Delayed Cord Clamping With Oxygen In Extremely Low Gestation Infants (DOXIE)

This study is being conducted to compare the incidence of preterm infants (up to 28+6 weeks GA) who achieve a peripheral oxygen saturation of 80 percent by 5 minutes of life (MOL) given mask CPAP/PPV with an FiO2 of 1.0 during DCC for 90 seconds (HI Group) to infants given mask CPAP/PPV with an FiO2 of .30 during DCC for 90 seconds (LO Group).

Study Overview

• Status: Recruiting
• Conditions: Respiratory Insufficiency; Hyperoxia; IVH- Intraventricular Hemorrhage; Extreme Prematurity; Hypoxia Neonatal
• Intervention / Treatment: Procedure: Delayed Cord Clamping with Low Oxygen concentration; Procedure: Delayed Cord Clamping with High Oxygen concentration

Detailed Description

Prenatal consent will be obtained on infant's with estimated gestational age up to 28+6 weeks. Shortly before delivery, infant's will be randomly assigned to receive either Low oxygen concentration (FiO2 .30) OR High oxygen concentration (FiO2 1.0) during 90 seconds of delayed cord clamping.

Randomization and intervention will remain blinded to the clinical care team during the entire study period. The research team member will open a randomization card when notified of a subject's impending birth, review the protocol with the obstetric provider performing the procedure, set-up the sterile stabilization bed, and note the time it takes from delivery until the clamping and cutting of the umbilical cord in both groups.

The research team member will set the oxygen blender as indicated by the randomization card and cover the blender to blind the FiO2 setting. The research team member will not be involved in the clinical care of the infant. The oxygen blender will be concealed from the clinical care team to ensure resuscitation maneuvers will not be biased.

Data will be submitted to the statistician, who will remain blinded to the intervention for the duration of the study.

At delivery, the infant will be placed on a platform that allows the infant to be close to the mother and the umbilical cord to remain intact for DCC. These beds are equipped with an oxygen blender, humidifier, t-piece resuscitator with mask, necessary to provide CPAP/PPV. At some centers the bed will be equipped with a radian warmer (Ceramotherm, Wyer GmbH, Germany) to maintain thermoregulation on the infant during delayed cord clamping.

If an infant is randomized to the DCC and Low Oxygen concentration (DCC LO group), the following procedure will ensue:

During delayed cord clamping, the infant will be gently stimulated by drying the infant with a sterile towel and provide CPAP by 30 seconds of life. During delayed cord clamping, breathing assistance with CPAP of 5 cm H20 and a FiO2 0.3 will be provided.

If an infant is randomized to the DCC and High Oxygen concentration (DCC HI group), the following procedure will ensue:

During delayed cord clamping, the infant will be gently stimulated by drying the infant with a sterile towel and provide CPAP by 30 seconds of life. During delayed cord clamping, breathing assistance with CPAP of 5 cm H20 and a FiO2 1.0 will be provided.

Patency of the airway in both groups will be assessed by a Colorimetric CO2 detector. Lack of color change will indicate that the airway is not patent (obstructed), the pressure is not sufficient to expand the lungs, there was excessive air leak, or there was no or inadequate pulmonary blood flow. If there is no color change, the neonatal provider will reposition and reattempt to open the airway, if no improvement they will initiate PPV (starting PIP of 20 cm H20) by 60 seconds of life. Cord clamping will occur at 90 seconds or greater and the infant will be transferred to a standard neonatal warmer and resuscitated per NRP guidelines.

Additionally, when available heart rate data will be collected using a non-invasive dry-electrode monitor, (NeoBeat, Laerdal Medical, Stavanger, Norway) and applied over the infant's chest or abdomen to provide continuous display of heart rate during 90 seconds of DCC.

Pulse oximetry, ECG sensors and Near-Infrared Spectroscopy (NIRS) sensors will be applied after cord clamping. The NIRS sensor will be placed on the infant's forehead. Cerebral StO2, SpO2, blood pressure (once in the NICU) and Heart rate will be recorded every two seconds and linked with other variables. These variables will continue to be recorded for the first 24 hours of life.

Blood sample will be collected at two different time points: Cord blood sample (T1: Cord blood collected after the cord is cut) and at 2 hours of life or NICU admission (T2). This is extra few drops of blood that is drawn from the baby for medical purposes (cord blood from cord gases and admission blood work up).

Samples will be tested for oxidized and reduced glutathione which are the most reliable and comprehensive biomarkers of oxidative stress.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anup Katheria, MD; Phone Number: 858-939-4170; Email: anup.katheria@sharp.com
• Study Contact Backup: Name: Felix Ines, RCP-RRT; Phone Number: 858-939-4136; Email: felix.ines@sharp.com

Study Locations

• United States
  • California
    • Davis, California, United States, 95618
      • Recruiting
      • University of California Davis
      • Contact: Payam Vali, MD; Phone Number: 916-734-8672; Email: pvali@ucdavis.edu
    • San Diego, California, United States, 92123
      • Recruiting
      • Sharp Mary Birch Hospital for Women and Newborns
      • Contact: Felix Ines, RCP-RRT; Phone Number: 858-939-4136; Email: felix.ines@sharp.com
      • Contact: Anup C Katheria, MD; Phone Number: 858-939-4198; Email: anup.katheria@sharp.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• up to 28+6 weeks Gestational age
• Single and Multiple pregnancy
• All modes of delivery (vaginally or caesarean section)

Exclusion Criteria:

• Parents decline consent
• Congenital anomalies of the newborn
• Bleeding Accreta
• Monochorionic multiples with evidence of TTTS
• Fetal or maternal risk (i.e. compromise)
• Preterm Premature Rupture of Membranes prior to 20 weeks gestation
• Parents request no resuscitation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: DCC and Low Oxygen Concentration; During 90 seconds of delayed cord clamping, the infant will receive gentle stimulation and start CPAP by 30 seconds of life at an FiO2 .30, with CPAP of 5 cmH20. If the infant is apneic or there is no Pedicap color change the team will begin positive pressure ventilation (starting PIP of 20 cmH20) by 60 seconds of life. The infant will remain on this support up until the umbilical cord is clamped at 90 seconds or greater. Once the cord is clamped the infant resuscitation will continue according to unit protocol.	Procedure: Delayed Cord Clamping with Low Oxygen concentration; During delayed umbilical cord clamping of 90 seconds, breathing assistance with CPAP/PPV and low oxygen concentration (FiO2 0.30) will be provided.; Other Names: DCC with Low Oxygen concentration; DCC LO group
Experimental: DCC and High Oxygen Concentration; During 90 seconds of delayed cord clamping, the infant will receive gentle stimulation and start CPAP by 30 seconds of life at an FiO2 1.0, with CPAP of 5 cmH20. If the infant is apneic or there is no Pedicap color change the team will begin positive pressure ventilation (starting PIP of 20 cmH20) by 60 seconds of life. The infant will remain on this support up until the umbilical cord is clamped at 90 seconds or greater. Once the cord is clamped the infant resuscitation will continue according to unit protocol.	Procedure: Delayed Cord Clamping with High Oxygen concentration; During delayed umbilical cord clamping of 90 seconds, breathing assistance with CPAP/PPV and high oxygen concentration (FiO2 1.0) will be provided.; Other Names: DCC with High Oxygen concentration; DCC HI group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of administration of oxygen during delayed cord clamping and it's impact on the incidence of preterm infants (up to 28 +6 weeks) who achieve a peripheral oxygen saturation of 80 percent by 5 minutes of life	To assess the feasibility and compare the incidence of preterm infants (up to 28+6 weeks GA) who achieve a peripheral oxygen saturation of 80 percent by 5 MOL given mask CPAP/PPV with an FiO2 of 1.0 during DCC for 90 seconds (HI Group) to infants given mask CPAP/PPV with an FiO2 of .30 during DCC for 90 seconds (LO Group).	by 5 minutes of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All Grade IVH	Any Intraventricular Hemorrhage (grades 1-4)	Through study completion at hospital discharge, up to 6 months corrected gestational age (CGA)
Frequency of Grade III and IV intraventricular hemorrhage	Intraventricular hemorrhages (grades 3-4) (bleeding in the brain parenchyma and/or ventricular dilation	Through study completion at hospital discharge, up to 6 months corrected gestational age (CGA)
Resuscitation interventions	Resuscitation interventions including intubation, chest compressions, medications	In the first 10 minutes of life
Changes in heart rate (BPM) in the first 10 minutes of life	Changes in heart rate (BPM) in the first 10 minutes of life	In the first 10 minutes of life

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Inspired fractional oxygen (FiO2)	Changes in Inspired fractional oxygen (FiO2)	In the first 10 minutes of life
Duration of Hypoxia	Duration of Hypoxia (defined as oxygen saturation<25th percentile of target ranges defined by Dawson et al.) in the first 10 minutes after birth	The first 10 minutes of life in the delivery room
Duration of Hyperoxia	Duration of Hyperoxia (defined as oxygen saturation>95%) in the first 10 minutes after birth	The first 10 minutes of life in the delivery room
Changes in Mean airway pressure, MAP (cm H20)	Changes in Mean airway pressure, MAP (cm H20)	In the first 10 minutes of life
Duration of Positive Pressure Ventilation	Duration of positive pressure ventilation	The first 10 minutes of life in the delivery room
Blood pressures in the first 24 hours of life	Blood pressures every hour in the first 24 hours of life	In the first 24 hours of life
Cerebral tissue oxygenation in the first 24 hours of life	Cerebral tissue oxygenation in the first 24 hours of life	In the first 24 hours of life
Average oxygen saturation in the first 5 minutes after birth	Oxygen saturation in the first 5 minutes after birth	by 5 minutes of life
Average Heart rate in the first 5 minutes after birth	Heart rate in the first 5 minutes after birth	by 5 minutes of life
Intubation in the Delivery room or Neonatal Intensive Care Unit (NICU)	Intubation in the Delivery room or Neonatal Intensive Care Unit (NICU)	Birth through study completion at discharge, up to 6 months of corrected gestational age
Lowest and Highest Hemoglobin and/or Hematocrit	Hemoglobin and/or Hematocrit levels (before transfusion)	First 24 hours of life
Mean arterial blood pressure	Mean arterial blood pressure (collected hourly)	First 24 hours of life
Medication for Low Blood Pressure	Medication for Low Blood Pressure (e.g. hydrocortisone or pressors)	First 24 hours of life
CRIB-II (Clinical Risk Index for Babies)	CRIB-II (Clinical Risk Index for Babies)	First 12 hours of life
Duration of mechanical ventilation and/or CPAP	Number of days on mechanical ventilation and/or CPAP	Birth through study completion at discharge, up to 6 months of corrected gestational age
Surfactant administration	Surfactant administration	Immediately after intervention through study completion at hospital discharge, up to 6 months of corrected gestational age
Number of RBC Transfusions since birth	Number of RBC Transfusions since birth	First 10 days after birth
Patent Ductus Arteriosus requiring pharmacological or surgical treatment	Patent Ductus Arteriosus requiring pharmacological or surgical treatment	Through study completion at discharge, up to 6 months of corrected gestational age
Spontaneous Intestinal Perforation (SIP) requiring surgery or peritoneal drain	Spontaneous Intestinal Perforation (SIP) requiring surgery or peritoneal drain	Through study completion at discharge, up to 6 months of corrected gestational age
Necrotizing Enterocolitis (Modified Bell's stage 2-3)	Necrotizing Enterocolitis (Modified Bell's stage 2-3)	Through study completion at discharge, up to 6 months of corrected gestational age
Bronchopulmonary Dysplasia (mode of respiratory support administered at 36 weeks postmenstrual age; as defined and categorized in; Jensen, Dysart, Gantz, et al: Defining Bronchopulmonary Dysplasia) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6775872/	Bronchopulmonary Dysplasia (mode of respiratory support administered at 36 weeks postmenstrual age; as defined and categorized in; Jensen, Dysart, Gantz, et al: Defining Bronchopulmonary Dysplasia) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6775872/	Hospital course until 36 weeks PMA
Severe ROP (stage 3 or treated with laser or bevacizumab)	Severe ROP (stage 3 or treated with laser or bevacizumab)	After the intervention through study completion at hospital discharge, up to 6 months of corrected gestational age
Combined outcome of severe IVH and/or death	Combined outcome of severe IVH and/or death	Through study completion at death or discharge, up to 6 months of corrected gestational age
Death	Death	Through study completion at death or discharge, up to 6 months of corrected gestational age
SVC Flow	Superior Vena Cava flow by echocardiography	6 hours of life
RVO	Right Ventricular output by echocardiography	6 hours of life
Left Ventricular Output	Left Ventricular output by echocardiography	6 hours of life
Cognitive Composite Score	Composite Score (cognitive 45-155; higher scores are better) as assessed by the Bayley Scales of Infant and Toddler Development Fourth Edition	24 months corrected age
Language Composite Score	Composite Score (language 45-155; higher scores are better) as assessed by the Bayley Scales of Infant and Toddler Development Fourth Edition	24 months corrected age
Motor Composite Score	Composite Score (motor 45-155; higher scores are better) as assessed by the Bayley Scales of Infant and Toddler Development Fourth Edition	24 months corrected age
Cerebral Palsy	As assessed by Gross Motor Function Classification System (GMFCS) Levels 1-5	24 months corrected age
Neurodevelopmental Outcome at 2 Years of Age	Overall and Domain Scores- Ages and Stages, 3rd ed. Questionnaire	22-26 months corrected age
Pulsatility Index	Pulsatility index calculated from Doppler of the Middle Cerebral Artery	6 hours of life
Resistive Index	Resistive index calculated from Doppler of the Middle Cerebral Artery	6 hours of life
Changes in cerebral oxygenation saturation, StO2 (%)	Changes in cerebral oxygenation saturation, StO2 (%)	In the first 10 minutes of life
Changes in SpO2 (%) in the first 10 minutes of life	Changes in SpO2 (%) in the first 10 minutes of life	In the first 10 minutes of life
Inhaled Nitric Oxide	Use of Inhaled Nitric Oxide for Respiratory failure or Pulmonary Hypertension	Immediately after intervention through study completion at hospital discharge, up to 6 months of corrected gestational age
Glutathione (GSH/GSSG ratio)	Assessment of oxidative biomarkers from birth up to 2 hours of life	from birth up to NICU admission or in the first 2 hours of life
Thermoregulation	Assessment of thermoregulation (axillary temperatures measured in degrees Celsius) during delayed cord clamping on extremely low gestational infants	from 5 minutes of life up to NICU admission in the first 2 hours of life
Rate of Early Onset Sepsis	assessment of early onset sepsis with a positive blood or CSF culture at </= 72 HOL	From birth up to 72 hours of life
Rate of Late Onset Sepsis	assessment of late onset sepsis with a positive blood or CSF culture at > 72 HOL	From > 72 hours of life through study completion at death or discharge, up to 6 months of corrected gestational age

Collaborators and Investigators

• Sponsor: Sharp HealthCare
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Sharp Mary Birch Hospital for Women & Newborns
• Investigators: Principal Investigator: Anup Katheria, MD, Sharp HealthCare

Publications and helpful links

General Publications

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• Garey DM, Ward R, Rich W, Heldt G, Leone T, Finer NN. Tidal volume threshold for colorimetric carbon dioxide detectors available for use in neonates. Pediatrics. 2008 Jun;121(6):e1524-7. doi: 10.1542/peds.2007-2708. Epub 2008 May 5.
• Leone TA, Lange A, Rich W, Finer NN. Disposable colorimetric carbon dioxide detector use as an indicator of a patent airway during noninvasive mask ventilation. Pediatrics. 2006 Jul;118(1):e202-4. doi: 10.1542/peds.2005-2493. Epub 2006 Jun 26.
• Wang CL, Anderson C, Leone TA, Rich W, Govindaswami B, Finer NN. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics. 2008 Jun;121(6):1083-9. doi: 10.1542/peds.2007-1460.
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• SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network; Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, Yoder BA, Faix RG, Das A, Poole WK, Donovan EF, Newman NS, Ambalavanan N, Frantz ID 3rd, Buchter S, Sanchez PJ, Kennedy KA, Laroia N, Poindexter BB, Cotten CM, Van Meurs KP, Duara S, Narendran V, Sood BG, O'Shea TM, Bell EF, Bhandari V, Watterberg KL, Higgins RD. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010 May 27;362(21):1970-9. doi: 10.1056/NEJMoa0911783. Epub 2010 May 16. Erratum In: N Engl J Med. 2010 Jun 10;362(23):2235.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: May 27, 2020
• First Submitted That Met QC Criteria: May 29, 2020
• First Posted (Actual): June 2, 2020

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Continuous Positive Airway Pressure (CPAP); Delayed Cord Clamping; IVH- Intraventricular Hemorrhage; Hyperoxia in Neonates; Hypoxia Neonatal
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Respiratory Insufficiency; Hemorrhage; Hypoxia; Hyperoxia
• Other Study ID Numbers: DOXIE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available per NICHD requirements (National Institute of Child Health and Human Development)
• IPD Sharing Time Frame: 2 years after primary publication
• IPD Sharing Access Criteria: An archived dataset with documentation will be made available for additional users by outside investigators, in collaboration with the study investigators. We will work with NICHD program staff to develop a broad data sharing plan over time.
• IPD Sharing Supporting Information Type: SAP

Drug and device information, study documents

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