Respiratory Distress Syndrome, AdultEPOCHNCT02342756
Esophageal Pressure-Guided Optimal PEEP/mPaw in CMV and HFOV: The EPOCH Study
A study testing Targeting transpulmonary pressure to avoid VILI in people with Respiratory Distress Syndrome, Adult and Ventilator-Induced Lung Injury, run by University of Toronto at 2 sites in Canada.
Trial summary
The use of positive end-expiratory pressure (PEEP) has been shown to prevent the cycling end-expiratory collapse during mechanical ventilation and to maintain alveolar recruitment, keeping lung portions open, increasing the resting end-expiratory volume. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Respiratory Distress Syndrome, Adult, Ventilator-Induced Lung Injury
- What is being tested?
- Targeting transpulmonary pressure to avoid VILI
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 2 sitesCanada
- Study dates
- Jan 2015to Dec 2017
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Moderate or severe ARDS, defined according to the Berlin definition (2);
- Endotracheal intubation or tracheostomy
Who cannot join
- Severe heart failure/cardiogenic shock;
- Pulmonary arterial hypertension requiring systemic vasodilators;
- Contraindications to esophageal balloon: esophageal pathology (stricture, perforation, high grade of varices), recent history of esophageal or gastric surgery, upper GI tract bleeding, severe coagulopathy and nasal trauma;
- Contraindications to Electrical Impedance Tomography (EIT): a temporary or permanent pacemaker, or implantable cardioverter-defibrillator (ICD);
- Age < 16 years.
Trial locations and contacts
2 sites in 1 country.
Canada2 sites
Intensive Care Unit (ICU) of Mount Sinai Hospital
Toronto, Ontario, M5G 1X5
Medical Surgical ICU - Toronto General Hospital
Toronto, Ontario, M5G 2C4
About this study
The use of positive end-expiratory pressure (PEEP) has been shown to prevent the cycling end-expiratory collapse during mechanical ventilation and to maintain alveolar recruitment, keeping lung portions open, increasing the resting end-expiratory volume. On the other hand PEEP may also overdistend the already open lung, increasing stress and strain.
Theoretically high frequency oscillatory ventilation (HFOV) could be considered an ideal strategy in patients with ARDS for the small tidal volumes, but the expected benefits have not been shown yet.
Read more
PEEP and HFOV should be tailored on individual physiology. Assuming that the esophageal pressure is a good estimation of pleural pressure, transpulmonary pressure can be estimated by the difference between airway pressure and esophageal pressure (PL= Paw - Pes). A PL of 0 cmH2O at end-expiration should keep the airways open (even if distal zones are not certainly recruited) and a PL of 15 cmH2O should produce an overall increase of lung recruitment.
The investigators want to determine whether the prevention of atelectrauma by setting PEEP and mPaw to obtain 0 cmH2O of transpulmonary pressure at end expiratory volume is less injurious than lung recruitment limiting tidal overdistension by setting PEEP and mPaw at a threshold of 15 cmH2O of transpulmonary pressure.
The comparison between conventional ventilation with tidal volume of 6 ml/Kg and HFOV enables us to understand the role of different tidal volumes on preventing atelectrauma and inducing lung recruitment.
The use of non-invasive bedside techniques such as lung ultrasound, electrical impedance tomography, and transthoracic echocardiography are becoming necessary in ICU and may allow us to distinguish between lung recruitment and tidal overdistension at different PEEP/mPaw settings, in order to limit pulmonary and hemodynamic complications during CMV and HFOV.
Read the detailed description
The absolute value of esophageal pressure (Pes), measured during an end-expiratory pause can be considered a good surrogate for pleural pressure (Ppl), and the difference between airway pressure (Paw) and Pes a valid estimation of transpulmonary pressure (PL). Although this method has not been tested in large clinical trials yet, the utility of Pes in guiding therapy of ARDS has been shown in EPVent study.
Therefore, assuming that Pes is a good estimation of Ppl, PEEP and mPaw could be targeted to obtain different value of PL. A PL of 0 cmH2O at end-expiratory pause, should keep the airways open (even if distal zones are not certainly recruited) and a PL of 15 cmH2O at end-inspiratory pause should produce an overall increase of lung recruitment, limiting tidal overdistension. The comparison of these two different ventilatory settings allows us to determine whether the prevention of atelectrauma by setting PEEP and Paw of HFOV to obtain 0 cmH2O of transpulmonary pressure at end-expiratory occlusion is less injurious than lung recruitment limiting tidal overdistension by setting PEEP and mPaw at a threshold of 15 cmH2O of transpulmonary pressure.
The use of HFOV beside conventional ventilation, enables us to understand the role of these ventilatory strategies with different end-expiratory volumes, on preventing atelectrauma and inducing lung recruitment.
In addition the use of non-invasive bedside techniques as pleural and lung ultrasonography (PLUS), electrical impedance tomography (EIT), and transthoracic echocardiography (TTE) may allow us to distinguish between lung recruitment and tidal overdistension at different PEEP/mPaw settings, in order to limit pulmonary and hemodynamic complications during CMV and HFOV, and may help in the assessment of recruitable lungs.
Primary objective:
To determine whether the prevention of atelectrauma by setting PEEP (CMV) to obtain 0 cmH2O of transpulmonary pressure at end-expiratory occlusion and mPaw (HFOV) to obtain 0 cmH2O of mean transpulmonary pressure is less injurious than lung recruitment limiting tidal overdistension by setting PEEP (CMV) and mPaw (HFOV) at a threshold of 15 cmH2O of transpulmonary pressure. Plasma cytokines will be used to define the ventilator induced lung injury.
Secondary objectives:
- To assess lung recruitment and tidal overdistension with bedside non-invasive methods such as EIT and PLUS during CMV and HFOV, with PEEP and mPaw set to obtain a PL of 0 and a PL of 15 cmH2O.
- To assess if the impact of PEEP and HFOV set to obtain PL of 15 cmH2O is more dangerous for right ventricular function than PEEP to obtain PLEEO and PLHFOV of 0 cmH2O. TTE will be used to evaluate the heart function.
Study management:
For this pathophysiological study we will enroll 20 patients with moderate or severe ARDS, within 72 hours of arrival in our ICU.
- All patients will be supine, with the head of the bed elevated to 30 degrees.
- All patients will be deeply sedated and ventilated according to clinical practice.
- Monitoring will be provided at least with:
- Heart rate (HR) and cardiac rhythm.
- Mean arterial pressure (MAP) monitored by invasive blood pressure via an arterial catheter.
- Central venous pressure (CVP).
- Transcutaneous O2 saturation by pulse oximetry (SpO2),
- Airflow, airway pressure (Paw), tidal volume (Vt), end-tidal partial pressure of carbon dioxide (PETCO2)
- Immediately before the initiation of the study, the patients will be subjected to neuromuscular blockade with a cisatracurium intravenous bolus and continuous infusion titrated to achieve 0-2/4 twitches on facial nerve electrical stimulation.
- A nasogastric catheter with esophageal and gastric balloon will be placed. Esophageal pressure (Pes) will be measured during an end-inspiratory (PesEIO) and an end-expiratory occlusion (PesEEO) of the airway. The variation of esophageal pressure during tidal inflation (ΔPes) will be calculated as the difference between PesEIO and PesEEO. Transpulmonary pressure (PL) will be calculated as the difference between Paw and Pes (PL = Paw - Pes). The intragastric pressure will be measured only during an end-expiratory occlusion of the airway (IGP).
All study data will be transcribed directly on to standardized Case Report Forms (CRF).
Patients will be randomized to start the protocol with the controlled mechanical ventilation strategy or the high frequency oscillatory ventilation. A block-randomization scheme with opaque envelopes and block size of 2 will be used.
Study protocol:
Immediately after enrolment, Pes will be measured during an end-expiratory (PesEEO) and end-inspiratory occlusion (PesEIO). PEEP to reach a PLEEO of 0 cmH2O and PEEP to reach a PLEIO of 15 cmH2O will be calculated.
CMV phase A. PLEEO = 0
- Patients will be ventilated with CMV using the following parameters (in group 2 before starting PesEEO and PesEIO will be measured):
- Vt 6 ml/kg predicted body weight
- PEEP so that PLEEO = 0 cmH2O
- Respiratory Rate (RR) to reach pH 7.25-7.35
- FiO2 to have SpO2 ≥ 90%
- After 40 minutes at these settings, lung ultrasound will be performed to obtain a lung ultrasound score.
- After completing PLUS, TTE will be performed
- After completing TTE, EIT will be positioned and recordings of global and regional time courses of impedance changes and associated EIT images will be obtained
- Blood sample for cytokines measurement will be collected and the following parameters will be measured:
- Arterial blood gases
- Crs
- Alveolar dead space.
- PLEIO = 15
- Patients will be ventilated with the same Vt, RR and FiO2 of phase A. PEEP will be set at the value obtained to reach a PLEIO = 15 cmH2O.
- Same measurements will be repeated as in phase A (steps 2 to 5).
- PLEEO = 0
- Patients will be ventilated with the same Vt, RR and FiO2 of previous phases. PEEP will be set at the same value of phase A (PEEP so that PLEEO = 0 cmH2O).
- Same measurements will be repeated as in phase A (steps 2 to 5). PesEEO and PesEIO will be measured so that CMV phase is completed.
HFOV phase D. PL = 0
- Patients will be switched to HFOV. Pes will be measured and mPaw to reach a PLHFOV of 0 and of 15 will be calculated. Patients will be ventilated using the following parameters:
- Pressure amplitude 90 cmH2O
- mPaw to reach a PL of 0 cmH2O
- Respiratory Rate (RR) ≥ 5Hz to reach pH 7.25-7.35
- FiO2 to have SpO2 ≥ 90%
- Same measurements will be performed as in phase A (steps 2 to 4). Blood sample for cytokines measurement will be collected and the following parameters will be measured:
- Arterial blood gases.
- PL = 15
- Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 15 cmH2O.
- Same measurements will be performed as in phase D.
- PL = 0
- Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 0 cmH2O.
- Same measurements will be performed as in phase D. Then Pes will be measured and HFOV phase is completed.
- Being tested
- Targeting transpulmonary pressure to avoid VILI
- Keywords
- ARDS, HFOV
- Medical subject headings
- Respiratory Distress Syndrome, Ventilator-Induced Lung Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Targeting transpulmonary pressure to avoid VILIDevice
Set different values of PEEP (CMV) and mPaw (HFOV) to obtain determined values of transpulmonary pressure (0 and 15 centimeters of water) and to determine the impact of ventilation on VILI
| Study group | Role | What they receive |
|---|---|---|
| Group 1: CMV - HFOV | Experimental | Patients in group 1 will start with conventional mechanical ventilation with different values of PEEP (A-PEEP so that PLEEO = 0 cmH2O, B- PEEP so that PLEIO = 15 cmH2O, C- PEEP so that PLEEO = 0 cmH2O) and then will be ventilated with high frequency oscillatory ventilation (D- mPaw so that PL = 0 cmH2O, E- mPaw so that PL = 15 cmH2O, F- mPaw so that PL = 0 cmH2O)
Intervention: Device: Targeting transpulmonary pressure to avoid VILI Receives: Device: Targeting transpulmonary pressure to avoid VILI |
| Group 2: HFOV - CMV | Experimental | Patients in group 2 will start with high frequency oscillatory ventilation (D- mPaw so that PL = 0 cmH2O, E- mPaw so that PL = 15 cmH2O, F- mPaw so that PL = 0 cmH2O) and then will be ventilated with conventional mechanical ventilation with different values of PEEP (A-PEEP so that PLEEO = 0 cmH2O, B- PEEP so that PLEIO = 15 cmH2O, C- PEEP so that PLEEO = 0 cmH2O).
Intervention: Device: Targeting transpulmonary pressure to avoid VILI Receives: Device: Targeting transpulmonary pressure to avoid VILI |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ventilator-induced lung injury (VILI) in patients with ARDS as measured by serum cytokines
IL-6, TNF, IL-10, IL-1β, and IL-1ra and other cytokines will be detected in EDTA plasma with commercially available enzyme-linked immunosorbent assays (ELISA)
Measured: 1 hour after initiation of each experimental ventilation strategy
Secondary outcomes (2)
Assessment of lung recruitment and tidal overdistension
Lung ultrasound score (LUS), global and regional impedance (EIT).
Measured: 1 hour after initiation of each experimental ventilation strategy
Impact of transpulmonary pressure on right ventricular function (RV)
Measurements: Transthoracic echocardiography (TTE).
Measured: 1 hour after initiation of each experimental ventilation strategy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jan 2015 (estimated)
- Study startJan 2015
- Primary completionDec 2017 (estimated)
- Study completionDec 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Respiratory Distress Syndrome, AdultStudies of the same condition, open and under way.
- More trials run by University of TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- University Health Network, Toronto, Nihon Kohden
- Responsible party
- Principal investigator, Eddy Fan, University of Toronto
- Investigators
- Eddy Fan, MD, PhD, Principal investigator, University Health Network, TorontoFrancesca Facchin, MD, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02342756
- Sponsor's protocol ID
- 14-8253
- Acronym
- EPOCH
- Status last verified
- Jan 2015
- First submitted
- 15 Jan 2015
- Last updated
- 30 Jan 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest. 1997 Mar 1;99(5):944-52. doi: 10.1172/JCI119259.
PubMed 9062352Fan E, Needham DM, Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA. 2005 Dec 14;294(22):2889-96. doi: 10.1001/jama.294.22.2889.
PubMed 16352797Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008 Feb 13;299(6):637-45. doi: 10.1001/jama.299.6.637.
PubMed 18270352Talmor D, Sarge T, Malhotra A, O'Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med. 2008 Nov 13;359(20):2095-104. doi: 10.1056/NEJMoa0708638. Epub 2008 Nov 11.
PubMed 19001507Akoumianaki E, Maggiore SM, Valenza F, Bellani G, Jubran A, Loring SH, Pelosi P, Talmor D, Grasso S, Chiumello D, Guerin C, Patroniti N, Ranieri VM, Gattinoni L, Nava S, Terragni PP, Pesenti A, Tobin M, Mancebo J, Brochard L; PLUG Working Group (Acute Respiratory Failure Section of the European Society of Intensive Care Medicine). The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med. 2014 Mar 1;189(5):520-31. doi: 10.1164/rccm.201312-2193CI.
PubMed 24467647Bouhemad B, Brisson H, Le-Guen M, Arbelot C, Lu Q, Rouby JJ. Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment. Am J Respir Crit Care Med. 2011 Feb 1;183(3):341-7. doi: 10.1164/rccm.201003-0369OC. Epub 2010 Sep 17.
PubMed 20851923Volpicelli G, Elbarbary M, Blaivas M, Lichtenstein DA, Mathis G, Kirkpatrick AW, Melniker L, Gargani L, Noble VE, Via G, Dean A, Tsung JW, Soldati G, Copetti R, Bouhemad B, Reissig A, Agricola E, Rouby JJ, Arbelot C, Liteplo A, Sargsyan A, Silva F, Hoppmann R, Breitkreutz R, Seibel A, Neri L, Storti E, Petrovic T; International Liaison Committee on Lung Ultrasound (ILC-LUS) for International Consensus Conference on Lung Ultrasound (ICC-LUS). International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012 Apr;38(4):577-91. doi: 10.1007/s00134-012-2513-4. Epub 2012 Mar 6.
PubMed 22392031Repesse X, Charron C, Vieillard-Baron A. Right ventricular failure in acute lung injury and acute respiratory distress syndrome. Minerva Anestesiol. 2012 Aug;78(8):941-8. Epub 2012 Jun 7.
PubMed 22672932Fichet J, Moreau L, Genee O, Legras A, Mercier E, Garot D, Dequin PF, Perrotin D. Feasibility of right ventricular longitudinal systolic function evaluation with transthoracic echocardiographic indices derived from tricuspid annular motion: a preliminary study in acute respiratory distress syndrome. Echocardiography. 2012 May;29(5):513-21. doi: 10.1111/j.1540-8175.2011.01650.x. Epub 2012 Feb 13.
PubMed 22324535Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD, Lamontagne F, Granton JT, Arabi YM, Arroliga AC, Stewart TE, Slutsky AS, Meade MO; OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):795-805. doi: 10.1056/NEJMoa1215554. Epub 2013 Jan 22.
PubMed 23339639Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, Rowan K, Cuthbertson BH; OSCAR Study Group. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):806-13. doi: 10.1056/NEJMoa1215716. Epub 2013 Jan 22.
PubMed 23339638Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, Slutsky AS, Gattinoni L, Ranieri VM. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007 Jan 15;175(2):160-6. doi: 10.1164/rccm.200607-915OC. Epub 2006 Oct 12.
PubMed 17038660Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967 Aug 12;2(7511):319-23. doi: 10.1016/s0140-6736(67)90168-7. No abstract available.
PubMed 4143721ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.
PubMed 22797452
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Esophageal Pressure-Guided Optimal PEEP/mPaw in CMV and HFOV: The EPOCH Study
- ClinicalTrials.gov ID
- NCT02342756
- Acronym / sponsor ID
- EPOCH / 14-8253
- Keywords
- ARDS, HFOV
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- University of TorontoUniversity, hospital or other
- Collaborators
- University Health Network, Toronto, Nihon Kohden
- Study start
- Jan 2015
- Primary completion
- Dec 2017 (estimated)
- Study completion
- Dec 2017 (estimated)
- First posted
- 21 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The use of positive end-expiratory pressure (PEEP) has been shown to prevent the cycling end-expiratory collapse during mechanical ventilation and to maintain alveolar recruitment, keeping lung portions open, increasing the resting end-expiratory volume. On the other hand PEEP may also overdistend the already open lung, increasing stress and strain.
Theoretically high frequency oscillatory ventilation (HFOV) could be considered an ideal strategy in patients with ARDS for the small tidal volumes, but the expected benefits have not been shown yet.
PEEP and HFOV should be tailored on individual physiology. Assuming that the esophageal pressure is a good estimation of pleural pressure, transpulmonary pressure can be estimated by the difference between airway pressure and esophageal pressure (PL= Paw - Pes). A PL of 0 cmH2O at end-expiration should keep the airways open (even if distal zones are not certainly recruited) and a PL of 15 cmH2O should produce an overall increase of lung recruitment.
The investigators want to determine whether the prevention of atelectrauma by setting PEEP and mPaw to obtain 0 cmH2O of transpulmonary pressure at end expiratory volume is less injurious than lung recruitment limiting tidal overdistension by setting PEEP and mPaw at a threshold of 15 cmH2O of transpulmonary pressure.
The comparison between conventional ventilation with tidal volume of 6 ml/Kg and HFOV enables us to understand the role of different tidal volumes on preventing atelectrauma and inducing lung recruitment.
The use of non-invasive bedside techniques such as lung ultrasound, electrical impedance tomography, and transthoracic echocardiography are becoming necessary in ICU and may allow us to distinguish between lung recruitment and tidal overdistension at different PEEP/mPaw settings, in order to limit pulmonary and hemodynamic complications during CMV and HFOV.
Detailed description
The absolute value of esophageal pressure (Pes), measured during an end-expiratory pause can be considered a good surrogate for pleural pressure (Ppl), and the difference between airway pressure (Paw) and Pes a valid estimation of transpulmonary pressure (PL). Although this method has not been tested in large clinical trials yet, the utility of Pes in guiding therapy of ARDS has been shown in EPVent study.
Therefore, assuming that Pes is a good estimation of Ppl, PEEP and mPaw could be targeted to obtain different value of PL. A PL of 0 cmH2O at end-expiratory pause, should keep the airways open (even if distal zones are not certainly recruited) and a PL of 15 cmH2O at end-inspiratory pause should produce an overall increase of lung recruitment, limiting tidal overdistension. The comparison of these two different ventilatory settings allows us to determine whether the prevention of atelectrauma by setting PEEP and Paw of HFOV to obtain 0 cmH2O of transpulmonary pressure at end-expiratory occlusion is less injurious than lung recruitment limiting tidal overdistension by setting PEEP and mPaw at a threshold of 15 cmH2O of transpulmonary pressure.
The use of HFOV beside conventional ventilation, enables us to understand the role of these ventilatory strategies with different end-expiratory volumes, on preventing atelectrauma and inducing lung recruitment.
In addition the use of non-invasive bedside techniques as pleural and lung ultrasonography (PLUS), electrical impedance tomography (EIT), and transthoracic echocardiography (TTE) may allow us to distinguish between lung recruitment and tidal overdistension at different PEEP/mPaw settings, in order to limit pulmonary and hemodynamic complications during CMV and HFOV, and may help in the assessment of recruitable lungs.
Primary objective:
To determine whether the prevention of atelectrauma by setting PEEP (CMV) to obtain 0 cmH2O of transpulmonary pressure at end-expiratory occlusion and mPaw (HFOV) to obtain 0 cmH2O of mean transpulmonary pressure is less injurious than lung recruitment limiting tidal overdistension by setting PEEP (CMV) and mPaw (HFOV) at a threshold of 15 cmH2O of transpulmonary pressure. Plasma cytokines will be used to define the ventilator induced lung injury.
Secondary objectives:
- To assess lung recruitment and tidal overdistension with bedside non-invasive methods such as EIT and PLUS during CMV and HFOV, with PEEP and mPaw set to obtain a PL of 0 and a PL of 15 cmH2O.
- To assess if the impact of PEEP and HFOV set to obtain PL of 15 cmH2O is more dangerous for right ventricular function than PEEP to obtain PLEEO and PLHFOV of 0 cmH2O. TTE will be used to evaluate the heart function.
Study management:
For this pathophysiological study we will enroll 20 patients with moderate or severe ARDS, within 72 hours of arrival in our ICU.
- All patients will be supine, with the head of the bed elevated to 30 degrees.
- All patients will be deeply sedated and ventilated according to clinical practice.
- Monitoring will be provided at least with:
- Heart rate (HR) and cardiac rhythm.
- Mean arterial pressure (MAP) monitored by invasive blood pressure via an arterial catheter.
- Central venous pressure (CVP).
- Transcutaneous O2 saturation by pulse oximetry (SpO2),
- Airflow, airway pressure (Paw), tidal volume (Vt), end-tidal partial pressure of carbon dioxide (PETCO2)
- Immediately before the initiation of the study, the patients will be subjected to neuromuscular blockade with a cisatracurium intravenous bolus and continuous infusion titrated to achieve 0-2/4 twitches on facial nerve electrical stimulation.
- A nasogastric catheter with esophageal and gastric balloon will be placed. Esophageal pressure (Pes) will be measured during an end-inspiratory (PesEIO) and an end-expiratory occlusion (PesEEO) of the airway. The variation of esophageal pressure during tidal inflation (ΔPes) will be calculated as the difference between PesEIO and PesEEO. Transpulmonary pressure (PL) will be calculated as the difference between Paw and Pes (PL = Paw - Pes). The intragastric pressure will be measured only during an end-expiratory occlusion of the airway (IGP).
All study data will be transcribed directly on to standardized Case Report Forms (CRF).
Patients will be randomized to start the protocol with the controlled mechanical ventilation strategy or the high frequency oscillatory ventilation. A block-randomization scheme with opaque envelopes and block size of 2 will be used.
Study protocol:
Immediately after enrolment, Pes will be measured during an end-expiratory (PesEEO) and end-inspiratory occlusion (PesEIO). PEEP to reach a PLEEO of 0 cmH2O and PEEP to reach a PLEIO of 15 cmH2O will be calculated.
CMV phase A. PLEEO = 0
- Patients will be ventilated with CMV using the following parameters (in group 2 before starting PesEEO and PesEIO will be measured):
- Vt 6 ml/kg predicted body weight
- PEEP so that PLEEO = 0 cmH2O
- Respiratory Rate (RR) to reach pH 7.25-7.35
- FiO2 to have SpO2 ≥ 90%
- After 40 minutes at these settings, lung ultrasound will be performed to obtain a lung ultrasound score.
- After completing PLUS, TTE will be performed
- After completing TTE, EIT will be positioned and recordings of global and regional time courses of impedance changes and associated EIT images will be obtained
- Blood sample for cytokines measurement will be collected and the following parameters will be measured:
- Arterial blood gases
- Crs
- Alveolar dead space.
- PLEIO = 15
- Patients will be ventilated with the same Vt, RR and FiO2 of phase A. PEEP will be set at the value obtained to reach a PLEIO = 15 cmH2O.
- Same measurements will be repeated as in phase A (steps 2 to 5).
- PLEEO = 0
- Patients will be ventilated with the same Vt, RR and FiO2 of previous phases. PEEP will be set at the same value of phase A (PEEP so that PLEEO = 0 cmH2O).
- Same measurements will be repeated as in phase A (steps 2 to 5). PesEEO and PesEIO will be measured so that CMV phase is completed.
HFOV phase D. PL = 0
- Patients will be switched to HFOV. Pes will be measured and mPaw to reach a PLHFOV of 0 and of 15 will be calculated. Patients will be ventilated using the following parameters:
- Pressure amplitude 90 cmH2O
- mPaw to reach a PL of 0 cmH2O
- Respiratory Rate (RR) ≥ 5Hz to reach pH 7.25-7.35
- FiO2 to have SpO2 ≥ 90%
- Same measurements will be performed as in phase A (steps 2 to 4). Blood sample for cytokines measurement will be collected and the following parameters will be measured:
- Arterial blood gases.
- PL = 15
- Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 15 cmH2O.
- Same measurements will be performed as in phase D.
- PL = 0
- Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 0 cmH2O.
- Same measurements will be performed as in phase D. Then Pes will be measured and HFOV phase is completed.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group 1: CMV - HFOV | Experimental | Device: Targeting transpulmonary pressure to avoid VILIPatients in group 1 will start with conventional mechanical ventilation with different values of PEEP (A-PEEP so that PLEEO = 0 cmH2O, B- PEEP so that PLEIO = 15 cmH2O, C- PEEP so that PLEEO = 0 cmH2O) and then will be ventilated with high frequency oscillatory ventilation (D- mPaw so that PL = 0 cmH2O, E- mPaw so that PL = 15 cmH2O, F- mPaw so that PL = 0 cmH2O) Intervention: Device: Targeting transpulmonary pressure to avoid VILI |
| Group 2: HFOV - CMV | Experimental | Device: Targeting transpulmonary pressure to avoid VILIPatients in group 2 will start with high frequency oscillatory ventilation (D- mPaw so that PL = 0 cmH2O, E- mPaw so that PL = 15 cmH2O, F- mPaw so that PL = 0 cmH2O) and then will be ventilated with conventional mechanical ventilation with different values of PEEP (A-PEEP so that PLEEO = 0 cmH2O, B- PEEP so that PLEIO = 15 cmH2O, C- PEEP so that PLEEO = 0 cmH2O). Intervention: Device: Targeting transpulmonary pressure to avoid VILI |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- Moderate or severe ARDS, defined according to the Berlin definition (2);
- Endotracheal intubation or tracheostomy
Key exclusion criteria (5 listed)
- Severe heart failure/cardiogenic shock;
- Pulmonary arterial hypertension requiring systemic vasodilators;
- Contraindications to esophageal balloon: esophageal pathology (stricture, perforation, high grade of varices), recent history of esophageal or gastric surgery, upper GI tract bleeding, severe coagulopathy and nasal trauma;
- Contraindications to Electrical Impedance Tomography (EIT): a temporary or permanent pacemaker, or implantable cardioverter-defibrillator (ICD);
- Age < 16 years.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Targeting transpulmonary pressure to avoid VILISet different values of PEEP (CMV) and mPaw (HFOV) to obtain determined values of transpulmonary pressure (0 and 15 centimeters of water) and to determine the impact of ventilation on VILI | Device | Group 1: CMV - HFOV, Group 2: HFOV - CMV |
Primary outcome
Ventilator-induced lung injury (VILI) in patients with ARDS as measured by serum cytokines
Time frame: 1 hour after initiation of each experimental ventilation strategy
IL-6, TNF, IL-10, IL-1β, and IL-1ra and other cytokines will be detected in EDTA plasma with commercially available enzyme-linked immunosorbent assays (ELISA)
2 secondary outcomes
Assessment of lung recruitment and tidal overdistension
Time frame: 1 hour after initiation of each experimental ventilation strategy
Impact of transpulmonary pressure on right ventricular function (RV)
Time frame: 1 hour after initiation of each experimental ventilation strategy
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2015.
- Background: PubMed 9062352Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest. 1997 Mar 1;99(5):944-52. doi: 10.1172/JCI119259.
- Background: PubMed 16352797Fan E, Needham DM, Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA. 2005 Dec 14;294(22):2889-96. doi: 10.1001/jama.294.22.2889.
- Background: PubMed 18270352Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008 Feb 13;299(6):637-45. doi: 10.1001/jama.299.6.637.
- Background: PubMed 19001507Talmor D, Sarge T, Malhotra A, O'Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med. 2008 Nov 13;359(20):2095-104. doi: 10.1056/NEJMoa0708638. Epub 2008 Nov 11.
- Background: PubMed 24467647Akoumianaki E, Maggiore SM, Valenza F, Bellani G, Jubran A, Loring SH, Pelosi P, Talmor D, Grasso S, Chiumello D, Guerin C, Patroniti N, Ranieri VM, Gattinoni L, Nava S, Terragni PP, Pesenti A, Tobin M, Mancebo J, Brochard L; PLUG Working Group (Acute Respiratory Failure Section of the European Society of Intensive Care Medicine). The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med. 2014 Mar 1;189(5):520-31. doi: 10.1164/rccm.201312-2193CI.
- Background: PubMed 20851923Bouhemad B, Brisson H, Le-Guen M, Arbelot C, Lu Q, Rouby JJ. Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment. Am J Respir Crit Care Med. 2011 Feb 1;183(3):341-7. doi: 10.1164/rccm.201003-0369OC. Epub 2010 Sep 17.
- Background: PubMed 22392031Volpicelli G, Elbarbary M, Blaivas M, Lichtenstein DA, Mathis G, Kirkpatrick AW, Melniker L, Gargani L, Noble VE, Via G, Dean A, Tsung JW, Soldati G, Copetti R, Bouhemad B, Reissig A, Agricola E, Rouby JJ, Arbelot C, Liteplo A, Sargsyan A, Silva F, Hoppmann R, Breitkreutz R, Seibel A, Neri L, Storti E, Petrovic T; International Liaison Committee on Lung Ultrasound (ILC-LUS) for International Consensus Conference on Lung Ultrasound (ICC-LUS). International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012 Apr;38(4):577-91. doi: 10.1007/s00134-012-2513-4. Epub 2012 Mar 6.
- Background: PubMed 22672932Repesse X, Charron C, Vieillard-Baron A. Right ventricular failure in acute lung injury and acute respiratory distress syndrome. Minerva Anestesiol. 2012 Aug;78(8):941-8. Epub 2012 Jun 7.
- Background: PubMed 22324535Fichet J, Moreau L, Genee O, Legras A, Mercier E, Garot D, Dequin PF, Perrotin D. Feasibility of right ventricular longitudinal systolic function evaluation with transthoracic echocardiographic indices derived from tricuspid annular motion: a preliminary study in acute respiratory distress syndrome. Echocardiography. 2012 May;29(5):513-21. doi: 10.1111/j.1540-8175.2011.01650.x. Epub 2012 Feb 13.
- Background: PubMed 23339639Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD, Lamontagne F, Granton JT, Arabi YM, Arroliga AC, Stewart TE, Slutsky AS, Meade MO; OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):795-805. doi: 10.1056/NEJMoa1215554. Epub 2013 Jan 22.
- Background: PubMed 23339638Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, Rowan K, Cuthbertson BH; OSCAR Study Group. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):806-13. doi: 10.1056/NEJMoa1215716. Epub 2013 Jan 22.
- Background: PubMed 17038660Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, Slutsky AS, Gattinoni L, Ranieri VM. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007 Jan 15;175(2):160-6. doi: 10.1164/rccm.200607-915OC. Epub 2006 Oct 12.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Eddy Fan, MD, PhD principal investigator
University Health Network, Toronto
Francesca Facchin, MD principal investigator
University Health Network, Toronto
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Targeting transpulmonary pressure to avoid VILI in people with Respiratory Distress Syndrome, Adult and Ventilator-Induced Lung Injury, run by University of Toronto at 2 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 30 Jan 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ventilator-induced lung injury (VILI) in patients with ARDS as measured by serum cytokines (time frame: 1 hour after initiation of each experimental ventilation strategy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02342756, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2015.