Work of Breathing During Non-invasive Ventilation in Premature Neonates

Background/Rationale:

Historically, respiratory insufficiency and respiratory failure have been frequent sources of
morbidity and mortality in premature neonates. Intubation for invasive mechanical ventilation
has been a life-saving therapy for many of these patients, but is not without risks. These
risks include pulmonary complications such as volutrauma, extrapulmonary air leak syndromes,
and traumatic injury to the large airways; non-pulmonary complications such as retinopathy of
prematurity; and long-term complications such as bronchopulmonary dysplasia [Miller, Badiee].
Concern over these effects of prolonged mechanical ventilation has led to the development of
non-invasive forms of respiratory support.

Non-invasive ventilation (NIV) is a frequently used modality of respiratory support for
premature neonates in the setting of respiratory insufficiency or recent weaning from
invasive ventilation. Synchronized NIV is effective at decreasing respiratory effort as
compared to unsynchronized NIV and nasal continuous positive airway pressure (NCPAP) [Chang].
Synchronizing NIV in premature neonates to the patient's own respiratory efforts is difficult
because of the large air leaks, weak inspiratory efforts, and high respiratory rates inherent
to this population [Vignaux].

A novel method of synchronization, neurally adjusted ventilatory assist (NAVA) uses
electrodes on a functional naso/orogastric tube (Edi catheter) to detect diaphragm
contractions and time the onset, duration, and peak inspiratory pressure of supporting
breaths with the electrical activity of the diaphragm (Edi) [Sinderby]. NAVA can be used with
both invasive and non-invasive ventilation modalities, and there have been several small
studies examining invasive NAVA in children and adults [Stein, de la Olivia]. Fewer studies
have examined NIV NAVA in these populations, and only two clinical trials have examined NIV
NAVA in premature neonates [Beck, Lee]. Beck and colleagues in Canada showed feasibility and
preservation of synchrony during NIV NAVA in premature neonates [Beck]. Lee and colleagues in
Korea showed fewer asynchrony events, lower trigger delay, and lower peak inspiratory
pressures with NIV NAVA compared to non-invasive pressure support ventilation in premature
neonates [Lee]. Neither study examined work of breathing (WOB) in preterm neonates ventilated
with NIV NAVA.

Work of breathing during assisted ventilation is the portion of the driving pressure for
ventilation contributed by the patient's respiratory muscles. A research team at Arkansas
Children's Hospital was able to demonstrate that NAVA achieves reduced response time, work of
breathing, and asynchrony with neurally triggered breaths as compared to pneumatically
triggered breaths in an animal model [Heulitt]. This team was also able to show similar
results in a clinical study of intubated pediatric patients with bronchiolitis [Clement]. A
recently completed study at this institution looked at work of breathing in neonatal pigs
comparing NIV NAVA with the unsynchronized nasal intermittent positive pressure (NIPPV) mode
currently used at this hospital. Using the pressure-time product (PTP) as a measure of WOB
this study was able to show that WOB was lower with NAVA. The PTP cannot be reliably used in
infants on NIV because the nasal prong interface allows large air leaks at the nose and
mouth, which interfere with accurate measurements.

Thoracoabdominal asynchrony (TAA) is an important correlate of WOB and increased respiratory
load in preterm infants and can be measured without invasive monitoring. TAA can be measured
using a respiratory inductance plethysmography (RIP) bands around the patient's chest and
abdomen to quantify chest wall and abdominal movement. The degree of asynchrony between the
two compartments is reflected in the phase angle (θ), which can be calculated from the RIP
band measurements.

This study will examine estimated WOB in a population of premature neonates with respiratory
insufficiency currently on non-invasive support. Infants will serve as their own controls and
will be studied on NIV NAVA and NIPPV. Order of assignment will be randomized. Researchers
will use RIP bands to measure thoracic and abdominal movement, then calculate the phase angle
(θ) as an estimate of WOB. Study personnel will measure other respiratory parameters
correlating with ventilation and gas exchange including the following: tidal volume
(arbitrary units, AU), minute ventilation (AU/min), respiratory rate, transcutaneous oxygen
and carbon dioxide, oxygen saturation and FiO2 requirement, peak inspiratory pressure, and
delivered end expiratory pressure. Investigators will also evaluate measures of breathing
asynchrony to include trigger delay (time between initial increase in Edi signal and
initiation of delivered ventilator flow) and asynchrony index (number of asynchrony events
divided by total events, as a percent).

Study Design/Procedures/Population:

Fifteen premature neonates of between 1-2 kilogram current weight, with gestational age at
birth between 24-34 weeks, and receiving non-invasive ventilation will be enrolled in the
study. Inclusion criteria will be as follows: respiratory insufficiency currently requiring
non-invasive ventilation (either NIPPV or NAVA), current FiO2 requirement less than 0.40, and
clinical stability. Exclusion criteria will be as follows: ionotropic support, clinical
instability (temperature instability, heart failure, bleeding, active infection, significant
apnea or bradycardia), known major congenital anomalies (congenital heart disease, abdominal
wall defects, gastrointestinal tract defects, cleft palate, or neurologic defects), known
cystic fibrosis, nitric oxide use, and cyanotic congenital heart disease.

At the beginning of the study, RIP bands will be placed around the infant's chest and
abdomen. An Edi catheter will be placed and the current gastric catheter may or may not be
removed. Infants will be ventilated with the Servo i ventilator equipped with NIV NAVA
software {Maquet, Solna, Sweden}. Data will be continuously and simultaneously acquired using
the MP100 Biopac data acquisition system. Data acquired will be as follows: heart rate,
oxygen saturation, transcutaneous CO2 and O2, PIP, PEEP, rib cage and abdominal RIP signals,
summed tidal volume, and Edi. Infants will receive 15 minute trials of NIV NAVA and NIPPV in
random order with the first 10 minutes after changing to be considered a washout period and
the last 5 minutes used for data collection. The data recorded from the two RIP bands will be
used to calculate the phase angle (θ) as an estimate of WOB.

Risks and Benefits:

Infants often have gagging and may have vomiting when a gastric tube, such as the NAVA
catheter, is removed or replaced. Rarely, patients could have a gastric tube go into a place
besides the stomach or coil in the esophagus. Researchers should be able to detect if this
occurs using the placement screen on the ventilator because the NAVA catheter has electrodes
on it that detect the electrical activity of the heart and diaphragm, which can be used to
determine the location.

In extremely low birth weight infants, transcutaneous monitors (TCOMs) can cause skin
burning. These effects are not seen in larger babies like those included in this study.

There is a small risk of loss of confidentiality inherent in all research. Investigators will
do everything possible to protect the participants' confidentiality.

There may or may not be direct medical benefit to the infants involved in this study. The
infants will have continuous carbon dioxide and oxygen monitoring during the study and if any
patient has any problems, study personnel will be able to detect and respond to this quickly.
If a patient shows improvement while using NAVA, investigators may be able to suggest to the
treatment team that this mode be continued. If using NAVA improves work of breathing in
babies, then the researchers hope the information learned from this study will benefit other
infants needing respiratory support in the future.

Data Handling/Recordkeeping:

The principal investigator will carefully monitor study procedures to protect the safety of
research subjects, the quality of the data and the integrity of the study. Each patient will
be assigned a unique identifying code or number. The key to the code will be kept in a locked
file in the principal investigator's office. Only the principal investigator and
co-investigators will have access to the code and information that identifies the subject in
the study.

Data Analysis:

The primary hypothesis is that phase angle (θ) using respiratory inductance plethysmography
will be decreased with the use of NAVA in comparison to NIPPV in our study sample.

Data collected will be checked for outliers and extreme values, as well as distributional
assumptions of the parametric statistical tests. Repeated measures ANOVA will be used to
compare the primary and secondary outcomes under the two ventilation methods when such
assumptions are met. When significant deviation from assumptions is encountered,
nonparametric alternatives will be used. Statistical analyses will be performed using Stata
(College Station, TX) statistical software.

Sample Size, Power Calculation:

Investigators plan to recruit 15-20 neonates who are 24-34 weeks gestation with respiratory
insufficiency. Based on the results in the animal model, a 30% reduction in the primary
outcome is expected. Since the average phase angle was found to be variable among preterm
infants (ranged from 2.8-162.9), there are several scenarios of the sample size and power
calculation presented for analysis [Ulm]. A sample size of 15 neonates achieves 82% power to
detect a 30% change in the primary outcome with an estimated standard deviation of
differences of 18.8, 37.5, or 56.3 respectively for an average phase angle of 50, 100, and
150 degrees with the use of NIPPV. All calculations assume a significance level of 0.05 using
a two-sided paired t-test.

Ethical Considerations:

This study will be conducted in accordance with all applicable government regulations and
University of Arkansas for Medical Sciences (UAMS) research policies and procedures. This
protocol and any amendments will be submitted and approved by the UAMS Institutional Review
Board (IRB). The formal consent of each subject, using the IRB-approved consent form, will be
obtained before that subject is submitted to any study procedure. All subjects for this study
will be provided a consent form describing this study and providing sufficient information in
language suitable for subjects to make an informed decision about their participation in this
study. The person obtaining consent will thoroughly explain each element of the document and
outline the risks and benefits, alternate treatment(s), and requirements of the study. The
consent process will take place in a quiet and private room or by phone, and subjects may
take as much time as needed to make a decision about their participation. Phone consent will
be obtained with a witness and consent will be faxed to parent(s). Phone consent will only be
obtained in the event that the parents are unable to be present.

Participation privacy will be maintained and questions regarding participation will be
answered. No coercion or undue influence will be used in the consent process. The consent
form must be signed by the subject, the parent and the individual obtaining the consent. A
copy of the signed consent will be given to the participant, and the informed consent process
will be documented in each subject's research record.

Dissemination of Data:

Results of this study may be used for presentations, posters, or publications. The
publications will not contain any identifiable information that could be linked to a
participant.

Inclusion Criteria:

- Gestational age at birth between 24 and 34 weeks

- Receiving noninvasive ventilation

- Between 1 and 2 kg current weight

- Current FiO2 requirement less than 0.40

- Clinical stability

Exclusion Criteria:

- Known major congenital anomalies (congenital heart disease, abdominal wall defects,
gastrointestinal tract defects, cleft palate, or neurologic defects)

- Clinical instability (temperature instability, heart failure, bleeding, active
infection, significant apnea or bradycardia)

- Known cystic fibrosis

- Use of inhaled nitric oxide

- Cyanotic congenital heart disease