Infants With Severe Acute Respiratory Distress Syndrome: The Prone Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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Short-Term Effect of Prone Positioning in Infants With Severe Acute Respiratory Distress Syndrome

Conditions
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Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Surfactant Dysfunction, Infant

Intervention / Treatment
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* Other: Prone positioning


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single center randomized controlled study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prone Group<br>Turn patient in prone position after surfactant administration. After 6 hours turn patient in supine position and perform EIT and LUS. | Other: Prone positioning<br>* Turn patient in prone position after surfactant administration.<br>|
| No Intervention: Supine Group<br>Leave patient in supine position after surfactant administration. After 6 hours perform EIT and LUS. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygenation saturation index | Oxygenation saturation index (OSI) defined by [FiO2 x mean airway pressure x 100]/Peripheral oxygen saturation (SpO2) in millibar [mbar] (wean FiO2 to maintain SpO2 ≤ 97% to calculate OSI). OSI values will be calculated after a stable value of SpO2 and mean airway pressure (MAP) will be reached (see ventilation management). The OSI gradient will be calculated as follows: 100*((OSI (0) - OSI (6h)) / OSI (0) = change of OSI in %. OSI (0) accounts for the OSI prior to the prone position (intervention) and OSI (6h) accounts for the OSI six hours after the intervention. | Change from baseline oxygenation saturation index at 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chang in Lung Ultrasound | Each lung (left and right) is divided into 6 areas (upper anterior, lower anterior, upper lateral, lower lateral, upper posterior, lower posterior). The Lung Ultrasound Score is assigned as follows: 0 indicates A-pattern (defined by the presence of the only A-lines); 1, B-pattern (defined as the presence of ≥3 well-spaced B-lines); 2, severe B pattern (defined as the presence of crowded and coalescent B-lines with or without consolidations limited to the subpleural space); and 3, extended consolidations. The total LUS score ranges from 0 (best) to 36. | Change from baseline LUS score at 6 hours | 
| Change in the Distribution of the End-Expiratory Lung Volume | End-expiratory lung impedance (EELV) is the average of the measured impedance at the end of expiration [arbitrary units]. | Change from baseline EELV at 6 hours | 
| Change in the Distribution of the Tidal Volume | Tidal volume is the average difference of end-inspiratory and end-expiratory impedance measurements [arbitrary units]. | Change from baseline tidal volume at 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Respiratory Distress Syndrome, Electrical Impedance Tomography, Lung Ultrasonography, Prone Position, Infants