Late Permissive Hypercapnia for Intubated and Ventilated Preterm Infants

Study Overview
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Brief Summary
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Preterm infants, less than 37 weeks gestation with respiratory distress syndrome, who remain ventilated between 7 and 14 days after birth will be randomized to a ventilator strategy of either a higher level of permissive hypercapnia or of a lower level of permissive hypercapnia to determine if either strategy will increase the number of alive ventilator-free days in the 28 days after randomization.

Detailed Description
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22.0 to 36.6 weeks gestational age preterm infants with respiratory distress syndrome, who remain ventilated between 7 and 14 days after birth will be randomized to one of two ventilator strategies: 1) a higher level of permissive hypercapnia or 2) a lower level of permissive hypercapnia to determine if either strategy will increase the number of alive ventilator-free days in the 28 days after randomization. After parental consent obtained, intubated, mechanically ventilated infants will be randomized by use of sequentially numbered sealed opaque envelopes to the treatment assignment. Randomized infants will be stratified by gestational age at delivery (< 26 weeks, ≥ 26 wks but less than 29 weeks, and ≥ 29 weeks). Multiple births will be randomized to the same group. The envelope will be opened only on days 7-14 when infant meets criteria. Clinicians will follow pre-specified algorithms of extubation and reintubation criteria to wean infants from mechanical ventilation. The ventilation algorithms may be set aside until the infant is deemed stable enough to allow resumption of the study algorithm. Infant will be extubated within 24 hours of meeting extubation criteria and documented on a single blood gas. A trial of extubation per attending physician is allowed independent of the trial protocol.All other care is per unit standard. Reports of routine follow-up after discharge in babies < 27 weeks gestation will be obtained to determine neurodevelopmental impairment on this subset of babies.

Official Title
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A Randomized Controlled Trial of pH-Controlled Late Permissive Hypercapnia for Intubated and Ventilated Preterm Infants

Conditions
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Premature Neonate

Intervention / Treatment
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* Other: Higher permissive hypercapnia
* Other: Lower Permissive Hypercapnia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age at least 22 but less than 37 weeks; Intubated on mechanical ventilation for respiratory distress syndrome on days 7-14 after birth; Admitted to Neonatal Intensive Care Unit before 7 days after birth; Informed consent per parent(s) Exclusion Criteria: Major malformation Neuromuscular condition that affects respiration Terminal illness Attending physician has made a decision to withhold or limit support for the infant

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 14 Days

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Higher permissive hypercapnia<br>Extubation criteria: partial pressure carbon dioxide (pCO2) ≥ 60mmHg with an upper limit ≤ 75mmHg; pH ≥ 7.20; oxygen saturation (SpO2) ≥ 88% with fraction of inspired oxygen (FiO2) ≤ 0.50; mean airway pressure (MAP) < 8 cm H2O, ventilator rate ≤ 20 bpm, amplitude < 2X MAP if on high frequency ventilation (HFV); hemodynamically stable (clinically acceptable blood pressure and perfusion per clinical team opinion). In addition, reintubation may occur if any of the following are met: PCO2 > 75mmHg; pH < 7.20; FiO2 ≥0.80 required to maintain SpO2 ≥ 88% for one hour; hemodynamic instability; clinically defined shock; repetitive apnea (> 1 episode per hour) requiring bag and mask ventilation; sepsis; and/or need for surgery. | Other: Higher permissive hypercapnia<br>* pCO2 ≥ 60mmHg with an upper limit ≤ 75mmHg; pH ≥ 7.20 from a capillary or arterial blood sample;<br>|
| Active Comparator: Lower permissive hypercapnia<br>Extubation criteria: pCO2 ≥ 40mmHg with an upper limit ≤ 55mmHg; pH ≥ 7.25; SpO2 ≥ 88% with FiO2 ≤ 0.50; mean airway pressure (MAP) < 8 cm H2O, ventilator rate ≤ 20 bpm, amplitude < 2X MAP if on high frequency ventilation (HFV); hemodynamically stable (clinically acceptable blood pressure and perfusion per clinical team opinion). In addition, reintubation may occur if any of the following are met: PCO2 > 55mmHg; pH < 7.25; FiO2 ≥0.80 required to maintain SpO2 ≥ 88% for one hour; hemodynamic instability; clinically defined shock; repetitive apnea (> 1 episode per hour) requiring bag and mask ventilation; sepsis; and/or need for surgery. | Other: Lower Permissive Hypercapnia<br>* pCO2 ≥ 40mmHg with an upper limit ≤ 55mmHg; pH ≥ 7.25 from a capillary or arterial blood sample;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alive Ventilator-free Days from Randomization to 28 Days after randomization | Number of days from time of randomization through 28 days after randomization | From randomization until 28 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Causes of Death | All causes of death between randomization and anticipated 120 days after birth | Randomization to 120 days after birth | 
| Incidence of bronchopulmonary dysplasia BPD | Defined as need for supplemental oxygen per physiologic definition | Measured at 36 weeks postmenstrual age | 
| Open label treatment with postnatal steroids for bronchopulmonary dysplasia | Any treatment with postnatal steroids for bronchopulmonary dysplasia | Randomization to 120 days after birth | 
| Number of days alive, Continuous Positive Airway Pressure (CPAP)-free | Number of days alive, not receiving CPAP from randomization to 28 days post randomization | Randomization to 28 days post randomization | 
| Number of days alive, supplemental oxygen free | Number of days alive, not receiving oxygen from randomization to 28 days post randomization | Randomization to 28 days post randomization | 
| Neurodevelopmental Impairment | Results of Bayley Scales of Development, Version III | Measured at 22-26 months corrected gestational age | 
| Growth Indices-Weight | Weekly weights taken per clinical standard | Randomization to 28 days post randomization | 
| Growth Indices-Head Circumference | Weekly head circumferences taken per clinical standard | Randomization to 28 days post randomization | 
| Pulmonary Hypertension | Documentation of presence of pulmonary hypertension by echocardiogram | Routine echocardiogram performed at 28+/- 7 days after birth | 
| Intracranial Hemorrhage | Evidence of new or increased intracranial hemorrhage as documented on clinically obtained cranial ultrasounds closest to day 28 after birth | On routine head ultrasound closest to 28 days after birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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respiratory distress syndrome, permissive hypercapnia, ventilator strategy