Multicentre paired non-inferiority study of the cardiorespiratory monitoring performance of the wireless and non-adhesive Bambi® belt measuring diaphragm activity in neonates: study protocol

Study design

This multicentre paired non-inferiority study will be performed in the NICU of Máxima Medical Center (MMC) in Veldhoven and the Emma Children’s Hospital of the Amsterdam University Medical Centre (AmsterdamUMC), both located in the Netherlands. Each patient will be simultaneously measured with the belt and ECG/CI (paired design). To compare the devices, a non-inferiority/equivalence framework will be used. Here, equivalence is defined as the limit of agreement of the HR/RR between the belt and ECG/CI being within prespecified margins (see table 1 for the margins). Non-inferiority is defined as the performance of clinical event detection and quality criteria not being worse than prespecified margins.

Study population

Preterm and term infants being routinely monitored with the standard cardiorespiratory monitor (Intellivue MP90, Philips Healthcare, Eindhoven, The Netherlands) are included in the study. To ensure a representative sample of the target population, infants in different age groups will be included. Infants with chest skin lesions, congenital anomalies, and other scenario’s preventing belt placement, such as (effects of) surgery or wrap for therapeutic hypothermia, will be excluded.

Primary outcome

As HR-monitoring is clinically most relied on and both ECG and dEMG provide the HR by measuring cardiac electrical activity, while CI and dEMG measure respiration with a different technique, the HR is considered the primary outcome.3 16 This will be studied with three criteria, which will be compared with the prespecified margins in table 1: (1) Reliable monitoring performance through second-to-second HR measurement agreement in terms of differences in measured HR between the belt and the ECG/CI monitoring; (2) The detection of a composite cardiac event consisting of bradycardia (HR <100 beats per minute for at least five seconds)17 and tachycardia (HR >180 beats per minute for at least ten seconds)18 between the belt and the ECG measured with adhesive electrodes. The minimal duration of a bradycardia or tachycardia will prevent the inclusion of technical errors (short drops or increases in the HR) in our analysis and is lower for bradycardia compared with tachycardia as bradycardias are shorter events.1 The thresholds are empirically chosen to detect all low and high HR-values; (3) Non-inferior quality (percentage of time with HR recordings without data loss).

Moreover, we will perform subgroup analyses to investigate whether the HR measurement performance is consistent under different clinical activities (eg, kangaroo care, feeding) and in the different age groups.

Secondary outcomes

The secondary outcome is the measured RR. This will be studied using the following three criteria, which will be compared with the prespecified margins in table 1:

1. Comparing the trend in RR values provided by the belt and CI, based on the difference in the 10 min moving averages. The RR-trend is studied as this is used in the clinical practice to detect for example increases in RR over time as a marker of clinical deterioration of a patient.3 Since CI is widely used for neonatal respiratory monitoring, it is used as the reference technique.

2. Next to comparing the RR-trend, the ability to detect apnoea and tachypnoea is studied as the detection of these critical respiratory events based on RR is another purpose of the respiratory monitoring. Clinically relevant apnoeas are considered when indicated by a RR <20 breaths per minute measured with CI for at least 10 s, associated with a desaturation (arterial oxygen saturation as measured by pulse oximetry (SpO₂) <80% for at least 10 s) and/or bradycardia (HR <100 beats per minute for at least five seconds) (objective apnoea measurement).17 A RR <20 breaths per minute is chosen for the apnoea definition as we solely use the numerical RR-values, because despite the two different measurement techniques this endpoint is equal, and to capture all periods of low breathing frequency.

   Tachypnoea is defined as a prolonged period of the averaged (moving average with a window size of 10 min) RR >60 breaths per minute and >100 breaths per minute (approximately two times the average normal RR).19 To cover short and long periods of tachypnoea, 3 different durations are studied (30 s, 60 s and 10 min).

3. Calculating the percentage of time with reliable respiratory monitoring (without data loss and with an acceptable signal-to-noise ratio).

Data collection

The following basic characteristics and demographic information will be collected at the baseline of the study: gestational age, birth weight, gender, age and weight at day of measurement, relevant medical status (respiratory support, medication and underlying illness during measurement), chest circumference, nipple distance, skin type at study start by visual inspection (normal, dry, flaky, oily, moist, other).

Sample size calculation

A power calculation is performed for the primary outcome using data collected in a previous study.15 Among the three criteria, criteria 1 needs the largest sample size and is used for our study. This resulted in 39 required infants to achieve 80% power with an overall 5% type I error with a Bonferroni correction (details in the statistical analysis plan (SAP) in online supplemental file 1).

In addition, an interim analysis will be performed as the power calculation was based on the previous study and recruitment of infants without being able to answer research questions is unethical.20 This will be performed after including one-third of the infants for sample size adaption using the method of Mehta and Pocock.21 If the conditional power falls within the predefined ‘promising zone’, the sample size will be increased to an upper limit of 52 infants. Otherwise, the study will proceed with the original sample size. To ensure that a representative sample of the age distribution of infants at a NICU, infants in different postmenstrual age groups will be recruited with the same proportions as in the target population (minimally 10 infants <30 weeks, between 30–32 weeks and >32 weeks).

Study procedures

The Bambi® belt system is a non CE-certified medical device, designed for wireless cardiorespiratory monitoring of (pre)term infants in a hospital environment. All included infants will be monitored with the belt in addition to standard ECG/CI for 24 hours to obtain representative clinical scenarios throughout the entire day. The measurement setup is visualised in figure 1 and consists of (1) dEMG measurement with the belt and (2) the extraction of patient monitor data.

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In the belt, three dry electrodes are incorporated (figure 2). When placing the belt at the height of the diaphragm, the outer two electrodes are in the nipple line and the middle electrode is in line with the sternum. The three ECG/CI electrodes are attached at the original location without hindering belt placement. The electrical signal of the diaphragm measured with the belt is wirelessly transmitted to the receiver module (REM) by the sensor module (SEM). The REM processes the dEMG signal to obtain the ECG and respiration signal (averaged diaphragmatic activity). An inbuilt algorithm provides the HR and RR out of the ECG and respiration signal respectively. This data is transported to a bedside computer. The data from the patient monitor (ECG, HR, RR and SpO₂) is extracted from the bedside monitor using an isolated cable and is also transported to the bedside computer.

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The belt data from the REM and patient monitor are recorded and synchronised using a dedicated software package (Polybench, Applied Biosignals, Weener, Germany) on a personal bedside computer. Data is recorded at a sample rate of 1–500 Hz for rate and waveform data, respectively. The bedside software also provides the possibility to make measurements annotations by nurses and researchers during data recording, such as repositioning of the infant, nursing and kangaroo care.

During the study, daily routine care proceeds as usual. The location of the belt is regularly checked and if necessary repositioned (similar to the clinical practice). Notifications are visualised when contact between skin and the belt is lost (Leads off) or when there is no connection between the SEM and REM (Bluetooth Loss Error). In case of the first notification, the belt may be repositioned, while in case of Bluetooth loss the battery level of the SEM or blocking of this sensor (eg, by an arm) are checked.

Preferably, the belt stays in place during the study. However, the belt can be removed during diagnostic imaging, patient handling, or in case of skin irritation at the belt location. The reason for removal will be annotated. If the belt is removed, the medical staff, parents and one of the dedicated researchers will decide together if the belt can be reapplied.

Recruitment

Parents of all eligible infants are approached for consent to obtain a sample as heterogeneous and representative as possible. Preferably, infants are included as soon as possible after birth. During the 24 hours, the study can be terminated if requested by parents or the treating physicians. In case of withdrawal of a subject, an extra subject will be included.

Safety

Being a medical device study, this study was classified as a moderate risk.22 A specified monitor plan for the study is made based on risk-classification.

Summary and descriptive statistics

Categorical data will be summarised by numbers of counts and percentages. Continuous data will be summarised by mean, SD if data is normal and median, IQR if data are skewed. Minimum and maximum values will also be presented for continuous data when appropriate.

Statistical analysis of the primary outcome

Statistical analysis of secondary outcomes

Secondary analyses, based on the same statistical methods for the criteria of the primary outcome, include all secondary endpoints (apnoea and tachypnoea detection, RR-trend analysis (see SAP)) and evaluation during different scenarios.