Short title REPORT-BPD feasibility study

Design A mixed methods observational cohort feasibility study

Study Setting Neonatal Intensive Care Unit at University Hospitals Plymouth NHS Trust

Aim To explore the feasibility of measuring the right ventricular function of the premature heart to develop a prediction model to identify early BronchoPulmonary Dysplasia in premature infants.

Objectives 1. To assess the feasibility and acceptability of the study procedures e.g., recruitment, echo scans performance, data collection, storage, and analysis.

2. To identify the sensitive echo parameters in assessing the right ventricle function of the heart to be included in a prediction model to identify early BPD in premature infants.

Study Participants Preterm infants born <32 weeks of gestational age, their parents and healthcare professionals involved in the care of the study's preterm infants.

Sample size 40 preterm infants

Follow-up Each preterm infant will be followed up till they are 36 weeks of post menstrual age (PMA) or until discharge home whichever comes first.

Study Period 18 months

Outcome Measures

1. Establishing sensitive and feasible echo parameters for detecting right ventricle dysfunction associated with early BPD pulmonary vascular changes.
2. Suitability of eligibility criteria and sample characteristics.
3. Fidelity to the study procedures such as recruitment, data collection including echo scans performance at the set time points.
4. Recruitment, accrual, and retention rates.

RATIONALE The current research findings demonstrated a persistently elevated myocardial performance index of the right ventricle (RV) in the first two weeks of postnatal life (WoPL) in preterm infants with incipient BPD. The identification of the early myocardial dysfunction of RV that is associated with early pulmonary vascular disease (PVD) through echo scan examination in the first two WoPL can potentially serve as a marker for detecting preterm infants with an early BPD.

Data from 1,735 infants born between 23-30 weeks of gestational age (GA) showed that the proportion of preterm infants born < 31 weeks needing oxygen decreases from birth to the 7th day of postnatal life (DoPL). This is followed by a steep rise in the number of infants requiring oxygen in the same cohort at the start of the second week of postnatal life (WoPL). The number of preterm infants needing extra oxygen, peaks at the 14th DoPL. These studies indicate that the pathological pulmonary changes start as early as the first 10 DoPL. Furthermore, studies have identified the end of the first week of postnatal life (WoPL) and the beginning of the second WoPL as the time point when early respiratory problems start to surface. According to the vascular theory, the pathological processes affecting the pulmonary vascular bed are already happening before the appearance of the clinical signs associated with early BPD. The proposed study (REPORT-BPD) aims to capture the early burden exerted on the RV by early BPD and its associated pulmonary vascular changes through performing functional echo examinations at two time points, 5th and 9th day of postnatal life (DoPL) and utilising the findings to construct a prediction model.

To our knowledge, no study has used functional echo examinations to assess extra load or strain imposed by early BPD on the RV on the two time points (5th & 9th DoPL) in the first 10 DoPL.

The cardiac muscle of the preterm infant's heart has premature function. The premature heart reduced contractility is secondary to several reasons such as less myofibrils per cross-sectional area together with immature internal organisation. In addition, there is a lower number of β-adrenergic receptors and underdeveloped sympathetic nervous network. Furthermore, the underdeveloped intrinsic myocardial function following preterm birth is the result of abnormal right ventricle performance with remodelling after birth that persists in the first year of life.

Current research supports the vascular theory as the main pathophysiology of BPD i.e., the pathological process of BPD starts in the pulmonary vascular bed prior to the involvement of the parenchyma of the lungs. So, when the early BPD respiratory insufficiency starts to manifest clinically on 7th day of postnatal life, the adverse haemodynamic changes are already ongoing. In addition, the immaturity of the right ventricle (RV) will render the RV more sensitive to the extra burden imposed by the negative haemodynamic effects of early BPD causing worsening of the RV dysfunction.

In summary, the rationale of the study is outlined nicely by a quote from Niccolo Michiavelli; an Italian diplomat, philosopher and historian, who lived during the renaissance (1469 - 1527):

"In the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure." To the best our knowledge, this is the first study that assesses the right ventricle dysfunction through two echo scans performed at two specified time points before and after the 7th day of postnatal life when early BPD respiratory insufficiency starts to be evident. Then, the data generated will be utilised to formulate a prediction model for early BPD. In other words, since it is very difficult to diagnose early BPD, this study will utilise highly specialised technologies in analysing the echo images and the data generated will be used to formulate a prediction model to identify BPD at its early stage. Additionally, the rationale behind incorporating qualitative work is because it is important to explore the experiences of parents and clinicians in participating in REPORT-BPD study to inform the design of a larger trial by addressing any gaps identified during this study.

OBJECTIVES

1. To assess the feasibility and acceptability of the study procedures e.g., recruitment, echo scans performance, data collection, storage, and analysis.
2. To identify the sensitive echo parameters in assessing the right ventricle function of the heart to be included in a prediction model to identify early BPD in premature infants.

STUDY DESIGN This is a longitudinal, observational, cohort and feasibility study. STUDY SETTING This study will be conducted at the regional tertiary neonatal intensive care unit (NICU) at University Hospitals Plymouth NHS Trust (UHP), Plymouth. The total NICU capacity is 40 neonatal admissions (6 intensive care cots, 6 high dependency care cots, 10 special care cots and 18 cots in transitional care ward).

SAMPLE AND RECRUITMENT

Sample size

The exploratory nature of this feasibility study dictated to set a realistic target of recruiting 40 preterm infants who are born before 32 weeks of gestation.

The regional tertiary NICU at the UHP admitted 89, 101 and 69 preterm infants who were born before 32 PMA in the years 2018, 2019 and 2020, respectively. Based on the careful examination of the data of the admissions in 2018; two thirds of these preterm infants met the inclusion criteria of the proposed study with one third of them i.e., eligible preterm infants developed moderate - severe BPD.

Therefore, the proposed feasibility study realistic sample size is 40 preterm infants over an 18-month recruitment period.

Participants

The participant whose data will be subjected to the trial analysis - both for the primary analysis and any applicable secondary analyses are:

1. Infants survived till the gestational age when the diagnosis of no BPD or BPD with its severity can be established.

2. Infants who died before the set gestational age (36 weeks PMA) with severe BPD is being the main cause of death.

   Participant identification

   The identification of eligible infants for the study will be carried out by the neonatal clinical team once a preterm infant is admitted to the regional tertiary NICU at UHP, either from the delivery suite in UHP or from another neonatal unit in the region for continuity of care. The neonatal clinical team will be consisted of the clinicians who are working in the neonatal unit such as, consultant neonatologists, trainee doctors, advanced neonatal nurse practitioners, neonatal staff nurses. While the neonatal research team is consisted of the clinicians such as, consultant neonatologists, trainee doctors and advanced nurse practitioners, who are good clinical practice (GCP) trained and registered in the study delegates' log.

   The neonatal clinical team will inform the neonatal research team of the potential recruits to instigate the recruitment process.

   Screening

   The screening process will occur on the possible two time points:

   • Timepoint 1: If possible, antenatal screening will be carried out. The obstetric or midwifery team will inform the neonatal clinical team of the admitted women with preterm labour. This will be followed by screening for eligibility by the clinical neonatal team by reviewing the medical notes. Then the clinical neonatal team will inform the neonatal research team if the unborn infant is deemed a potential recruit so the initial conversation can happen antenatally.
   • Timepoint 2: If screening is not possible at timepoint 1 parents of the suitable preterm infants will be approached in the second day after the birth of their infant.

   A screening log will be maintained.

   Consent

   All parents will be spoken to in person by the neonatal research team, who are also part of the neonatal clinical team, in the antenatal wards, in the delivery suite antenatally or in the neonatal unit postnatally. The neonatal research team members will clearly introduce themselves and state that this conversation will be about the parents and their preterm infants' participation in REPORT-BPD study. The talk will focus on providing a clear verbal explanation of the research project and why the parents and their preterm infants are invited to participate in this study, together with giving them a patient/parent information sheet (PIS) and informed consent form. The parents will also be given contact details for the chief investigator (CI) and the neonatal research team in case they wish to seek further information about the study.

   Informed and written consent to enter the study will be sought from each participant, in this case participants' parents. Signed parents' informed consent forms will be obtained prior to the participation in the study. If parents are interested in participating, a neonatal consultant, a senior trainee doctor or senior advanced nurse practitioner who is a member of the neonatal research team, will be able to dedicate some of their time to obtain consent at the second day after the birth of the potential recruit. All participants will be made aware that they are free to withdraw at any time from the study without giving reasons and without prejudicing further treatment.

   A delegation log will be maintained to ensure that the medical practitioners registered as a study delegate who are participating in the consenting process of this study, are duly authorised, completed a Good Clinical Practice (GCP) training, experienced clinicians and competent to participate according to the ethically approved protocol, principles of GCP and Declaration of Helsinki.

   DATA COLLECTION

   As per the standards of care echo scans are performed when one or more of the following clinical indications are present:

   • Preterm infants who require mechanical ventilation or non-invasive respiratory support (CPAP ≥ 4 cm H2O, High Flow ≥ 4 L/min).
   • Detection of a cardiac murmur in the first three days after birth.
   • Assessment of patent ductus arteriosus (PDA).
   • Preterm infants have central line in-situ, so echo is needed to assess line position.

   Three Data Collection Time Points

   Data Collection Point 1: First echo scan will be performed on the 5th Day of postnatal life (DoPL) together with the following data will be collected:

   • Current weight in grams.

   • Vital signs:

     o Heart rate.

     o Respiratory rate.

     o Oxygen saturation.

     • Temperature.
     • BP including systolic, diastolic, and mean BP.

   • Acquisition of the echo scan images.

   • Ventilatory support:

     o Mode of ventilation.

     o Mean airway pressure (MAP) used.

     o FiO2.

     2) Second echo scan will be performed on the 9th DoPL with the following will be collected:

   • Infant's weight in grams.

   • Vital signs:

     o Heart rate.

     o Respiratory rate.

     • Oxygen saturation.
     • Temperature.
     • BP including systolic, diastolic, and mean BP.

   • Acquisition of the echo scan images.

   • Ventilatory support:

     o Mode of ventilation.

     o Mean airway pressure (MAP) used.

     o FiO2.

     3) At 36 weeks of PMA or at discharge if discharged home before 36 weeks of PMA:

   • Ventilatory support:

     • Mode of ventilation.
     • Mean airway pressure (MAP) used.
     • FiO2.

   • Outcomes.

   STATISTICS AND DATA ANALYSIS

   The distribution of all continuous variables will be visualised to check for normality and summarised using appropriate descriptive statistics. At 36 weeks, infants will be categorised into two groups: (i) moderate or severe BPD and (ii) mild or no BPD.

   In order to help identify potential candidate variables for inclusion in a predictive model the following analyses will be undertaken. Differences in clinical characteristics and echo scan parameters between the two groups of infants will be visualised using boxplots. The comparison between the two groups will be further assessed using t-tests for normally distributed continuous variables and Mann-Whitney U tests for non-normally distributed variables. Chi-squared tests will be used to compare categorical variables between groups.

   The association among clinical and echo parameters will also be explored through visualisation using scatterplots and Pearson's or Spearman's correlations as appropriate. Analyses will be considered exploratory in nature and as such no adjustment for multiple comparisons will be made - interpretation of these analyses will consider the estimates of the between group differences and their 95% confidence intervals. Comparative analyses of the changes between the two timepoints when the echo scans performed i.e., 5th and 9th day of postnatal life, will be conducted.

INCLUSION CRITERIA

• Born at < 32 weeks gestational age.

• The echo scans are indicated as per the recommended neonatal practice:

  • Preterm infants who require mechanical ventilation or non-invasive respiratory support (CPAP ≥ 4 cm H2O, High Flow ≥ 4 L/min).
  • Detection of a cardiac murmur in the first three days after birth.
  • Assessment of patent ductus arteriosus (PDA).
  • Preterm infants have central line in-situ, so echo is needed to assess line position.

EXCLUSION CRITERIA

• Preterm infants with major congenital anomalies, such as pulmonary hypoplasia or congenital heart disease (except PFO or PDA).
• Preterm infants with a poor prospect of survival.
• Preterm infants whose parents do not consent.
• Preterm infants who are still in need of blood pressure supporting medications, such as, (inotropes) when the study echo scans are due.
• Preterm infants need inhaled nitric oxide gas when the study echo scans are due.

PDA - patent ductus arteriosus, PFO - patent foramen ovale

The exploratory nature of this feasibility study dictated to set a realistic target of recruiting 40 preterm infants who are born before 32 weeks of gestation.