Sharp Healthcare

UMBILICAL CORD MILKING IN NON VIGOROUS INFANTS (THE MINVI TRIAL)

PREMATURE INFANTS RECEIVING CORD MILKING OR DELAYED CORD CLAMPING

SHARP NEONATAL RESEARCH INSTITUTE CLINICAL CENTER (SHARP NRI-CC) - PROJECT SUMMARY RESEARCH IN EXTREMELY PRETERM INFANTS HAS LONG BEEN CONSTRAINED BY INADEQUATE ENROLLMENT AND FAILURE TO COMPLETE TRIALS. IN RESPONSE TO RFA-HD-23-002, THIS APPLICATION WILL DEMONSTRATE THAT THE SHARP NEONATAL RESEARCH INSTITUTE (NRI) CAN SUBSTANTIALLY CONTRIBUTE AS A CLINICAL CENTER (SHARP NRI-CC) IN THE EUNICE KENNEDY SHRIVER NICHD NEONATAL RESEARCH NETWORK (NRN) 2023-2029 CYCLE. AS A COMMUNITY HOSPITAL WITH HIGH PATIENT VOLUMES, CLINICAL TRIAL EXPERTISE, AND EXCEPTIONAL PARTICIPANT ENROLLMENT, THREE MAIN STRENGTHS UNDERSCORE SHARP’S APPLICATION INTO THE NRN: 1) TWO SHARP HOSPITALS COMBINED DELIVER OVER 10,000 BABIES IN SAN DIEGO COUNTY, WITH OVER 1,500 NICU ADMISSIONS ANNUALLY; 2) A HIGHLY EXPERIENCED GROUP OF CLINICAL TRIALISTS AND NEURODEVELOPMENTAL SPECIALISTS HAVE SUCCESSFULLY PARTICIPATED IN MULTIPLE CLINICAL TRIALS, INCLUDING PREVIOUS NRN EXPERIENCE DURING THE 2001-2005 CYCLE; 3) SHARP’S INTEGRATION OF NEONATAL RESEARCH INTO CLINICAL CARE WHICH ALLOWS FOR RECRUITMENT 24/7 THROUGH HIGHLY TRAINED PERSONNEL WHO ATTEND ALL HIGH-RISK DELIVERIES AND COMPLETE THE ANTENATAL CONSENT PROCESS, WITH CONSENT RATES OF OVER 80% FOR MANY CLINICAL TRIALS. SPECIFIC AIM 1: ENROLL DIVERSE HIGH-RISK NEONATES INTO CURRENT AND FUTURE NRN TRIALS. THE SHARP INVESTIGATIVE TEAM HAS DESIGNED AND SIMULTANEOUSLY LED SEVERAL LARGE MULTICENTER RANDOMIZED CONTROLLED TRIALS (RCT). THE SHARP NRI SERVES A UNIQUE POPULATION OF APPROXIMATELY 40% HISPANIC AND HAS A HIGH VOLUME OF MULTIPLE PREGNANCIES. SPECIFIC AIM 2: PARTICIPATE IN NRN TRIAL DESIGN AND HELP COMPLETE TRIALS EFFICIENTLY. THE PROPOSED SHARP NRI-CC PI, ANUP KATHERIA, MD, HAS A PROVEN TRACK RECORD OF EFFICIENCY, LEADERSHIP, AND EXPERTISE. HE DESIGNED AND LED SEVERAL LARGE MULTICENTER RCTS AND ROUTINELY CONDUCTS MULTIPLE TRIALS SIMULTANEOUSLY, INCLUDING PREMATURE INFANTS RECEIVING MILKING OR DELAYED CORD CLAMPING TRIAL (PREMOD2, 20 CENTERS, N=1,200, EST. COMPLETION 9/2022) AND COMPLETED ENROLLMENT IN THE UMBILICAL CORD MILKING IN NON-VIGOROUS INFANTS TRIAL (MINVI, 10 CENTERS, N=1,730). BOTH TRIALS ENROLLED NEARLY 3,000 PARTICIPANTS FOR SECONDARY STUDIES. DESPITE PREMOD2 BEING TEMPORARILY STOPPED, THESE TRIALS CONTINUED ENROLLING DURING THE PANDEMIC; ENROLLMENT WAS COMPLETED IN 6 AND 3 YEARS (WITH ONGOING 2-YEAR FOLLOW-UP), RESPECTIVELY. HIS EXPERIENCED INVESTIGATIVE TEAM INCLUDING TWO SENIOR INVESTIGATORS WHO LED THE NRN SUPPORT TRIAL AND ITS NEURODEVELOPMENTAL FOLLOW-UP COMPONENT, COUPLED WITH A PRODUCTIVE RESEARCH TEAM WITH A STRONG HISTORY OF CONDUCTING MULTIPLE NEONATAL CLINICAL STUDIES, WILL PROVIDE ADDITIONAL EXPERTISE TO THE NRN. SPECIFIC AIM 3: PRIORITIZE LONG-TERM NEURODEVELOPMENTAL FOLLOW-UP IN ALL RESEARCH TRIALS. THE SHARP HIGH RISK INFANT FOLLOW-UP PROGRAM PROVIDES LONGITUDINAL, COMPREHENSIVE NEURODEVELOPMENTAL ASSESSMENTS FOR NEWBORNS DELIVERED AT SHARP AND ENROLLED IN CLINICAL TRIALS THAT HELPED INCREASE THE OVERALL NEONATAL FOLLOW-UP RATES TO ABOVE 85% FOR RECENT CLINICAL RESEARCH TRIALS.

NEONATAL RESUSCITATION WITH INTACT CORD (NRIC)

HEALTH CARE AND OTHER FACILITIES

DELAYED CORD CLAMPING WITH OXYGEN IN EXTREMELY LOW GESTATIONAL AGE INFANTS (DOXIE) - BACKGROUND: CURRENT NEWBORN CARE PRACTICE IS TO DELAY CLAMPING AND CUTTING THE UMBILICAL CORD TO ALLOW FOR HEMODYNAMIC STABILIZATION. SUPPORTED BY NUMEROUS RANDOMIZED CONTROLLED TRIALS AND META-ANALYSES, DELAYED CORD CLAMPING (DCC) IS ENDORSED BY BOTH NEONATAL AND OBSTETRICAL GOVERNING BODIES. LIMITED OXYGENATION DATA ON DCC IN EXTREMELY PRETERM INFANTS SUGGESTS THEY REMAIN HYPOXIC IMMEDIATELY AFTER BIRTH. THIS MAY BE DUE TO DIFFERENCES IN HOW INFANTS TRANSITION DURING DCC. IMMEDIATELY AFTER DELIVERY, EXTREMELY PRETERM INFANTS ATTEMPT TO INITIATE LUNG AERATION AND GAS EXCHANGE. ANIMAL STUDIES HAVE DEMONSTRATED THAT DELAYING CLAMPING OF THE UMBILICAL CORD UNTIL BREATHING IS ESTABLISHED AVOIDS ADVERSE CEREBRAL AND CARDIAC HEMODYNAMICS, WHICH MAY REDUCE BLEEDING IN THE BRAIN, INCLUDING SEVERE INTRAVENTRICULAR HEMORRHAGE (SIVH). IN A MULTICENTER TRIAL COMPARING DCC TO UMBILICAL CORD MILKING, 76 PERCENT OF PRETERM NEWBORNS BETWEEN 230-276 WEEKS GESTATION WHO RECEIVED DCC WITHOUT RESPIRATORY SUPPORT INITIATED RESPIRATIONS PRIOR TO CORD CLAMPING, YET STILL HAD RELATIVE HYPOXIA DEMONSTRATED BY A LOW 5-MINUTE ARTERIAL OXYGEN SATURATION (SPO2 73 PERCENT (95% CI 71.4, 75.6)). TWO RECENT ANALYSES FOUND THAT PRETERM INFANTS WITH A 5-MINUTE SPO2 < 80 PERCENT WERE MORE LIKELY TO HAVE SIVH OR DEATH. SUPPLEMENTAL OXYGEN PROVIDED DURING DCC WITH RESULTANT LUNG AERATION MAY DECREASE SIGNIFICANT MORBIDITIES AND DEATH IN EXTREMELY PRETERM INFANTS. A PILOT STUDY WITH DETAILED ASSESSMENTS OF HEMODYNAMICS AND ORGAN FUNCTION IMMEDIATELY AFTER BIRTH IS NEEDED TO DETERMINE THE EFFICACY AND SAFETY OF PROVIDING 100 PERCENT OXYGEN DURING DCC. DESIGN: THIS RANDOMIZED DOUBLE-BLINDED PILOT TRIAL WILL ENROLL 140 EXTREMELY LOW GESTATIONAL AGE INFANTS (230- 276 WEEKS GESTATION) WHO RECEIVE DCC OF AT LEAST 60 SECONDS WITH CAREFULLY DETAILED HEMODYNAMIC ASSESSMENTS AND SIMULTANEOUS VIDEO RECORDINGS. THE STUDY WILL EVALUATE INFANTS PROVIDING CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) AND/OR POSITIVE PRESSURE VENTILATION (PPV) BY FACE MASK WITH AN INSPIRED FRACTIONAL OXYGEN (FIO2) OF 1.0 (HI GROUP) DURING DCC COMPARED TO INFANTS GIVEN MASK CPAP/PPV WITH AN INSPIRED FIO2 OF 0.30 DURING DCC (LO GROUP). DUE TO THE NATURE OF THE INTERVENTION, BOTH ARMS RECEIVE CPAP/PPV WITH IDENTICAL CORD CLAMPING TIMES AND RESPIRATORY SUPPORT, THE STUDY CAN BE BLINDED BY COVERING THE OXYGEN BLENDER, AVOIDING ANY POSTNATAL TREATMENT BIAS. ONCE THE CORD IS CLAMPED AND CUT, EACH INFANT IS RESUSCITATED AS PER USUAL PROTOCOL (CPAP/PPV WITH A STARTING FIO2 0.30) BY THE CLINICAL TEAM. WE WILL COLLECT PHYSIOLOGICAL PARAMETERS FROM BIRTH THROUGH THE FIRST 24 HOURS OF LIFE (INCLUDING DETAILED BREATHING ASSESSMENTS FROM VIDEO RECORDINGS AT BIRTH/ RESUSCITATION SUITE). IF WE REDUCE HYPOXIA IN EXTREMELY PRETERM INFANTS BY PROVIDING SUPPLEMENTAL OXYGEN DURING THE PERIOD OF DELAYED CORD CLAMPING, THERE MAY BE A DRAMATIC REDUCTION IN MORBIDITY AND MORTALITY. DEPENDING ON THE FINDINGS, RESULTS WILL BE USED TO DESIGN A MORE DEFINITIVE LARGER, MULTICENTER R01 TRIAL POWERED FOR IMPORTANT CLINICAL OUTCOMES SUCH AS SEVERE IVH OR DEATH AND NEURODEVELOPMENTAL OUTCOMES.

EVALUATION OF UMBILICAL CORD MILKING ON SYSTEMIC BLOOD FLOW IN PREMATURE INFANTS