Cardio-respiratory Events in Preterm Infants During Transition
Condition: Apnea of Prematurity; Apneic Spells of Newborn Nos; Patent Ductus Arteriosus; Premature Birth; Desaturation of Blood; Bradycardia Neonatal
MeSH terms: Premature Birth; Bradycardia; Ductus Arteriosus, Patent
Study type: Observational

Summary: 
      Cardio-respiratory events (CRE), defined as intermittent episodes of hypoxemia and/or
      bradycardia, are particularly common among preterm infants. It has been previously shown that
      CRE result in transient brain hypoxia and hypoperfusion and may represent a possible risk
      factor for neurodevelopmental impairment and retinopathy of prematurity. The high
      cardio-respiratory instability typically seen in preterm infants during the first 72 hours of
      life may influence CRE occurrence, with possible clinical implications. This study aims to
      characterize CRE features in this transitional period and to evaluate whether specific
      neonatal and clinical characteristics are associated with different CRE types.

      Newborn infants with gestational age (GA) <32 weeks or birth weight (BW) <1500 g are
      enrolled. Congenital malformations and mechanical ventilation are exclusion criteria. During
      the first 72 hours, heart rate (HR) and peripheral oxygen saturation (SpO2) are continuously
      monitored, and an echocardiogram is performed to assess the status of the ductus arteriosus.
      CRE are clustered into isolated desaturation (ID, SpO2<85%), isolated bradycardia (IB, HR<100
      bpm or <70% baseline), combined desaturation and bradycardia (DB, occurrence of the two
      events within a 60-sec window). According to their duration and SpO2 and/or HR nadir values,
      CRE are also classified as mild (SpO2 80-84% and HR 80-100 bpm and duration <60 sec),
      moderate (SpO2 70-79% or HR 80-60 bpm or duration 61-120 sec) or severe (SpO2 <70% or HR <60
      bpm or duration >120 sec). A generalized estimating equation (GEE) will be used to examine
      the impact of relevant variables on CRE type and severity.
    

Detailed description: 
      Background Cardio-respiratory events (CRE), defined as intermittent hypoxic and/or
      bradycardic episodes, are very common among premature infants. The poor respiratory drive,
      together with the increased metabolic oxygen consumption and the reduced total blood oxygen
      carrying capacity of this population significantly enhance CRE frequency and severity.

      Evidence from animal models has shown that CRE, either alone or combined to specific clinical
      factors (i.e., intrauterine growth restriction, support modality, need for supplemental
      oxygen etc.), can trigger oxidative stress, which may contribute to adverse neonatal
      outcomes. In particular, a significant association between CRE and the development of
      retinopathy of prematurity (ROP) has been largely established, with evidence of a positive
      correlation between ROP severity and CRE duration, depth of desaturation, and persistency
      after 3 to 5 weeks of age. A critical role for CRE on early brain development has also been
      suggested by several studies showing a relationship between the ensuing hypoxic burden and
      poor neurodevelopment from early infancy up to early school age. Eventually, a possible
      association between CRE severity and the development of bronchopulmonary dysplasia has been
      recently reported in very-low-birth-weight (VLBW) neonates.

      Most of the available literature on CRE characteristics, physiological mechanisms and effects
      in the premature population, however, is based on infants aged 2-weeks or older, while data
      from the transitional period, defined as the first 72 hours after birth, are scarce.

      The transitional period represents a critical phase of physiological adaptation and may
      affect several organ systems, most notably the heart and the lungs. In particular, the
      dynamic cardiovascular changes that characterize the transition from fetal to neonatal
      circulation may enhance preterm infants' cardiorespiratory instability, with possible effects
      on CRE characteristics. In turn, the hemodynamic and respiratory disturbances that
      characterize post-natal transition may exacerbate the clinical burden of CRE during this
      period, with possible clinical implications.

      This study aims to characterize CRE during transitional periods in VLBW preterm infants, and
      to evaluate whether specific neonatal characteristics may have an influence on CRE type and
      severity.

      Methods Infants born at S. Orsola-Malpighi Hospital are consecutively enrolled in this
      observational, prospective study if fulfilling the following eligibility criteria:
      gestational age (GA) <32 weeks' gestation, birth weight <1500 g, 0-12 hours of life, written
      informed consent obtained from the parents/legal guardians of each infant.

      Peripheral oxygen saturation (SpO2) and heart rate (HR) are routinely monitored during
      hospital stay using a Masimo Radical 7 (Masimo Corporation, Irvine, CA, USA) pulse oximeter
      with a 1-Hz sampling frequency.

      Isolated desaturations (ID) are defined as SpO2 <85% and classified into mild (SpO2 80-84%),
      moderate (SpO2 70-79%) and severe (SpO2 <70%).

      Isolated bradycardias (IB) are defined as any HR drop <100 bpm or >30% from baseline values,
      calculated daily over the first 72 hours of life, and further stratified into mild (HR 80-100
      bpm or any drop between 31-50% of the baseline), moderate (HR 60-79 bpm or any drop between
      51-70% of baseline) or severe (HR <60 bpm or any drop >70% of baseline).

      Desaturations and bradycardias occurring within a 60-sec time window are considered as
      combined events (DB).

      Event duration is calculated as the period spent below the SpO2 and HR thresholds described
      for CRE definition. According to their duration, CRE are defined as mild (10-60 sec),
      moderate (61-120 sec), or severe (>120 sec).

      Neonatal clinical characteristics The following antenatal and neonatal data are tracked down
      on a specific case report form: GA, antenatal steroids (complete course vs. incomplete course
      or not given) evidence of reversed end-diastolic flow at antenatal umbilical Doppler (uREDF)
      (present vs. absent); ventilatory status over the first 72 hours of life (continuous positive
      airway pressure [CPAP] vs. nasal cannulas or self-ventilating in air [SVIA]).

      A screening echocardiogram is routinely performed at the time of enrollment using an
      ultrasound scanner CX50 (Philips Healthcare) with a 12-MHz probe, and repeated 6-12 hourly in
      the presence of a patent ductus arteriosus (PDA) or 12-24 hourly if there is no evidence of
      PDA. Based on echocardiographic features, the ductal status is classified as follows: no
      evidence of PDA (noPDA), restrictive PDA (rPDA; restrictive shunt pattern and left atrium to
      aortic root ratio [LA:Ao] ratio <1.5), hemodynamically significant PDA (hsPDA; pulsatile
      shunt pattern, LA:Ao ratio ≥1.5 or presence of reversed end-diastolic flow (REDF) either in
      the descending aorta or in the anterior cerebral artery).

      Statistical analysis Generalized estimating equation (GEE) models will be used to analyze the
      effect of GA, uREDF, antenatal steroids, ductal and ventilatory status on CRE type (ID, IB,
      DB) and severity (mild, moderate and severe) and the relation of different neonatal
      characteristics and event types with event duration. Variations in the daily number of ID, IB
      and DB over the 3 days of life, adjusted for the effective hours of recording, will be
      analyzed using Repeated Measures ANOVA (RM-ANOVA). IBM SPSS, version 25.0, will be used for
      statistical analysis. The significance level is set at p<0.05.
    

Intervention name(s): pulse oximetry monitoring
Intervention type(s): Device
Intervention description(s): pulse oximetry monitoring as per routine clinical practice
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Preterm newborns age 0 to 72 hours of life with non-invasive ventilatory support.
      
Keywords: cardio-respiratory events; preterm infants; transitional period; desaturation; bradycardia; apnea