responsiveness in critically ill patients showing spontaneous breathing activity. By abolishing the inspiratory increase in intrathoracic pressure, EEO increases venous return and CO that could act as a volume challenge for detecting preload responsiveness.
The EEO consists in the interruption of the inspiratory pressure delivered by the ventilator by means of a manual end-expiratory occlusion of the airways for 15 seconds. Usually, on the main screen of the ventilator is displayed an "end-expiratory" maneuver button, since the stop on inspiratory pressure is also used to calculated totale end expiratory positive pressure.
3)Fluid challenge consisting in 4 ml/kg of intravenous crystalloids (both saline 0,9% or Ringer Acetate or Lactate were allowed), administered in 10 minutes.
The Fluid challenge is administered by the attending physician to correct hemodynamic instability during the surgical procedure or in intensive care unit (see also eligibility).
All the patients received hemodynamic monitoring with the MostCare system which provides all the hemodynamic variables evaluated in the study before and after fluid challenge administration (PP, SVI, arterial elastance, cardiac cycle efficiency).
The protocol defines:
1) The two tests will be used before fluid challenge in the same patient, and well be delivered following an order obtained by using opaque sealed envelopes to define which test (SIGH35, EEO) will be firstly delivered.
This is NOT a randomized trial since there is NOT a random allocation to intervention /control group. In fact, when if patient presents the predetermined criteria for inclusion, without exclusion criteria, then he/she will be tested with Sigh35 and EEO before FC administration.
Because of a potential statistical bias in the delivering the three tests always in the same order, the opaque sealed envelope will contain different orders.
Each test will be delivered according to definition (SIGH 35 in 4 seconds, EEO in 15 seconds) and a pause of 3 minutes will separate each test from the others,
The variations of stroke volume, cardiac output, pulse pressure and systolic pressure will be recorded after each test and will be compared to the baseline values (pre-test values).
Each test will be administered only one time unless the occurrence of cough or sporadic extrasystoles after SIGH35. For these reasons SIGH35 will be repeated for a maximum of another time. The occurrence of triggering of ventilator will determine the failure of EEO.
2) Each test will be delivered by an expert ICU physician with minimum 5 years’ experience
3) Predetermined cut-offs have been described in the literature for SIGH35 (35% of pulse pressure reduction with respect to the baseline), EEO (5% of cardiac index increase with respect to the baseline).
However, since a ROC curve approach will be used in the study, the cut offs of each test will be defined by the ROC curve constructed after fluid challenge administration and response.
Intervention code [1] 296181 0
Diagnosis / Prognosis
Intervention code [2] 296183 0
Treatment: Other
Comparator / control treatment

The gold standard for both EEO and SIgh35 will be the response of a patient to the administration of the fluid challenge. A patient will be considered responder if the stroke volume index increases of at least 10% with respect to the baseline value after FC administration.The response of a patient to the fluid challenge will be assessed by means of hemodynamic monitoring with the MostCare system.
Control group
Active

Outcomes
Primary outcome [1] 299936 0
The primary end point (SIGH35 ROC curve) will be assessed by means of calculation of ROC curve; we will consider clinically relevant an AUC of at least 0.85 and a failure an AUC equal or less than 0.70.
Timepoint [1] 299936 0
Single timepoint. The end of fluid challenge administration
Secondary outcome [1] 328585 0
As secondary end point, AUC of SIGH35 will be compared to AUC of EEO. For EEO the ROC curve was constructed to test the ability of the percent change during the last 5 seconds of the maneuver in PP, CI and SVI
Timepoint [1] 328585 0
Single timepoint. The end of the FC

Eligibility
Key inclusion criteria
1) Acute circulatory failure defined by a systolic arterial pressure less than or equal to 90 mm Hg (or fall of systolic arterial pressure of at least 50 mm Hg in known hypertensive patients) and one or more of the following signs: 1) urinary flow less than or equal to 0.5 mL/kg/min for greater than or equal to 2 hours, 2) tachycardia greater than or equal to 100 bpm, or 3) presence of skin mottling. 2) PSV with inspiratory support level (PS) between 8 and 15 cmH2O and positive end-expiratory pressure (PEEP) between 5 and 10 cmH2O; 3) stable ventilatory pattern.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) severe myocardial or valvular dysfunction; 2) cardiac arrhythmias; 3) severe acute respiratory distress syndrome (ARDS); 4) haemodialysis or continuous hemofiltration; 5) Body Mass Index equal or greater to 30; 6) altered arterial waveform; 7) diagnosis of pneumothorax.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis
We use a statistical software (MedCalc statistical software 13.0, MedCalc, Ostend, Belgium) for all the statistical tests. Data distribution are evaluated by means of the one-sample Kolmogorov-Smirnov test. Continuous variables are presented as mean +/- standard deviation, while categorical as percentage (95% confidence interval [CI].
For identifying possible extrasystoles or arrhythmic patterns not recognized at the bedside, the beat-to-beat pulse pressure values obtained after EEO and SIGH35 are analyzed using the ROUT method for outliers identification with Q set at 0.1%.
The primary end point will be assessed by means comparison of the areas (AUC) under receiver operating characteristic (ROC) curves comparison: considering the data reported in the literature, we assumed that the AUC of the SIGH35 should be of at least 0.85 to be clinically relevant. This value was compared to the null hypothesis (AUC = 0.65; ratio of samples sizes in negative and positive groups of 1:1): the calculated sample size is 50 patients. Considering the possibility of the occurrence extrasystoles during the beat-to-beat evaluation of the EEOT and the SIGH, the sample size is inflated by the 20% to account for the rate of loss of patients during the post-hoc data analysis. The final sample size is 60 patients.
For SIGH35, ROC curves (95% CI) will be constructed for percent changes of SAP, PP and SVI, between baseline and nadir after SIGH35 vs. the response to the fluid challenge. For EEO the ROC curve was constructed to test the ability of the percent change during the last 5 seconds of the maneuver of SAP, PP and SVI. A patient was considered responder if FC increases CI = 10%.
The comparison of AUCs of EEO and SIGH35 is performed by using a non-parametric paired technique.
Differences in hemodynamic and respiratory parameters for responders and non-responders at baseline are assessed using the unpaired Student’s t-test, while changes before and after FC by means of the paired Student’s t-test. Discrete variables are analyzed using the Chi-squared or Fisher’s exact test, depending on the number of observations.
For all tests, the null hypothesis is rejected for p values < 0.05.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2019
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/12/2019
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment outside Australia
Country [1] 8339 0
Italy
State/province [1] 8339 0
Novara, Milan
Country [2] 21342 0
Spain
State/province [2] 21342 0
Cadice

Funding & Sponsors
Funding source category [1] 294752 0
Self funded/Unfunded
Name [1] 294752 0
Antonio Messina
Country [1] 294752 0
Italy
Primary sponsor type
Individual
Name
antonio messina
Address
Corso Mazzini, 18
28100 Novara - Italy
ICU Maggiore Hospital della Carita'
Country
Italy
Secondary sponsor category [1] 293602 0
Individual
Name [1] 293602 0
Stefano Romagnoli
Address [1] 293602 0
AOU Careggi
Largo G. Alessandro Brambilla, 3, 50134
Firenze - Italy
Country [1] 293602 0
Italy

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296167 0
Comitato Etico interaziendale AOU Maggiore della Carita'
Ethics committee address [1] 296167 0
Corso Mazzini,18 - 28100 Novara (NO)
Italy
Ethics committee country [1] 296167 0
Italy
Date submitted for ethics approval [1] 296167 0
10/11/2016
Approval date [1] 296167 0
19/12/2016
Ethics approval number [1] 296167 0

Summary
Brief summary
Assessing fluid responsiveness in ICU patients undergoing pressure support ventilation is challenging. Insofar, the hemodynamic testes proposed for this purpose have drawbacks and cannot be applied extensively.
Sigh35 is a novel reliable hemodynamic test who is based on different physiological purposes.
The primary end point will be assessed by means of calculation of ROC curve. For SIGH35 , receiver operating characteristic (ROC) curves (95% CI) will be constructed for percent changes of systolic arterial pressure, pulse pressure (PP) and stroke volume index (SVI), between baseline and nadir after SIGH35 vs. the response to the fluid challange.
As secondary end point, AUC of SIGH35 will be compared to AUC of EEO. For EEO the ROC curve was constructed to test the ability of the percent change during the last 5 seconds of the maneuver in PP, CI and SVI.
Comparison of AUCs of EEO and SIGH35 is performed by using a nonparametric paired technique, as described previously.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69830 0
Dr Antonio Messina
Address 69830 0
AOU Maggiore della Carita'
Corso Mazzini, 18
28100 Novara (Italy)
Intensive Care Unit
Country 69830 0
Italy
Phone 69830 0
+3903213733380
Fax 69830 0
Email 69830 0
mess81rc@gmail.com
Contact person for public queries
Name 69831 0
Antonio Messina
Address 69831 0
AOU Maggiore della Carita'
Corso Mazzini, 18
28100 Novara (Italy)
Intensive Care Unit
Country 69831 0
Italy
Phone 69831 0
+3903213733380
Fax 69831 0
Email 69831 0
mess81rc@gmail.com
Contact person for scientific queries
Name 69832 0
Antonio Messina
Address 69832 0
AOU Maggiore della Carita'
Corso Mazzini, 18
28100 Novara (Italy)
Intensive Care Unit
Country 69832 0
Italy
Phone 69832 0
+3903213733380
Fax 69832 0
Email 69832 0
mess81rc@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.