Dead Space and Inhaled Nitric Oxide in Pediatric Acute Respiratory Distress Syndrome (DiNO)

The goal of this observational study is to determine whether a marker of dead space (the end-tidal to alveolar dead space fraction [AVDSf]) is more strongly associated with mortality risk than markers of oxygenation abnormality (oxygenation index) and to determine whether dead space (AVDSf) is an important marker of heterogeneity in the inhaled nitric oxide (iNO) treatment effect for children with acute respiratory distress syndrome (ARDS).

The study aims are:

1. To validate AVDSf for risk stratification of mortality in pediatric ARDS
2. To determine if there is heterogeneity in treatment effect for iNO defined by AVDSf
3. To detect the association between AVDSf and microvascular dysfunction trajectory and whether iNO therapy modifies this association

This is a prospective, multicenter observational study of 1260 mechanically ventilated children with moderate to severe ARDS. In a subgroup of 450 children with severe ARDS, longitudinal blood samples will be obtained to measure plasma protein markers.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome

• Study Type: Observational
• Enrollment (Estimated): 1260

Contacts and Locations

• Study Contact: Name: Jeni Kwok; Phone Number: 3233617939; Email: dinostudy@chla.usc.edu
• Study Contact Backup: Name: Anoopindar Bhalla, MD; Phone Number: 3233617939; Email: abhalla@chla.usc.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital Los Angeles
      • Contact: Jeni Kwok, JD; Phone Number: 16330 323-660-2450; Email: ymkwok@chla.usc.edu
      • Principal Investigator: Anoopindar Bhalla, MD
  • Colorado
    • Denver, Colorado, United States, 80204
      • Not yet recruiting
      • Children's Hospital Colorado
      • Contact: Aline Maddux; Email: aline.maddux@childrenscolorado.org
      • Principal Investigator: Aline Maddux, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Not yet recruiting
      • Boston Children's Hospital
      • Contact: Sally Vitali; Email: sally.vitali@childrens.harvard.edu
      • Principal Investigator: Sally Vitali, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Active, not recruiting
      • University of Michigan / CS Mott Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Not yet recruiting
      • University of Nebraska Medical Center / Children's Hospital and Medical Center
      • Contact: Eleanor Gradidge; Email: egradidge@childrensnebraska.org
      • Principal Investigator: Eleanor Gradidge, MD
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Not yet recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Steve Standage; Email: steve.standage@cchmc.org
      • Principal Investigator: Steve Standage, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Not yet recruiting
      • Children's Hospital of Philadelphia
      • Contact: Adam Himebauch; Email: himebaucha@chop.edu
      • Principal Investigator: Adam Himebauch, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Not yet recruiting
      • Texas Children's Hospital Baylor College of Medicine
      • Contact: Manpreet Virk; Email: manpreet.virk@bcm.edu
      • Principal Investigator: Manpreet Virk, MD
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Not yet recruiting
      • American Family Children's Hospital / University of Wisconsin-Madison
      • Contact: Awni Al-Subu; Email: al-subu@pediatrics.wisc.edu
      • Principal Investigator: Awni Al-Subu, MD
    • Milwaukee, Wisconsin, United States, 53226
      • Not yet recruiting
      • Children's Hospital of Wisconsin / Medical College of Wisconsin
      • Contact: Jasmine Dowell; Email: jdowell@mcw.edu
      • Principal Investigator: Jasmine Dowell, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Children with moderate to severe ARDS

Description

Inclusion Criteria:

• Age >37 weeks corrected gestational age to 21 years, including adults lacking the capacity to consent.
• Within 72 hours of the start of invasive mechanical ventilation and meet the criteria for pediatric ARDS (new infiltrate on chest imaging and a known ARDS risk factor within 7 days of the onset of hypoxemia) and either meet criteria for moderate or severe pediatric ARDS between 4-72 hours of IMV (OI ≥ 8 or OSI ≥ 7.5) OR have an OI ≥ 20 or an OSI ≥ 14 x 15 minutes between 0-4 hours of IMV.
• Subgroup of children eligible for longituduinal Blood Collection: Children with severe PARDS (OI ≥ 16 or an OSI ≥ 12 between 4-72 hours of IMV) or those with an OI ≥ 20 or an OSI ≥ 14 for 15 minutes between 0-4 hours of IMV will be eligible for collection of longitudinal plasma samples.

Exclusion Criteria:

• Non-conventional invasive mechanical ventilation (i.e. High Frequency Oscillatory Ventilation, Airway Pressure Release Ventilation) at the time of ICU admission
• ECMO or iNO (or other inhaled pulmonary vasodilator therapy) at the time of ICU admission
• Significant lower airways obstruction (examination of ventilator and capnography waveforms by site study or medical team)
• Air leak >20% (endotracheal tube, tracheostomy tube, or thoracostomy tube)
• Home Invasive Mechanical Ventilation
• Cyanotic Congenital Heart Disease
• Previous enrollment in the DiNO study
• Do not resuscitate order at the time of pediatric ARDS diagnosis.
• Blood gas not obtained prior to initiation of ECMO, iNO, or non-conventional ventilation.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Children with moderate to severe ARDS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that experience all-cause mortality within 28 days from start of invasive mechanical ventilation	28 day all-cause mortality	From the start of invasive mechanical ventilation to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that experience all-cause mortality within 90 days from start of invasive mechanical ventilation	90 day all-cause mortality	From the start of invasive mechanical ventilation to 90 days
28-Day Ventilator-Free Days	The number of days within the first 28 days of invasive mechanical ventilation for ARDS that a patient is alive and free of mechanical ventilation.	From the start of invasive mechanical ventilation to 28 days
The days on invasive mechanical ventilation for survivors of ARDS	The number of days that a patient that survives is on invasive mechanical ventilation (up to 90 days)	From the start of invasive mechanical ventilation to the end of invasive mechanical ventilation (or 90 days after the start of invasive mechanical ventilation if the patient is still on invasive mechanical ventilation at 90 days)
The number of non-pulmonary organ failure free days within the first 14 days of invasive mechanical ventilation	Organ failure criteria will be determined with the Pediatric Organ Dysfunction Information Update Mandate. We will identify the number of days in the first 14 days of ARDS that a patient is alive and without any non-pulmonary organ failures.	From the start of invasive mechanical ventilation to 14 days
The number of non-pulmonary organ failures 21 days after the start of invasive mechanical ventilation	Organ failure criteria will be determined with the Pediatric Organ Dysfunction Information Update Mandate. The number of non-pulmonary organ failures on day 21 after the start of invasive mechanical ventilation will be identified. Patients that experience mortality prior to 21 days will be considered to have failure of all non-pulmonary organs.	21 days after the start of invasive mechanical ventilation
The number of non-pulmonary organ failures 28 days after the start of invasive mechanical ventilation	Organ failure criteria will be determined with the Pediatric Organ Dysfunction Information Update Mandate. The number of non-pulmonary organ failures on day 28 after the start of invasive mechanical ventilation will be identified. Patients that experience mortality prior to 28 days will be considered to have failure of all non-pulmonary organs.	28 days after the start of invasive mechanical ventilation
The number of non-pulmonary organs that newly meet failure criteria or have an increase in the severity of organ failure within the first 14 days of invasive mechanical ventilation	Organ failure criteria will be determined with the Pediatric Organ Dysfunction Information Update Mandate. We will identify the number of organs during the first 14 days of invasive mechanical ventilation that either have worsening of the severity of failure or new failure after the first day of invasive mechanical ventilation.	From the start of invasive mechanical ventilation to 14 days
The development of renal failure within the first 14 days of invasive mechanical ventilation	Renal organ failure criteria will be determined with the Pediatric Organ Dysfunction Information Update Mandate. We will identify whether during the first 14 days of invasive mechanical ventilation there is new renal failure after the first day of invasive mechanical ventilation.	From the start of invasive mechanical ventilation to 14 days
Non-pulmonary organ failure phenotypes that develop within the first 14 days of invasive mechanical ventilation	Organ failure criteria will be determined with the Pediatric Organ Dysfunction Information Update Mandate. We will identify 14-day non-pulmonary organ failure free phenotypes using clustering analyses.	From the start of invasive mechanical ventilation to 14 days
Cumulative non-pulmonary organ failure severity in the first 14 days of invasive mechanical ventilation	Organ failure scores will be quantified daily with the Pediatric Logistic Organ Dysfunction (PELOD-2) score. Children that die will be assigned the maximum value. The score will be summed over the first 14 days of invasive mechanical ventilation.	From the start of invasive mechanical ventilation to 14 days
The change in functional status score from baseline to hospital discharge	The baseline functional status score and the intensive care unit discharge functional status score will be compared and new morbidities will be identified. If the patient is still in the hospital after 90 days of the start of invasive mechanical ventilation the functional status score at 90 days will be used rather than the functional status score at hospital discharge.	From baseline to hospital discharge (or 90 days after the start of invasive mechanical ventilation)
The change in pediatric overall performance score from baseline to hospital discharge	The baseline pediatric overall performance score and the hospital discharge pediatric overall performance score will be compared and new morbidities will be identified. If the patient is still in the hospital after 90 days of the start of invasive mechanical ventilation the pediatric overall performance score at 90 days will be used rather than the pediatric overall performance score at hospital discharge.	From baseline to hospital discharge (or 90 days after the start of invasive mechanical ventilation)
The change in pediatric cerebral performance score from baseline to hospital discharge	The baseline pediatric cerebral performance score and the hospital discharge pediatric cerebral performance score will be compared and new morbidities will be identified. If the patient is still in the hospital after 90 days of the start of invasive mechanical ventilation the pediatric cerebral performance score at 90 days will be used rather than the pediatric cerebral performance score at hospital discharge.	From baseline to hospital discharge (or 90 days after the start of invasive mechanical ventilation)
All-cause mortality or the use of extracorporeal membrane oxygenation (ECMO) therapy within 28 days after the start of invasive mechanical ventilation	Patients who experience mortality or use of ECMO within 28 days of the start of invasive mechanical ventilation	From the start of invasive mechanical ventilation to 28 days

Collaborators and Investigators

• Sponsor: Children's Hospital Los Angeles
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Anoopindar M Bhalla, MD, Children's Hospital Los Angeles

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: November 8, 2024
• First Submitted That Met QC Criteria: November 13, 2024
• First Posted (Actual): November 15, 2024

Study Record Updates

• Last Update Posted (Actual): November 15, 2024
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Pediatrics; Mechanical Ventilation; Inhaled Nitric Oxide
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease; Lung Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: CHLA-24-00209; R01HL173488 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified public use dataset will be created.
• IPD Sharing Time Frame: available in 2029

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No