Clinical trial NCT05002478: Infants with Severe Acute Respiratory Distress Syndrome: the Prone Trial
Official title: Short-Term Effect of Prone Positioning in Infants with Severe Acute Respiratory Distress Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS)
Surfactant Dysfunction
Infant
Keywords: Acute Respiratory Distress Syndrome
Electrical Impedance Tomography
Lung Ultrasonography
Prone Position
Infants
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2021-08-12
Enrollment: 14
Sex: ALL
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single center randomized controlled study
Primary purpose: TREATMENT

Brief summary: The main objective is to determine the short-term effect of prone positioning in infants with infection-associated severe acute respiratory distress syndrome. The investigators compare oxygenation parameters and measurements from electrical impedance tomography (EIT) and lung ultrasonography (LUS) in mechanically ventilated infants in prone position versus supine position after surfactant administration.

Detailed description: The acute respiratory distress syndrome (ARDS) is an acute lung injury that can be triggered by pulmonary (direct lung injury) and extrapulmonary (indirect lung injury) etiologies. Pediatric ARDS (pARDS) occurs in approximately 3% of children admitted to intensive care units (ICUs) and is associated with approximately 17% mortality. The primary etiologies of pARDS have been summarized as pneumonia (35%), aspiration (15%), sepsis (13%), near-drowning (9%), cardiac disease (7%), and other clinical conditions (21%). ARDS manifests as pulmonary inflammation, alveolar edema, and hypoxemic respiratory failure. Mechanical ventilation remains an essential component in the care of patients with ARDS. Many adjunctive treatments rely on pathophysiological considerations. The pathophysiology of ARDS is characterized by inflammatory, proliferative, and fibrotic phases. The different phases induce a ventilation-perfusion mismatch. Inflammation causes surfactant inactivation and depletion. A number of clinical studies have reported clinical benefits following the instillation of exogenous surfactant in pediatric patients with acute respiratory failure. On the other side, prone positioning seem to be a promising intervention in critically ill infants and children with infection-associated acute lung injury. However, data conflict on the use of prone positioning in pediatric patients with acute lung injury.

Turning patients with moderate to severe lung disease into prone position has shown many positive effects. Prolonged intervals of prone positioning have been associated with a decrease in mortality in adult patients with acute respiratory failure. An increase in partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) has been described after 4 hours in prone position in adult patients with severe acute respiratory failure. Similarly, a decrease of the oxygenation index has been found after 8 hours of prone positioning in adult patients with respiratory failure from coronavirus disease of 2019 (COVID-19) associated acute respiratory distress syndrome. The process of prone positioning appeared safe also in critically ill infants and children. In a randomized control trial, it has been shown that in 90% of prone positioning oxygenation index decreased of more than 10% in children with acute lung injury.

Electrical impedance tomography (EIT) and lung ultrasound (LUS) are two non-invasive methods to monitor aeration and lung function parameters. EIT can quantify regional distribution of ventilation as well as improvement in end-expiratory air content. EIT has been used at bedside in critically ill adult patients to measure effects of prone position and also in infants with respiratory distress syndrome. On the other side, LUS has become an increasingly popular diagnostic bedside tool for lung examination. It is considered reliable and fast to detect various lung-related pathologies, such as pneumonia, atelectasis, pneumothorax, and interstitial syndrome.

The main objective is to determine the short-term effect of prone positioning in infants with infection-associated severe acute respiratory distress syndrome. To accomplish this, oxygenation parameters and measurements from EIT and LUS will be compared in mechanically ventilated infants in prone position versus supine position after surfactant administration.

Eligibility criteria: Inclusion Criteria:

* Patients hospitalized at Pediatric Intensive Care Unit (PICU) or Neonatal Intensive Care Unit (NICU) of the Medical University Vienna.
* Patients aged \>36 weeks (corrected gestational age) and \<24 months.
* Patient intubated and mechanically ventilated for at least 6 hours, with an expected requirement of invasive ventilatory support for at least 12 hours.
* Clinical picture strongly suggestive for acute bronchiolitis or pneumonia (fever, fine crackles, prolonged expiration, lung hyperinflation and/or findings of new infiltrates consistent with acute pulmonary parenchymal disease on chest X-ray).
* Severe pediatric acute respiratory distress syndrome (ARDS), defined by OSI ≥12.3 (wean FIO2 to maintain SpO2 ≤ 97% to calculate oxygen saturation index).
* Written informed consent obtained from parents.

Exclusion Criteria:

* Clinical context

  * Need for O2 supplementation to maintain SpO2\>94% in the 4 weeks preceding hospitalization in the PICU/NICU
  * Cyanotic congenital heart disease Cardiogenic pulmonary edema
  * Severe pulmonary hypertension
  * Untreated pneumothorax
  * Severe neurological abnormalities
  * Other severe congenital anomalies such as congenital diaphragmatic hernia
  * Ongoing cardiopulmonary resuscitation or limitation of life support
* Contradictions for prone positioning (adapted from Guerin, C., et al., Prone positioning in severe acute respiratory distress syndrome. N Engl J Med, 2013. 368(23): p. 2159-68):

  * Intracranial pressure \>30 millimeters of mercury (mmHg) in supine position or cerebral perfusion pressure \<60 mmHg
  * Massive hemoptysis requiring an immediate surgical or interventional radiology procedure
  * Tracheal surgery or sternotomy during the previous 15 days
  * Serious facial trauma or facial surgery during the previous 15 days
  * Deep venous thrombosis treated for less than 2 days
  * Cardiac pacemaker inserted in the last 2 days
  * Unstable spine, femur, or pelvic fractures
  * Use of extracorporeal membrane oxygenation (ECMO) before inclusion
  * Lung transplantation
  * Burns on more than 20% of the body surface
* Other non-inclusion criteria

  * Indication not to attempt resuscitation
  * Patient already recruited for other clinical studies
  * Patients who already received surfactant in the last 4 weeks
  * Thoracic skin lesions or wounds on the thorax, where the EIT-electrode-belt would be placed

Primary outcomes:
measure: Change in Oxygenation saturation index
timeFrame: Change from baseline oxygenation saturation index at 6 hours
Secondary outcomes:
measure: Chang in Lung Ultrasound
timeFrame: Change from baseline LUS score at 6 hours
measure: Change in the Distribution of the End-Expiratory Lung Volume
timeFrame: Change from baseline EELV at 6 hours
measure: Change in the Distribution of the Tidal Volume
timeFrame: Change from baseline tidal volume at 6 hours
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Tobias Werther
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cheifetz IM. Pediatric ARDS. Respir Care. 2017 Jun;62(6):718-731. doi: 10.4187/respcare.05591.
citation: Khemani RG, Smith L, Lopez-Fernandez YM, Kwok J, Morzov R, Klein MJ, Yehya N, Willson D, Kneyber MCJ, Lillie J, Fernandez A, Newth CJL, Jouvet P, Thomas NJ; Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology (PARDIE) Investigators; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study. Lancet Respir Med. 2019 Feb;7(2):115-128. doi: 10.1016/S2213-2600(18)30344-8. Epub 2018 Oct 22.
citation: Santschi M, Randolph AG, Rimensberger PC, Jouvet P; Pediatric Acute Lung Injury Mechanical Ventilation Investigators; Pediatric Acute Lung Injury and Sepsis Investigators Network; European Society of Pediatric and Neonatal Intensive Care. Mechanical ventilation strategies in children with acute lung injury: a survey on stated practice pattern*. Pediatr Crit Care Med. 2013 Sep;14(7):e332-7. doi: 10.1097/PCC.0b013e31828a89a2.
citation: Orloff KE, Turner DA, Rehder KJ. The Current State of Pediatric Acute Respiratory Distress Syndrome. Pediatr Allergy Immunol Pulmonol. 2019 Jun 1;32(2):35-44. doi: 10.1089/ped.2019.0999. Epub 2019 Jun 17.
citation: Mok YH, Lee JH, Rehder KJ, Turner DA. Adjunctive treatments in pediatric acute respiratory distress syndrome. Expert Rev Respir Med. 2014 Dec;8(6):703-16. doi: 10.1586/17476348.2014.948854. Epub 2014 Aug 13.
citation: Gattinoni L, Taccone P, Carlesso E, Marini JJ. Prone position in acute respiratory distress syndrome. Rationale, indications, and limits. Am J Respir Crit Care Med. 2013 Dec 1;188(11):1286-93. doi: 10.1164/rccm.201308-1532CI.
citation: De Luca D, Cogo P, Kneyber MC, Biban P, Semple MG, Perez-Gil J, Conti G, Tissieres P, Rimensberger PC. Surfactant therapies for pediatric and neonatal ARDS: ESPNIC expert consensus opinion for future research steps. Crit Care. 2021 Feb 22;25(1):75. doi: 10.1186/s13054-021-03489-6.
citation: Amigoni A, Pettenazzo A, Stritoni V, Circelli M. Erratum to: Surfactants in Acute Respiratory Distress Syndrome in Infants and Children: Past, Present and Future. Clin Drug Investig. 2017 Jul;37(7):711. doi: 10.1007/s40261-017-0544-x. No abstract available.
citation: Luchetti M, Ferrero F, Gallini C, Natale A, Pigna A, Tortorolo L, Marraro G. Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure. Pediatr Crit Care Med. 2002 Jul;3(3):261-268. doi: 10.1097/00130478-200207000-00011.
citation: Jat KR, Chawla D. Surfactant therapy for bronchiolitis in critically ill infants. Cochrane Database Syst Rev. 2015 Aug 24;2015(8):CD009194. doi: 10.1002/14651858.CD009194.pub3.
citation: Willson DF, Thomas NJ, Markovitz BP, Bauman LA, DiCarlo JV, Pon S, Jacobs BR, Jefferson LS, Conaway MR, Egan EA; Pediatric Acute Lung Injury and Sepsis Investigators. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA. 2005 Jan 26;293(4):470-6. doi: 10.1001/jama.293.4.470.
citation: Ward NS. Effects of prone position ventilation in ARDS. An evidence-based review of the literature. Crit Care Clin. 2002 Jan;18(1):35-44. doi: 10.1016/s0749-0704(03)00063-0.
citation: Lupton-Smith A, Argent A, Rimensberger P, Frerichs I, Morrow B. Prone Positioning Improves Ventilation Homogeneity in Children With Acute Respiratory Distress Syndrome. Pediatr Crit Care Med. 2017 May;18(5):e229-e234. doi: 10.1097/PCC.0000000000001145.
citation: Sud S, Friedrich JO, Taccone P, Polli F, Adhikari NK, Latini R, Pesenti A, Guerin C, Mancebo J, Curley MA, Fernandez R, Chan MC, Beuret P, Voggenreiter G, Sud M, Tognoni G, Gattinoni L. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med. 2010 Apr;36(4):585-99. doi: 10.1007/s00134-009-1748-1. Epub 2010 Feb 4.
citation: Curley MA, Hibberd PL, Fineman LD, Wypij D, Shih MC, Thompson JE, Grant MJ, Barr FE, Cvijanovich NZ, Sorce L, Luckett PM, Matthay MA, Arnold JH. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA. 2005 Jul 13;294(2):229-37. doi: 10.1001/jama.294.2.229.
citation: Munshi L, Del Sorbo L, Adhikari NKJ, Hodgson CL, Wunsch H, Meade MO, Uleryk E, Mancebo J, Pesenti A, Ranieri VM, Fan E. Prone Position for Acute Respiratory Distress Syndrome. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2017 Oct;14(Supplement_4):S280-S288. doi: 10.1513/AnnalsATS.201704-343OT.
citation: Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20.
citation: Chatte G, Sab JM, Dubois JM, Sirodot M, Gaussorgues P, Robert D. Prone position in mechanically ventilated patients with severe acute respiratory failure. Am J Respir Crit Care Med. 1997 Feb;155(2):473-8. doi: 10.1164/ajrccm.155.2.9032181.
citation: Mittermaier M, Pickerodt P, Kurth F, de Jarcy LB, Uhrig A, Garcia C, Machleidt F, Pergantis P, Weber S, Li Y, Breitbart A, Bremer F, Knape P, Dewey M, Doellinger F, Weber-Carstens S, Slutsky AS, Kuebler WM, Suttorp N, Muller-Redetzky H. Evaluation of PEEP and prone positioning in early COVID-19 ARDS. EClinicalMedicine. 2020 Nov;28:100579. doi: 10.1016/j.eclinm.2020.100579. Epub 2020 Oct 11.
citation: Fineman LD, LaBrecque MA, Shih MC, Curley MA. Prone positioning can be safely performed in critically ill infants and children. Pediatr Crit Care Med. 2006 Sep;7(5):413-22. doi: 10.1097/01.PCC.0000235263.86365.B3.
citation: Baudin F, Emeriaud G, Essouri S, Beck J, Portefaix A, Javouhey E, Guerin C. Physiological Effect of Prone Position in Children with Severe Bronchiolitis: A Randomized Cross-Over Study (BRONCHIO-DV). J Pediatr. 2019 Feb;205:112-119.e4. doi: 10.1016/j.jpeds.2018.09.066. Epub 2018 Nov 14.
citation: Becher T, Kott M, Schadler D, Vogt B, Meinel T, Weiler N, Frerichs I. Influence of tidal volume on ventilation inhomogeneity assessed by electrical impedance tomography during controlled mechanical ventilation. Physiol Meas. 2015 Jun;36(6):1137-46. doi: 10.1088/0967-3334/36/6/1137. Epub 2015 May 26.
citation: Dalla Corte F, Mauri T, Spinelli E, Lazzeri M, Turrini C, Albanese M, Abbruzzese C, Lissoni A, Galazzi A, Eronia N, Bronco A, Maffezzini E, Pesenti A, Foti G, Bellani G, Grasselli G. Dynamic bedside assessment of the physiologic effects of prone position in acute respiratory distress syndrome patients by electrical impedance tomography. Minerva Anestesiol. 2020 Oct;86(10):1057-1064. doi: 10.23736/S0375-9393.20.14130-0. Epub 2020 May 22.
citation: Corsini I, Parri N, Ficial B, Dani C. Lung ultrasound in the neonatal intensive care unit: Review of the literature and future perspectives. Pediatr Pulmonol. 2020 Jul;55(7):1550-1562. doi: 10.1002/ppul.24792. Epub 2020 Apr 27.
citation: Khemani RG, Smith LS, Zimmerman JJ, Erickson S; Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015 Jun;16(5 Suppl 1):S23-40. doi: 10.1097/PCC.0000000000000432.
citation: Curley MA, Arnold JH, Thompson JE, Fackler JC, Grant MJ, Fineman LD, Cvijanovich N, Barr FE, Molitor-Kirsch S, Steinhorn DM, Matthay MA, Hibberd PL; Pediatric Prone Positioning Study Group. Clinical trial design--effect of prone positioning on clinical outcomes in infants and children with acute respiratory distress syndrome. J Crit Care. 2006 Mar;21(1):23-32; discussion 32-7. doi: 10.1016/j.jcrc.2005.12.004.
citation: Rey-Santano C, Mielgo VE, Andres L, Ruiz-del-Yerro E, Valls-i-Soler A, Murgia X. Acute and sustained effects of aerosolized vs. bolus surfactant therapy in premature lambs with respiratory distress syndrome. Pediatr Res. 2013 May;73(5):639-46. doi: 10.1038/pr.2013.24. Epub 2013 Feb 12.
citation: Bianco F, Ricci F, Catozzi C, Murgia X, Schlun M, Bucholski A, Hetzer U, Bonelli S, Lombardini M, Pasini E, Nutini M, Pertile M, Minocchieri S, Simonato M, Rosa B, Pieraccini G, Moneti G, Lorenzini L, Catinella S, Villetti G, Civelli M, Pioselli B, Cogo P, Carnielli V, Dani C, Salomone F. From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy. Respir Res. 2019 Jul 2;20(1):134. doi: 10.1186/s12931-019-1096-9.