Sigh in Acute Hypoxemic Respiratory Failure

NCT03201263 | Completed

• 1 other identifier: Sigh study
• Study Type: interventional
• Target: 258
• Locations: 7 countries
• Sites: 19

Brief Summary

Mortality of intubated acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) patients remains considerably high (around 40%) (Bellani 2016). Early implementation of a specific mechanical ventilation mode that enhances lung protection in patients with mild to moderate AHRF and ARDS on spontaneous breathing may have a tremendous impact on clinical practice. Previous studies showed that the addition of cyclic short recruitment maneuvers (Sigh) to assisted mechanical ventilation: improves oxygenation without increasing ventilation pressures and FiO2; decreases the tidal volumes by decreasing the patient's inspiratory drive; increases the EELV by regional alveolar recruitment; decreases regional heterogeneity of lung parenchyma; decreases patients' inspiratory efforts limiting transpulmonary pressure; improves regional compliances. Thus, physiologic studies generated the hypothesis that addition of Sigh to pressure support ventilation (PSV, the most common assisted mechanical ventilation mode) might decrease ventilation pressures and FiO2, and limit regional lung strain and stress through various synergic mechanisms potentially yielding decreased risk of VILI, faster weaning and improved clinical outcomes. The investigators conceived a pilot RCT to verify clinical feasibility of the addition of Sigh to PSV in comparison to standard PSV. The investigators will enrol 258 intubated spontaneously breathing patients with mild to moderate AHRF and ARDS admitted to the ICU. Patients will be randomized through an online automatic centralized and computerized system to the following study groups (1:1 ratio):

• PSV group: will be treated by protective PSV settings until day 28 or death or performance of spontaneous breathing trial (SBT);
• PSV+Sigh group: will be treated by protective PSV settings with the addition of Sigh until day 28 or death or performance of spontaneous breathing trial (SBT). Indications on ventilation settings, weaning, spontaneous breathing trial and rescue treatment will be specified.

Conditions

Respiratory Failure; Acute Respiratory Distress Syndrome; Ventilator Lung

Outcome Measures

Primary Outcomes (1)

• Clinical feasibility of PSV+Sigh vs. standard of carde (PSV)

  Feasibility will be assessed by measuring the number of patients in each group experiencing at least one of the following failure criteria: * switch to controlled ventilation following presence of predefined criteria; * use of PEEP ≥15 cmH2O, prone positioning, inhaled nitric oxide, extracorporeal membrane oxygenation; * re-intubation within 48 hours from extubation following predefined criteria. Based on previous data, the expected rate of failure in patients undergoing PSV will be 22% and we hypothesize a rate of 15% for patients in the PSV+Sigh group. Furthermore, we assume a non-inferiority of the treatment with PSV+Sigh, with a tolerance of 5%. Thus, a sample size of 258 patients (with 129 patients per study arm) will be sufficient to assess feasibility of the PSV+Sigh strategy in this pilot phase with power of 0.8 and alpha 0.05.

  2 years

Secondary Outcomes (6)

• Clinical safety of PSV+Sigh comparing adverse events between 2 groups

  2 years

• Quantification of the prevalence of Sigh responders

  2 years

• Mortality

  2 years

• Ventilator-free days

  2 years

• Number of days on assisted ventilation until day 28

  28 days

Study Arms (2)

PSV group

ACTIVE COMPARATOR

Will be treated by standard of care for patients undergoing assisted mechanical ventilation (e.g., protective PSV settings, protocolized weaning, etc.).

Procedure: Standard of care

PSV+Sigh group

EXPERIMENTAL

Will be treated by standard of care for patients undergoing assisted mechanical ventilation (e.g., protective PSV settings, protocolized weaning, etc.) + Sigh (short cyclic recruitment breath once every minute) until death or spontaneous breathing trial and extubation.

Procedure: Sigh

Interventions

Sigh PROCEDURE

Application of cyclic pressure control breath delivered at 30 cmH2O for 3 seconds once per minute in patients undergoing pressure support ventilation

Also known as: Short cyclic recruitment breath

PSV+Sigh group

Standard of care PROCEDURE

Standard of care

PSV group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• patients intubated since \>24 hours and ≤7 days,
• undergoing PSV since \>4 and ≤24 hours,
• PaO2/FiO2 ratio ≤300 mmHg (measured at clinical positive end-expiratory pressure \[PEEP\] and FiO2 values)
• clinical PEEP ≥5 cmH2O,
• Richmond Agitation-Sedation Scale (RASS) value of -2 to 0

You may not qualify if:

• patients with PEEP ≥15 cmH2O;
• PaCO2 \>60 mmHg;
• Arterial pH \<7.30;
• Age \<18 year-old;
• PaO2/FiO2 ratio ≤100 mmHg (measured at clinical PEEP and FiO2 values);
• central nervous system or neuromuscular disorders;
• history of severe chronic obstructive pulmonary disease or fibrosis;
• AHRF fully explained by cardiac failure or fluid overload (e.g., left ventricle ejection fraction ≤40% with no other risk factor);
• impossibility to titrate sedation to desired RASS value of -2 to 0;
• evidence of active air leak from the lung (e.g., pneumothorax);
• cardiovascular instability (e.g., systolic blood pressure \[SBP\] \<90 mmHg despite vasopressors);
• clinical suspect of elevated intracranial pressure;
• extracorporeal support;
• moribund status;
• refusal by the attending physician.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead
• European Society of Intensive Care Medicine: collaborator
• University of Milan: collaborator
• University of Milano Bicocca: collaborator

Study Sites (19)

Tiantan Hospital

Beijing, China

Location

CHU Angers

Angers, France

Location

CHU Clermont-Ferrand

Clermont-Ferrand, France

Location

Hospital de la croix rousse

Lyon, France

Location

GH Sud Ile-de-France

Melun, France

Location

UNIVERSITÄTSKLINIKUM Schleswig-Holstein Campus Kiel

Kiel, Germany

Location

General hospital of Larissa

Larissa, Greece

Location

Ospedale di Catanzaro Pugliese Ciaccio

Catanzaro, Italy

Location

Arcispedale Sant'Anna

Ferrara, Italy

Location

Ospedale San Martino

Genova, Italy

Location

Ospedale Maggiore Policlinico Cà Granda

Milan, 20122, Italy

Location

Istituto Clinico Humanitas

Milan, Italy

Location

Ospedale L. Sacco

Milan, Italy

Location

Ospedale Niguarda

Milan, Italy

Location

Ospedale San Gerardo

Monza, Italy

Location

Ospedale Gemelli

Rome, Italy

Location

Vall d'Hebron

Barcelona, Spain

Location

Foundacion J Diaz

Madrid, Spain

Location

Barking, Havering and Redbridge Hospital

Romford, United Kingdom

Location

Related Publications (27)

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• Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2014 Mar 6;370(10):980. doi: 10.1056/NEJMc1400293. No abstract available.

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• Mauri T, Foti G, Zanella A, Bombino M, Confalonieri A, Patroniti N, Bellani G, Pesenti A. Long-term extracorporeal membrane oxygenation with minimal ventilatory support: a new paradigm for severe ARDS? Minerva Anestesiol. 2012 Mar;78(3):385-9.

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• Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, Bruno F, Slutsky AS. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999 Jul 7;282(1):54-61. doi: 10.1001/jama.282.1.54.

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• Kallet RH, Matthay MA. Hyperoxic acute lung injury. Respir Care. 2013 Jan;58(1):123-41. doi: 10.4187/respcare.01963.

  PMID: 23271823 BACKGROUND

• Bellani G, Guerra L, Musch G, Zanella A, Patroniti N, Mauri T, Messa C, Pesenti A. Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury. Am J Respir Crit Care Med. 2011 May 1;183(9):1193-9. doi: 10.1164/rccm.201008-1318OC. Epub 2011 Jan 21.

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  PMID: 23263584 BACKGROUND

• Foti G, Cereda M, Sparacino ME, De Marchi L, Villa F, Pesenti A. Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med. 2000 May;26(5):501-7. doi: 10.1007/s001340051196.

  PMID: 10923722 BACKGROUND

• Patroniti N, Foti G, Cortinovis B, Maggioni E, Bigatello LM, Cereda M, Pesenti A. Sigh improves gas exchange and lung volume in patients with acute respiratory distress syndrome undergoing pressure support ventilation. Anesthesiology. 2002 Apr;96(4):788-94. doi: 10.1097/00000542-200204000-00004.

  PMID: 11964584 BACKGROUND

• Nacoti M, Spagnolli E, Bonanomi E, Barbanti C, Cereda M, Fumagalli R. Sigh improves gas exchange and respiratory mechanics in children undergoing pressure support after major surgery. Minerva Anestesiol. 2012 Aug;78(8):920-9. Epub 2012 Apr 27.

  PMID: 22531559 BACKGROUND

• Mauri T, Eronia N, Abbruzzese C, Marcolin R, Coppadoro A, Spadaro S, Patroniti N, Bellani G, Pesenti A. Effects of Sigh on Regional Lung Strain and Ventilation Heterogeneity in Acute Respiratory Failure Patients Undergoing Assisted Mechanical Ventilation. Crit Care Med. 2015 Sep;43(9):1823-31. doi: 10.1097/CCM.0000000000001083.

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• Tabuchi A, Nickles HT, Kim M, Semple JW, Koch E, Brochard L, Slutsky AS, Pries AR, Kuebler WM. Acute Lung Injury Causes Asynchronous Alveolar Ventilation That Can Be Corrected by Individual Sighs. Am J Respir Crit Care Med. 2016 Feb 15;193(4):396-406. doi: 10.1164/rccm.201505-0901OC.

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• Guldner A, Braune A, Carvalho N, Beda A, Zeidler S, Wiedemann B, Wunderlich G, Andreeff M, Uhlig C, Spieth PM, Koch T, Pelosi P, Kotzerke J, de Abreu MG. Higher levels of spontaneous breathing induce lung recruitment and reduce global stress/strain in experimental lung injury. Anesthesiology. 2014 Mar;120(3):673-82. doi: 10.1097/ALN.0000000000000124.

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• Moraes L, Santos CL, Santos RS, Cruz FF, Saddy F, Morales MM, Capelozzi VL, Silva PL, de Abreu MG, Garcia CS, Pelosi P, Rocco PR. Effects of sigh during pressure control and pressure support ventilation in pulmonary and extrapulmonary mild acute lung injury. Crit Care. 2014 Aug 12;18(4):474. doi: 10.1186/s13054-014-0474-4.

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• Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, Hibbert CL, Truesdale A, Clemens F, Cooper N, Firmin RK, Elbourne D; CESAR trial collaboration. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009 Oct 17;374(9698):1351-63. doi: 10.1016/S0140-6736(09)61069-2. Epub 2009 Sep 15.

  PMID: 19762075 RESULT

• Rezoagli E, Fornari C, Fumagalli R, Grasselli G, Volta CA, Navalesi P, Knafelj R, Brochard L, Pesenti A, Mauri T, Foti G; Pleural Pressure Working Group (PLUG). Heterogeneous impact of Sighs on mortality in patients with acute hypoxemic respiratory failure: insights from the PROTECTION study. Ann Intensive Care. 2024 Oct 5;14(1):153. doi: 10.1186/s13613-024-01385-0.

  PMID: 39368033 DERIVED

• Mauri T, Foti G, Fornari C, Grasselli G, Pinciroli R, Lovisari F, Tubiolo D, Volta CA, Spadaro S, Rona R, Rondelli E, Navalesi P, Garofalo E, Knafelj R, Gorjup V, Colombo R, Cortegiani A, Zhou JX, D'Andrea R, Calamai I, Vidal Gonzalez A, Roca O, Grieco DL, Jovaisa T, Bampalis D, Becher T, Battaglini D, Ge H, Luz M, Constantin JM, Ranieri M, Guerin C, Mancebo J, Pelosi P, Fumagalli R, Brochard L, Pesenti A; PROTECTION Trial Collaborators. Sigh in Patients With Acute Hypoxemic Respiratory Failure and ARDS: The PROTECTION Pilot Randomized Clinical Trial. Chest. 2021 Apr;159(4):1426-1436. doi: 10.1016/j.chest.2020.10.079. Epub 2020 Nov 13.

  PMID: 33197403 DERIVED

• Mauri T, Foti G, Fornari C, Constantin JM, Guerin C, Pelosi P, Ranieri M, Conti S, Tubiolo D, Rondelli E, Lovisari F, Fossali T, Spadaro S, Grieco DL, Navalesi P, Calamai I, Becher T, Roca O, Wang YM, Knafelj R, Cortegiani A, Mancebo J, Brochard L, Pesenti A; Protection Study Group. Pressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial. Trials. 2018 Aug 29;19(1):460. doi: 10.1186/s13063-018-2828-8.

  PMID: 30157955 DERIVED

MeSH Terms

Conditions

Respiratory Insufficiency; Respiratory Distress Syndrome

Interventions

SigH protein, bacteria; Standard of Care

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Lung Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Tommaso Mauri, MD

  Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  PRINCIPAL INVESTIGATOR

• Laurent Brochard, MD

  St Michael Hospital, Toronto, Canada

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised controlled trial, 2 groups, 1:1 randomisation

Study Record Dates

• First Submitted: June 19, 2017
• First Posted: June 28, 2017
• Study Start: December 20, 2017
• Primary Completion: May 9, 2019
• Study Completion: May 9, 2019
• Last Updated: April 23, 2021

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); IT (9); ES (2); GB (1); GR (1); CN (1); FR (4)