DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS AT HIGH RISK OF RESPIRATORY DISTRESS SYNDROME Vermont Oxford Network

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS STEERING COMMITTEE Jeanette M. Conner, PhD, MS Vermont Oxford Network Alan DeKlerk, MBChB, Maimonides Medical Center Rose DeKlerk RNC, New York Presbyterian Medical Center Michael S. Dunn, MD, FRCPC, Sunnybrook & Women’s Hospital Joseph Kaempf, MD, Providence St. Vincent Medical Center Maureen Reilly, RRCP, NRCP, Sunnybrook & Women’s Hospital Roger F. Soll, MD, Chair, Vermont Oxford Network EXPERT CONSULTANT Jen-Tien Wung, MD, New York Presbyterian Medical Center

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS PATIENT SAFETY AND DATA COMMITTEE Steve Block, MD, Chair Wake Forest University School of Medicine Walter Ambrosius, PhD Arthur Kopelman, MD East Carolina University

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS AT HIGH RISK OF RESPIRATORY DISTRESS SYNDROME: BACKGROUND and RATIONALE

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS What is the best approach to take in the stabilization of premature infants at high risk of developing respiratory distress syndrome? delivery room intubation and prophylactic surfactant administration with continued ventilator support administration without continued ventilator support early stabilization on nasal continuous positive airway pressure (NCPAP)

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS What is current practice regarding intubation and surfactant administration for high risk infants (gestational age less than 30 weeks) in centers participating in the Vermont Oxford Network?

SURFACTANT TREATMENT AND ENDOTRACHEAL INTUBATION BY GESTATIONAL AGE <24 24 25 26 27 28 29 30 31 32 >32 Gestational Age (weeks) 52,397 Infants 401 to 1500 Grams at 335 NICUS in 1998 and 1999

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS What is the rationale for early or prophylactic intubation and surfactant administration for high risk infants less than 30 weeks gestation?

PROPHYLACTIC SURFACTANT ADMINISTRATION ADVANTAGES: improved distribution decreased barotrauma need for aggressive resuscitation practice increased utilization/cost DISADVANTAGES:

EFFECT ON PNEUMOTHORAX PROPHYLACTIC vs. SELECTIVE SURFACTANT EFFECT ON PNEUMOTHORAX Decreased Risk Increased STUDY 0.2 0.5 1.0 2.0 4.0 Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 TYPICAL ESTIMATE 0.2 0.5 1.0 2.0 4.0 Soll 2001 Relative Risk and 95% CI

PROPHYLACTIC vs. SELECTIVE SURFACTANT EFFECT ON NEONATAL MORTALITY Decreased Risk Increased STUDY 0.2 0.5 1.0 2.0 4.0 Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 Bevilacqua 1997 TYPICAL ESTIMATE 0.2 0.5 1.0 2.0 4.0 Soll 2001 Relative Risk and 95% CI

NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE What about the early application of Nasal Continuous Positive Airway Pressure (NCPAP)?

NASAL CPAP and OUTCOME OF PRETERM INFANTS Comparison of clinical outcome before (n=57) and after (n=59) introduction of nasal continuous positive airway pressure De Klerk AM and De Klerk RK. J Paediatr Child Health 2001

PROPHYLACTIC APPLICATION OF NASAL CPAP RANDOMIZED CONTROLLED TRIAL OF 82 VLBW INFANTS (HAN AND COWORKERS 1987) Risk Difference Decreased Risk Increased OUTCOME ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 USE OF IPPV 0.09 (-0.12, 0.29) PNEUMOTHORAX -0.01 (-0.14, 0.12) SEPSIS -0.04 (-0.21, 0.13) NECROTIZING ENTEROCOLITIS -0.14 (-0.30, 0.02) IVH 0.15 (-0.02, 0.32) BRONCHOPULMONARY DYSPLASIA 0.13 (-0.03, 0.29) MORTALITY 0.07 (-0.03, 0.17) 0.2 0.5 1.0 2.0 4.0 HAN 1987 Relative Risk and 95% CI

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS What is the rationale for considering early or prophylactic intubation and surfactant administration followed by rapid extubation and stabilization on nasal CPAP?

NASAL CPAP AND EARLY SURFACTANT MECHANICAL VENTILATION OR DEATH VERDER H AND COWORKERS PEDIATRICS 1999

NASAL CPAP AND EARLY SURFACTANT MORTALITY VERDER H AND COWORKERS PEDIATRICS 1999

DELIVERY ROOM MANAGEMENT RESPIRATORY DISTRESS SYNDROME OF PREMATURE INFANTS AT HIGH RISK OF RESPIRATORY DISTRESS SYNDROME PROTOCOL

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS OBJECTIVE To compare the effect of three distinct methods of post-delivery stabilization and subsequent respiratory care on chronic lung disease and survival in premature infants at high risk of respiratory distress

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS The three approaches to post-delivery care: PS Group: Intubation, prophylactic surfactant administration shortly after delivery, stabilization on ventilator support NCPAP Group: Early stabilization on nasal continuous positive airway pressure (NCPAP) with selective intubation and surfactant administration for clinical indications ISX Group: Intubation, prophylactic surfactant administration, and rapid extubation to Nasal CPAP

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS : ENROLLMENT CRITERIA Eligibility: Admission to L & D high risk of preterm delivery at gestational age 26+0 to 29+6 weeks Inclusion Criteria: delivery imminent no maternal rupture of membranes > 14 days no potentially life threatening congenital anomaly or genetic syndrome no known lung maturity antenatal steroid status known written informed consent obtained (prior to delivery) Randomization: Prior to delivery Exclusion Criteria (s/p delivery): stillborn (apgar score of 0 at one minute) potentially life threatening congenital anomaly/genetic syndrome

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS STUDY DESIGN multicenter randomized clinical trial conducted at participating Vermont Oxford Network Centers

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS : TREATMENT GROUPS Eligible infants will have consent obtained prior to delivery. At imminent delivery premature infants will be randomized to either: Intubation, prophylactic surfactant administration, subsequent stabilization on ventilator support early stabilization on NCPAP and selective intubation and surfactant administration for clinical indications intubation prophylactic surfactant administration and rapid extubation to NCPAP. After delivery infants who meet all criteria will be enrolled in the trial.

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS: TREATMENT GROUPS PROPHYLACTIC SURFACTANT ADMINISTRATION (PS GROUP) Intubation in the delivery room between five and fifteen minutes of life Surfactant treatment s/p intubation Mechanical ventilation Extubation at anytime after 6 hours of age based on predefined criteria

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS: TREATMENT GROUPS EARLY APPLICATION OF NASAL CONTINUOUS POSITVE AIRWAY PRESSURE (NCPAP GROUP) Stabilization on standardized NCPAP system applied within five to fifteen minutes after delivery Bubble CPAP system at 5 cm H20 Predefined criteria for respiratory insufficiency requiring intubation and surfactant treatment

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS: TREATMENT GROUPS PROPHYLACTIC SURFACTANT ADMINISTRATION, RAPID EXTUBATION TO NASAL CONTINUOUS POSITVE AIRWAY PRESSURE (ISX GROUP) Intubation in the delivery room between five and fifteen minutes of life Surfactant treatment s/p intubation Rapid extubation to standardized nasal CPAP bubble system at 5 cm H20

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS CRITERIA FOR SELECTIVE INTUBATION AND SURFACTANT TREATMENT Intubation based on clinical status: apnea respiratory failure (PCO2 > 65 mmHg) hypoxemia (supplemental oxygen > 40%-60% to maintain oxygen saturation > 86%-94%) severe respiratory distress Surfactant treatment s/p intubation

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS PRIMARY OUTCOME MEASURE: Chronic Lung Disease or Mortality at 36 weeks adjusted age Chronic lung disease is defined as documented requirement for supplemental oxygen or respiratory support. Documented oxygen requirement will be defined as the need for supplemental oxygen to maintain an oxygen saturation  88%.

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS SAMPLE SIZE: Sample Size is based on: 20% reduction in the number of infants with chronic lung disease/death from 36% to 29% ( 0.05, ß 0.2) A total of 2106 infants will be enrolled: 702 per study group Will re-evaluate based on results of pilot study

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS SECONDARY OUTCOME MEASURES: Number of infants receiving surfactant treatment Number of surfactant doses Postnatal steroids Clinical status during first 28 days of life Clinical status at 36 & 40 weeks adjusted age Days on assisted ventilation Days on NCPAP Days on supplemental oxygen Growth, day 28 and discharge Pneumothorax Pulmonary hemorrhage Patent ductus arteriosus Necrotizing enterocolitis Intraventricular hemorrhage Steroids for chronic lung disease Mortality Duration of hospitalization Other complications of prematurity Health and developmental status at 2 years adjusted age

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS STUDY TIMELINE Study to be conducted in three stages Stage 1: Introduction of Nasal CPAP in routine NICU practice Stage 2: Pilot study of feasibility of delivery room interventions Stage 3: Formal enrollment of subjects in large pragmatic trial

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS Stage 1: Introduction of Nasal CPAP in routine NICU practice Build bubble CPAP devices Educate centers regarding use of bubble NCPAP Incorporate bubble NCPAP into daily routine of NICU Evaluate competence of centers in use of bubble CPAP February through April 2003

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS Stage 2: Pilot study of feasibility of delivery room interventions Educate centers regarding conduct of delivery room management trial Pilot study of randomization to all three arms of study May through October 2003 Determine feasibility of launching large pragmatic trial

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS Stage 3: Formal enrollment of subjects in large pragmatic trial In accordance with insights gained from feasibility study January 2004

DELIVERY ROOM MANAGEMENT OF PREMATURE INFANTS NETWORK CENTER PARTICIPATION Interested centers must identify a study team comprised of a neonatologist, nurse practitioner or nurse, and a respiratory therapist Team must commit to participating in a standardized education and training program Team must implement education and training program within their NICU and unit must establish a level of competency with the bubble CPAP system prior to initiating enrollment in pilot study