Breathing Effort in Covid-19 Pneumonia: Effects of Positive Pressure, Inspired Oxygen Fraction and Decubitus

• ClinicalTrials.gov Identifier: NCT04885517
• Recruitment Status: Recruiting
• First Posted: May 13, 2021
• Last Update Posted: May 14, 2021
• Sponsor: San Luigi Gonzaga Hospital
• Information provided by (Responsible Party): Pietro Caironi, San Luigi Gonzaga Hospital

Tracking Information

• First Submitted Date: May 11, 2021
• First Posted Date: May 13, 2021
• Last Update Posted Date: May 14, 2021
• Actual Study Start Date: February 1, 2021
• Estimated Primary Completion Date: August 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 12, 2021)

Esophageal pressure swings at different levels of positive end-expiratory pressure (PEEP) [ Time Frame: 160 minutes ]

The main outcome of the study is represented by the difference in esophageal pressure swings (expiratory minus inspiratory) between the three levels of end expiratory pressure applied (0-7-12 cmH2O)

Original Primary Outcome Measures (submitted: May 11, 2021)

Esophageal pressure swings at different levels of PEEP [ Time Frame: 160 minutes ]

The main outcome of the study is represented by the difference in esophageal pressure swings (expiratory minus inspiratory) between the three levels of end expiratory pressure applied (0-7-12 cmH2O)

Current Secondary Outcome Measures (submitted: May 12, 2021)

• Esophageal pressure swings at different levels of inspired oxygen fraction [ Time Frame: 160 minutes ]
  One of the secondary outcomes of the study is represented by the difference in esophageal pressure swings (expiratory minus inspiratory) between the two levels of FiO2 applied (0.5-1)
• Esophageal pressure swings at different decubiti [ Time Frame: 160 minutes ]
  One of the secondary outcomes of the study is represented by the difference in esophageal pressure swings (expiratory minus inspiratory) between the three decubiti applied (seated, supine, prone)

Original Secondary Outcome Measures (submitted: May 11, 2021)

• Esophageal pressure swings at different levels of FiO2 [ Time Frame: 160 minutes ]
  One of the secondary outcomes of the study is represented by the difference in esophageal pressure swings (expiratory minus inspiratory) between the two levels of FiO2 applied (0.5-1)
• Esophageal pressure swings at different decubiti [ Time Frame: 160 minutes ]
  One of the secondary outcomes of the study is represented by the difference in esophageal pressure swings (expiratory minus inspiratory) between the three decubiti applied (seated, supine, prone)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Breathing Effort in Covid-19 Pneumonia: Effects of Positive Pressure, Inspired Oxygen Fraction and Decubitus
• Official Title: Dynamic Transpulmonary Pressure in Covid-19 Pneumonia: Effects of Positive Pressure, Inspired Oxygen Fraction and Decubitus
• Brief Summary: The study investigates the role of positive pressure, inspired oxygen fraction and different decubiti (seated, supine, prone) on breathing effort (as assessed by esophageal pressure swings) in Covid-19 pneumonia (at different disease stages) and in other causes of respiratory failure. The hypothesis is that positive pressure might be deleterious in terms of breathing effort if the main pathological mechanism associated with Sars-CoV-2 infection in the lung is not alveolar damage (as in other causes of respiratory failure) but vascular impairment as previously reported. The effects of high inspired oxygen fractions and decubiti might also be different with respect to other causes of respiratory failure.
• Detailed Description: In spite of the overwhelming numbers of the current pandemic, many questions remain open regarding the pathophysiology of Covid-19 associated pneumonia. While some features of the disease (such as the oxygenation improvement associated with proning and/or continuous positive airway pressure) seem to line up with other causes of pneumonia characterized by primary alveolar damage, specific characteristics have been reported about Sars-CoV-2 lung infection which suggest a certain degree of parenchymal preservation and a predominant role of vascular impairment: the dissociation between lung volume and gas exchange, and the so called "happy hypoxemia" both evoke the possibility of mechanisms other than the loss of aeration as causes of hypoxia. Accordingly, evidence are now growing on the role of vascular dysregulation in this regard. It is probable, as previously put forward, that different stages exist in the disease which may account for the discordant findings of previous studies seeking to either associate or separate Covid-19 pneumonia and other causes of respiratory failure. In the present study we will compare the effects of three currently used approaches to improve gas exchange (continuous positive airway pressure, external oxygen administration and decubiti variations) in three different populations (1) early Covid-19 pneumonia, 2) severe late Covid-19 pneumonia and 3) non-Covid-19 pneumonia) in terms of breathing effort as assessed by esophageal pressure swings: our aim is to evaluate, in these populations, the real benefits (beyond the previously reported ones on gas exchange) of such strategies on lung rest. Our hypothesis is that, at least in the early stages of Covid-19 (and as opposed to other causes of respiratory failure), the application of positive pressure might be deleterious if no potential for recruitment, but rather a primary vascular impairment, is associated with hypoxia. If this will be the case the same (or a similar) degree of oxygenation improvement and a safer pattern of ventilation might be attained with the simple administration of oxygen or decubiti variations without the application of positive pressure, thus completely changing the current standards for the treatment of Covid-19 pneumonia.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: COVID-19 Pneumonia

Intervention

Device: Esophageal catheter

Patients are equipped with an esophageal catheter: positioning is performed after accurate nasopharyngeal anesthesia with lidocaine

Study Arms

• Experimental: Spontaneous breathing, Venturi Mask FiO2 0.5, seated decubitus
  Patient will be evaluated after 20 minutes of spontaneous breathing, with FiO2 0.5 (Venturi Mask), during seated decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Spontaneous breathing, Non Rebreathing Mask, seated decubitus
  Patient will be evaluated after 20 minutes of spontaneous breathing, with FiO2 1 (Non Rebreathing Mask), during seated decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Continuous Positive Airway Pressure (CPAP) 7 cmH2O, FiO2 0.5, seated decubitus
  Patient will be evaluated after 20 minutes of CPAP (7 cmH2O), with FiO2 0.5, during seated decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Continuous Positive Airway Pressure (CPAP) 7 cmH2O, FiO2 0.5, supine decubitus
  Patient will be evaluated after 20 minutes of CPAP (7 cmH2O), with FiO2 0.5, during supine decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Continuous Positive Airway Pressure (CPAP) 7 cmH2O, FiO2 0.5, prone decubitus
  Patient will be evaluated after 20 minutes of CPAP (7 cmH2O), with FiO2 0.5, during prone decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Continuous Positive Airway Pressure (CPAP) 7 cmH2O, FiO2 1, seated decubitus
  Patient will be evaluated after 20 minutes of CPAP (7 cmH2O), with FiO2 1.0, during seated decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Continuous Positive Airway Pressure (CPAP) 12 cmH2O, FiO2 0.5, seated decubitus
  Patient will be evaluated after 20 minutes of CPAP (12 cmH2O), with FiO2 0.5, during seated decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter
• Experimental: Continuous Positive Airway Pressure (CPAP) 12 cmH2O, FiO2 1, seated decubitus
  Patient will be evaluated after 20 minutes of CPAP (7 cmH2O), with FiO2 1.0, during seated decubitus. Respiratory, haemodynamics, and data on blood gas analysis will be obtained.
  Intervention: Device: Esophageal catheter

Publications *

• Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020 May 15;201(10):1299-1300. doi: 10.1164/rccm.202003-0817LE. No abstract available.
• Couzin-Frankel J. The mystery of the pandemic's 'happy hypoxia'. Science. 2020 May 1;368(6490):455-456. doi: 10.1126/science.368.6490.455. No abstract available.
• Aliberti S, Radovanovic D, Billi F, Sotgiu G, Costanzo M, Pilocane T, Saderi L, Gramegna A, Rovellini A, Perotto L, Monzani V, Santus P, Blasi F. Helmet CPAP treatment in patients with COVID-19 pneumonia: a multicentre cohort study. Eur Respir J. 2020 Oct 15;56(4):2001935. doi: 10.1183/13993003.01935-2020. Print 2020 Oct.
• Elharrar X, Trigui Y, Dols AM, Touchon F, Martinez S, Prud'homme E, Papazian L. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA. 2020 Jun 9;323(22):2336-2338. doi: 10.1001/jama.2020.8255.
• Chiumello D, Busana M, Coppola S, Romitti F, Formenti P, Bonifazi M, Pozzi T, Palumbo MM, Cressoni M, Herrmann P, Meissner K, Quintel M, Camporota L, Marini JJ, Gattinoni L. Physiological and quantitative CT-scan characterization of COVID-19 and typical ARDS: a matched cohort study. Intensive Care Med. 2020 Dec;46(12):2187-2196. doi: 10.1007/s00134-020-06281-2. Epub 2020 Oct 21.
• Marini JJ, Gattinoni L. Management of COVID-19 Respiratory Distress. JAMA. 2020 Jun 9;323(22):2329-2330. doi: 10.1001/jama.2020.6825. No abstract available.
• Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With COVID-19. JAMA. 2020 May 12;323(18):1839-1841. doi: 10.1001/jama.2020.4914. No abstract available.
• Gattinoni L, Giosa L, Bonifazi M, Pasticci I, Busana M, Macri M, Romitti F, Vassalli F, Quintel M. Targeting transpulmonary pressure to prevent ventilator-induced lung injury. Expert Rev Respir Med. 2019 Aug;13(8):737-746. doi: 10.1080/17476348.2019.1638767. Epub 2019 Jul 5.
• Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017 Feb 15;195(4):438-442. doi: 10.1164/rccm.201605-1081CP.
• Tonelli R, Fantini R, Tabbi L, Castaniere I, Pisani L, Pellegrino MR, Della Casa G, D'Amico R, Girardis M, Nava S, Clini EM, Marchioni A. Early Inspiratory Effort Assessment by Esophageal Manometry Predicts Noninvasive Ventilation Outcome in De Novo Respiratory Failure. A Pilot Study. Am J Respir Crit Care Med. 2020 Aug 15;202(4):558-567. doi: 10.1164/rccm.201912-2512OC.
• Goligher EC, Jonkman AH, Dianti J, Vaporidi K, Beitler JR, Patel BK, Yoshida T, Jaber S, Dres M, Mauri T, Bellani G, Demoule A, Brochard L, Heunks L. Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort. Intensive Care Med. 2020 Dec;46(12):2314-2326. doi: 10.1007/s00134-020-06288-9. Epub 2020 Nov 2.
• Apigo M, Schechtman J, Dhliwayo N, Al Tameemi M, Gazmuri RJ. Development of a work of breathing scale and monitoring need of intubation in COVID-19 pneumonia. Crit Care. 2020 Jul 31;24(1):477. doi: 10.1186/s13054-020-03176-y. No abstract available.
• Vaporidi K, Akoumianaki E, Telias I, Goligher EC, Brochard L, Georgopoulos D. Respiratory Drive in Critically Ill Patients. Pathophysiology and Clinical Implications. Am J Respir Crit Care Med. 2020 Jan 1;201(1):20-32. doi: 10.1164/rccm.201903-0596SO.
• Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, Camporota L. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med. 2020 Jun;46(6):1099-1102. doi: 10.1007/s00134-020-06033-2. Epub 2020 Apr 14. No abstract available.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 11, 2021): 72
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 1, 2021
• Estimated Primary Completion Date: August 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Group 1 (Covid-19 early pneumonia)

• Age > 18
• Positive Sars-CoV 2 nasal swab
• interstitial pneumonia at either CT scan or chest X-ray
• Respiratory failure requiring CPAP for less than 48 hours
• FiO2 ≤0.5 and CPAP≤10 cmH2O

Group 2 (Covid-19 severe pneumonia)

• Age > 18
• Positive Sars-CoV 2 nasal swab
• interstitial pneumonia at either CT scan or chest X-ray
• Respiratory failure requiring CPAP

• Signs of severity with CPAP 10 cmH2O and FiO2 0.5: pulse oximetry (SpO2) ≤ 93% associated to either:

  • Dyspnea
  • Two or more signs of increased respiratory effort (respiratory rate ≥25 bpm, use of accessory inspiratory muscles , tirage, intercostal space depression, nasal flaring, expiratory abdominal efforts, PaCO2 < 35)

Group 3 (Non Covid-19 pneumonia)

• Age > 18
• Negative Sars-CoV 2 nasal swab
• CT scan or chest X-ray non compatible with Covid-19 associated pneumonia
• Respiratory failure requiring CPAP

Exclusion Criteria:

Group 1 (Covid-19 early pneumonia)

• Concomitant chronic pulmonary disease
• Chronic heart failure New York Heart Association (NYHA) 3-4
• Bacterial pulmonary associated infection (diagnosed or suspected)
• Pulmonary embolism
• Acute cardiogenic pulmonary edema

• Signs of severity with CPAP 10 cmH2O and FiO2 0.5: SpO2≤ 93% associated to either:

  • Dyspnea
  • Two or more signs of increased respiratory effort (respiratory rate ≥25 bpm, use of accessory inspiratory muscles , tirage, intercostal space depression, nasal flaring, expiratory abdominal efforts, PaCO2 < 35)
• At least one sign of respiratory fatigue/decompensation (pH<7.30 with PaCO2 >45, respiratory rate <15 bpm, paradoxal abdominal breathing, mental status alteration)

Group 2 (Covid-19 severe pneumonia)

• Concomitant chronic pulmonary disease
• Chronic heart failure NYHA 3-4
• Bacterial pulmonary associated infection (diagnosed or suspected)
• Pulmonary embolism
• Acute cardiogenic pulmonary edema
• At least one sign of respiratory fatigue/decompensation (pH<7.30 with PaCO2 >45, respiratory rate <15 bpm, paradoxal abdominal breathing, mental status alteration)

Group 3 (Non Covid-19 pneumonia)

• Concomitant chronic pulmonary disease
• Chronic heart failure NYHA 3-4
• Bacterial pulmonary associated infection (diagnosed or suspected)
• Pulmonary embolism
• Acute cardiogenic pulmonary edema
• At least one sign of respiratory fatigue/decompensation (pH<7.30 with PaCO2 >45, respiratory rate <15 bpm, paradoxal abdominal breathing, mental status alteration)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pietro Caironi, Pr; +390119026386; pietro.caironi@unito.it

• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT04885517
• Other Study ID Numbers: 2782
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Pietro Caironi, San Luigi Gonzaga Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: San Luigi Gonzaga Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Pietro Caironi, MD; San Luigi Gonzaga Hospital
• Principal Investigator: Lorenzo Giosa, MD; San Luigi Gonzaga Hospital

• PRS Account: San Luigi Gonzaga Hospital
• Verification Date: May 2021