Esophageal Pressure-Guided Optimal PEEP/mPaw in CMV and HFOV: The EPOCH Study

Respiratory Distress Syndrome, Adult Clinical Trial

— EPOCH  

Official title:

Esophageal Pressure-Guided Optimal PEEP/mPaw in CMV and HFOV: The EPOCH Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02342756
• Other study ID #: 14-8253
• Status: Active, not recruiting
• Phase: N/A
• First received: January 15, 2015
• Last updated: January 29, 2015
• Start date: January 2015
• Est. completion date: December 2017

Study information

• Verified date: January 2015
• Source: University of Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review Committee
• Study type: Interventional

Clinical 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. 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.

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:

1. 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.

2. 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.

1. All patients will be supine, with the head of the bed elevated to 30 degrees.

2. All patients will be deeply sedated and ventilated according to clinical practice.

3. 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)

4. 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.

5. 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

1. Patients will be ventilated with CMV using the following parameters (in group 2 before starting PesEEO and PesEIO will be measured):

1. Vt 6 ml/kg predicted body weight

2. PEEP so that PLEEO = 0 cmH2O

3. Respiratory Rate (RR) to reach pH 7.25-7.35

4. FiO2 to have SpO2 ≥ 90%

2. After 40 minutes at these settings, lung ultrasound will be performed to obtain a lung ultrasound score.

3. After completing PLUS, TTE will be performed

4. 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

5. Blood sample for cytokines measurement will be collected and the following parameters will be measured:

• Arterial blood gases

• Crs

• Alveolar dead space.

B. PLEIO = 15

1. 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.

2. Same measurements will be repeated as in phase A (steps 2 to 5).

C. PLEEO = 0

1. 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).

2. 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

1. 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:

1. Pressure amplitude 90 cmH2O

2. mPaw to reach a PL of 0 cmH2O

3. Respiratory Rate (RR) ≥ 5Hz to reach pH 7.25-7.35

4. FiO2 to have SpO2 ≥ 90%

2. 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.

E. PL = 15

1. Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 15 cmH2O.

2. Same measurements will be performed as in phase D.

F. PL = 0

1. Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 0 cmH2O.

2. Same measurements will be performed as in phase D. Then Pes will be measured and HFOV phase is completed.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

• Moderate or severe ARDS, defined according to the Berlin definition (2);

• Endotracheal intubation or tracheostomy

Exclusion Criteria:

• 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lung Injury
• Lung Injury
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Ventilator-Induced Lung Injury

Intervention

Device:
• Targeting transpulmonary pressure to avoid VILI
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

Locations

Country	Name	City	State
Canada	Intensive Care Unit (ICU) of Mount Sinai Hospital	Toronto	Ontario
Canada	Medical Surgical ICU - Toronto General Hospital	Toronto	Ontario

Sponsors (3)

Lead Sponsor	Collaborator
University of Toronto	Nihon Kohden, University Health Network, Toronto

Country where clinical trial is conducted

Canada, 

References & Publications (14)

Akoumianaki E, Maggiore SM, Valenza F, Bellani G, Jubran A, Loring SH, Pelosi P, Talmor D, Grasso S, Chiumello D, Guérin 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. Review. — View Citation

ARDS 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. — View Citation

Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967 Aug 12;2(7511):319-23. — View Citation

Bouhemad 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. — View Citation

Fan E, Needham DM, Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA. 2005 Dec 14;294(22):2889-96. Review. — View Citation

Ferguson 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. — View Citation

Fichet J, Moreau L, Genée 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. — View Citation

Meade 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. — View Citation

Repessé 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. Review. — View Citation

Talmor 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. — View Citation

Terragni 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. Epub 2006 Oct 12. — View Citation

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. — View Citation

Volpicelli 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. Review. — View Citation

Young 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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ventilator-induced lung injury (VILI) in patients with ARDS as measured by serum cytokines	IL-6, TNF, IL-10, IL-1ß, and IL-1ra and other cytokines will be detected in EDTA plasma with commercially available enzyme-linked immunosorbent assays (ELISA)	1 hour after initiation of each experimental ventilation strategy	Yes
Secondary	Assessment of lung recruitment and tidal overdistension	Lung ultrasound score (LUS), global and regional impedance (EIT).	1 hour after initiation of each experimental ventilation strategy	No
Secondary	Impact of transpulmonary pressure on right ventricular function (RV)	Measurements: Transthoracic echocardiography (TTE).	1 hour after initiation of each experimental ventilation strategy	No