Prematurity-Related Ventilatory Control (PRE-VENT): Role in Respiratory Outcomes Clinical Research Centers (CRC)
Phase: NA
Conditions: Infant,Premature
Sponsor: University of Alabama at Birmingham

Pre-Vent Apnea 
 
 
ClinicalTrials.gov numbers: 
 
NCTpending (when available) for Aim 2  
NCTpending (when available) for Aim 3 
 
 
Principal Investigator(s): 
 
Namasivayam Ambalavanan MD, Univ of Alabama at Birmingham, Corresponding PI 
Premananda Indic PhD, University of Texas-Tyler (MPI) 
 
 
Other Investigators:  
 
Waldemar A. Carlo MD (UAB; Co-Inv) 
Arie Nakhmani PhD (UAB; Co-Inv) 
David Paydarfar MD (U Texas-Austin; Co-Inv) 
Elisabeth Salisbury PhD (U MASS; Co-Inv) 
Brett Turner MD (UAB; Co-Inv) 
 
Collaborators: PreVENT Consortium 
 
 
Version Date: 
October 26, 2017 
 
Funding: 
NIH/NHLBI U01 HL133536
1 

Contents 
 
Section 1. 
Abstract ............................................................................................................................... 4 
Section 2. 
Conflict of Interest Disclosures ........................................................................................... 5 
Section 3. 
Statement of Problem......................................................................................................... 6 
3.1. 
Primary Hypothesis or Question ............................................................................ 6 
3.2. 
Secondary Hypothesis or Questions (s) (if applicable) .......................................... 6 
3.3. 
Background and Rationale ..................................................................................... 6 
Section 4. 
Methods ............................................................................................................................ 12 
4.1. 
Study Population .................................................................................................. 12 
4.1.1. Inclusion Criteria ..................................................................................... 12 
4.1.2. Exclusion Criteria .................................................................................... 12 
4.2. 
Detailed Study Procedures .................................................................................. 12 
4.2.1. Screening ................................................................................................ 12 
4.2.2. Consent Procedures ................................................................................ 12 
4.2.3. Randomization Procedures ..................................................................... 12 
4.2.4. Study Intervention and Comparison ....................................................... 13 
4.2.5. Blinding/Masking .................................................................................... 14 
4.2.6. Control or Monitoring of Co-interventions............................................. 14 
4.2.7. Primary Outcome .................................................................................... 14 
4.2.8. Secondary Outcomes (if applicable) ....................................................... 15 
4.2.9. Additional Safety Outcomes (if applicable) ............................................ 15 
4.2.10. Compliance Monitoring .......................................................................... 15 
4.2.11. Study Specimens ..................................................................................... 15 
4.2.12. Post-hospital Procedures ........................................................................ 15 
4.2.13. Follow-up at 24 Months .......................................................................... 15 
4.2.14. Additional Follow-up Assessments ......................................................... 15 
4.3. 
Potential Risks and Benefits to Subjects .............................................................. 15 
Section 5. 
Analytical Plan ................................................................................................................... 18 
5.1. 
Statistical Analysis Plan ........................................................................................ 18 
5.2. 
Sample Size and Power Estimates ....................................................................... 18 
5.3. 
Available Population ............................................................................................ 19 
5.4. 
Projected Recruitment time ................................................................................ 19 
5.5. 
Study Monitoring Plan ......................................................................................... 19 
5.5.1. Reporting Adverse Events .......................... Error! Bookmark not defined. 
5.5.2. Data Monitoring Plan and Stopping Rules . Error! Bookmark not defined. 
Section 6. 
References ........................................................................................................................ 20 
 
3 

SECTION 1. 
ABSTRACT 
Study Objective  
Prospectively define and validate ventilatory mechanisms associated with resilience against or risk for 
development of impaired oxygenation at 36 weeks’ postmenstrual age (physiologic definition of BPD) 
and at follow-up (corrected age of 3 months)  
Study Design Type  
Aim 1: Prospective Observational Study 
Aims 2 and 3: Randomized Cross-over Comparative Effectiveness Trial 
Eligibility Criteria  
Aim 1: This study will enroll neonates in our Regional NICU (RNICU) at UAB as follows: 
Inclusion: 
• 
Inborn infants weighing 401-1,000 grams on admission and/or 220/7 to 286/7 (<29 weeks) inclusive 
completed weeks of gestation,  
• 
Infants eligible for full care and resuscitation as necessary, and surviving beyond 24 h of age 
• 
Enrollment at <1 week post-natal age 
• 
Informed consent from parent/guardian 
Exclusion 
• 
Refusal or withdrawal of consent 
• 
Major congenital malformations (e.g., not including patent ductus arteriosus, small hernia) 
Aim 2: This study will enroll the subset of infants from Aim 1 who are still intubated or on nasal IMV at 2 
weeks postnatal age, meet blood gas criteria (arterial or capillary arterialized blood gas values done q12-
24h, as most infants do not have an arterial line at 2 weeks: pH >7.25, PaCO2 >40 mm Hg), have TcCO2 
monitoring with TcCO2 values that trend and correlate appropriately with PaCO2, and are not judged too 
unstable by the Attending neonatologist. 
Aim 3: This study will enroll the subset of infants from Aim 1 who are receiving oxygen supplementation 
at 32w and 36w PMA, and are not judged too unstable by the Attending neonatologist. 
Study Intervention/Methods  
After parental consent is obtained, infants will be enrolled in prospective collection of continuous 
physiologic data from vital signs monitors (HR, RR, SpO2). In addition, intensive multiparametric 
physiologic monitoring and data collection (96 hours each) at three distinct time frames: 2 weeks 
postnatal age, 32 weeks post-menstrual age (PMA), 36 weeks PMA will be done, along with a sleep 
study at 36 w PMA and 3 months corrected age.  Aim 1 will be observational, using physiological data to 
develop predictive mathematical models for outcomes. Aim 2 will determine if late (at or beyond 
postnatal day 14) mild permissive hypercapnia is associated with reduction in apnea, bradycardia, and 
hypoxemic episodes and with improved stability of oxygenation. Aim 3 will determine if servo-controlled 
oxygen environment is associated with reduction in hypoxemic episodes and improved stability of 
oxygenation, as compared to oxygen administered by nasal cannula. 
 
Primary Outcome  
Hypoxemic episode (SpO2 <85% for >10s) frequency 
Secondary Outcome(s)  
Frequency of Hypoxemia (SpO2<85%), Bradycardia (HR<100/min), Bradycardia episode (HR<100/min for 
>10s); Apnea (RR=0 for >20s, or RR=0 for >10s + SpO2 <85% or HR<100/min); BPD defined using 
physiologic definition at 36w PMA  
4 

SECTION 2. 
CONFLICT OF INTEREST DISCLOSURES 
 
Per Title 42, Code of Federal Regulations, Part 50, Subpart F (50.604 Responsibilities of Institutions 
regarding Investigator financial conflicts of interest), as amended, institutions and all subrecipients are 
required to notify the grants officer of any financial conflicts of interest (FCOI) prior to expenditure of any 
funds and within 60 days of any subsequently identified FCOI. 
 
Financial Conflicts of Interest of the Institutions and Investigators  
No conflicts of interest exist with commercial entities.  
 
5 

SECTION 3. 
STATEMENT OF PROBLEM 
 
3.1. 
PRIMARY HYPOTHESIS OR QUESTION 
Aim 1: We hypothesize that mathematical models of personalized ventilatory patterns based on 
multiparametric vital signs monitoring and signal analysis methods will be able to predict hypoxemic 
episodes in individual infants before they occur. 
 
Aim 2: We hypothesize that late (at or beyond postnatal day 14) mild permissive hypercapnia is 
associated with reduction in hypoxemic episodes 
 
Aim 3: We hypothesize that servo-controlled oxygen environment is associated with reduction in 
hypoxemic episodes, as compared to oxygen administered by nasal cannula 
 
3.2. 
SECONDARY HYPOTHESIS OR QUESTIONS (S) (IF APPLICABLE) 
Aim 1: We hypothesize that mathematical models of personalized ventilatory patterns based on 
multiparametric vital signs monitoring and signal analysis methods will be able to predict (a) bradycardia 
events, (b) hypoxemic time, (c) bradycardia time, (d) apneic episodes  in individual infants before they 
occur,  
Aim 1: We hypothesize that mathematical models of personalized ventilatory patterns based on 
multiparametric vital signs monitoring and signal analysis methods will be able to identify patterns of 
ventilatory abnormalities associated with BPD with and without pulmonary hypertension, as well as with 
and without respiratory or feeding support at 3 months corrected age. 
Aim 2: We hypothesize that late (at or beyond postnatal day 14) mild permissive hypercapnia is 
associated with reduction in (a) bradycardia events, (b) hypoxemic time, (c) bradycardia time, (d) apneic 
episodes 
Aim 3: We hypothesize that servo-controlled oxygen environment is associated with reduction in (a) 
bradycardia events, (b) hypoxemic time, (c) bradycardia time, (d) apneic episodes 
 
 
3.3. 
BACKGROUND AND RATIONALE 
 
Aim 1:  
The respiratory rhythm is initiated by brainstem neural circuits that signal the timing and magnitude of 
each breath. Preterm infants have irregular breathing due to immaturity of these brainstem circuits. The 
irregularity in breathing can be quantified by the interbreath interval (IBI), the time interval between 
breaths, and its variations in time around the mean (the IBI variability) (1, 2). The probability density 
distribution (P) of IBIs follows a power law, P(IBI) ~ IBI-α, with the exponent α indicating the relative risk 
of insufficient breathing. With maturation, α increases from 2.6+0.4 at 41+4 wk to 3.2+0.4 at 47+6 wk 
PMA, indicating a decrease in apnea (p = 0.002) (1, 2). Analysis of IBI in infants indicates stochastic 
characteristics (1) as well as deterministic dynamic characteristics (e.g. low frequency oscillations with 
periodic apnea) (3).  
The Analytical Core with Drs. Indic, Paydarfar, and Bloch-Salisbury has pioneered an algorithm to 
capture both the stochastic as well as deterministic dynamic characteristics of IBI, providing a 
framework for computing the instantaneous estimates of variability in breathing (2, 4). In this point 
process model, a lognormal parametric structure represents the stochastic nature of IBI and a higher p-
6 

order autoregressive (AR (p)) model describes the dynamic nature of IBI (2). The descriptors used to 
study the instantaneous characteristics of IBI 
include: 1) mean IBI, M; 2) variance of IBI, V; 
3) skewness of IBI, S; 4) kurtosis of IBI, K; 5) 
mean respiratory rate, Mr ; 6) variance of 
respiratory rate, Vr ; 7) spectrum, and 8) 
poles. These parameters and descriptors 
provide an innovative approach for the 
assessment of instability of breathing in 
neonates. Figure 1 illustrates an example of 
IBI data along with the estimated µ and σ2. It 
is evident that σ2 shows fast step increases 
both prior and during the apnea event. 
Figure 
2 
indicates 
how 
both 
spectrum and predominant pole provides 
additional dynamic measures of IBI instability 
that precede apnea. Kolmogorov-Smirnov 
(KS) tests and autocorrelation plots indicate 
that the model is able to accurately capture 
the stochastic structure. Similar point process 
models have been developed for bradycardia 
and its severity. Integrated power spectrum 
dynamics 
are 
larger 
following 
apneic 
episodes, indicating that apnea induces 
instability in IBI that is maintained for at least 
several minutes following apnea (which is 
familiar to clinicians, as one episode of apnea 
is often followed by others) (Figure 3). 
  
In preterm infants, cardio-respiratory 
interactions are considered an important 
indication of the level of maturation of 
vagally-mediated autonomic effects on the 
heart, 
although 
the exact 
relationship 
between heart rate variability (HRV) and 
respiration in preterm infants has not been 
determined (5). The influence of respiration 
on heart rate variability (called “respiratory 
sinus arrhythmia” or RSA) is detected by a 
peak in the power spectrum of HRV at the 
breathing frequency. This signature of RSA 
occurs normally at the breathing frequency 
of ~1 Hz (60/min) in a preterm neonate, but 
may not be observed due to irregularity in 
breathing. We have developed a new 
framework for studying the interaction 
between heart rate variability and respiration in preterm infants (6). We quantified cardio-respiratory 
interactions in 11 preterm infants using multivariate autoregressive analysis and calculated the 
coherence as well as gain using causal approaches. The significance of the interactions in each infant 
Figure 1: (a) Instantaneous time varying estimated µ 
and σ2 for the IBI data from a preterm infant with local 
likelihood window W= 120 s, time step Δt = 0.05, α = 
0.01 (optimized by KS analysis), and p = 4 (optimized 
by AIC, autocorrelation function, and KS analysis). (b) 
KS plot (black line) of the time-rescaled quantiles 
derived from the model. (c) Autocorrelation function of 
the transformed times estimated for the first 60 lags. 
Dotted lines represent the 95% CI. (From Indic et al. 
2013) 
 
Figure 2: Instantaneous time-varying estimates of 
spectrum (a) and dynamics of predominant pole (b) of 
IBI data, for same infants as in Figure 2. (From Indic 
et al. 2013) 
7 

was determined by surrogate data analysis. The method 
was tested in control conditions as well as in two 
different experimental conditions; with and without use 
of mild vibrotactile intervention. Compared to traditional 
spectral techniques, this bivariate approach considers 
both the R-R interval and respiratory signal in a single 
modeling framework and is able to separate the 
mutually directional causal interactions between RR and 
respiration. 
The 
closed-loop 
causal 
formulation 
quantifies features otherwise not identifiable by 
standard measures of HRV and allows separation of 
interactions between RR and respiration occurring in 
both directions (6). Of note, we found a large percentage 
of power in the LF (0.01-0.015Hz) range due to pauses in 
breathing and slow frequency patterns in the respiratory 
signal. Our finding of a bidirectional interaction between 
HRV and respiration suggests that fluctuations in cardiac 
dynamics may also alter respiratory frequency and 
potentially induce apnea.   
 
 We have recently shown in a prospective cohort 
study of 145 ELBW infants that pulmonary hypertension 
is relatively common, affecting at least 1 in 6 ELBW 
infants, and persists to discharge in most survivors (7). It 
is possible that recurrent hypoxemic episodes induce 
hypoxic pulmonary vasoconstriction and increase the risk of pulmonary hypertension in the setting of 
BPD. This hypothesis will be rigorously tested in this Aim. 
 
Aim 2: 
Abnormal regulation of breathing is the underlying cause of apnea of prematurity. Gerhardt and 
Bancalari (8) demonstrated more than three decades ago that compared to gestational age, postnatal 
age and birth weight-matched control infants without apnea, infants with apnea had lower tidal 
volume  (4.4 + 1 vs 5.3 + 1.6 mL/kg), lower alveolar ventilation  (96 + 21 v 129 + 33 mL/kg/min), higher 
alveolar PCO2 (45.4 + 8.5 vs 35.6 + 4.7 mm Hg), lower esophageal pressure change (4.5 + 0.9 vs 6.0 + 1.8 
cm H2O), and flatter slope of the CO2 response curve (ΔVe/ΔPaco2 (20.2 +/- 10.6 vs 40.7 +/- 19.9 
mL/min/kg/mm Hg CO2). This impaired central chemosensitivity is improved by methylxanthines and 
may account for reduction of apnea by these agents. Importantly, Carlo (UAB Co-Inv) et al. (9) 
demonstrated in healthy preterm infants using electromyograms (EMGs) and hyperoxic CO2 rebreathing 
that the upper airway muscles (e.g. genioglossus and alae nasi) have a higher CO2 threshold compared 
to the posterior cricoarytenoid and diaphragm which may contribute to an imbalance between the 
negative pressure generated by the chest wall muscles and the concomitant upper airway dilation, 
leading to upper airway collapse and obstructive apnea.  
The baseline PaCO2 in both preterm infants is only 1.3 mm Hg above the apneic threshold 
compared to 3-4 mm Hg for adults (10) and this closeness suggests that small oscillations of PaCO2 in 
response to carotid body hyperactivity, mild hyperventilation, stimulation, etc may lead to apnea. In 
preterm infants, 
eupneic 
PaCO2 
was 
38.6+1 
mm 
Hg, 
the 
pre- 
periodic 
breathing 
PaCO2 apneic threshold was 37.3 + 1 mm Hg, the post-periodic PaCO2 was 37.2 + 1.4 mm Hg, and the 
transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was 
accompanied by a small increase in breathing frequency (10). 
Figure 
3. 
(a) 
Average 
power 
spectrum 
in 
a 
time 
frequency 
representation for the IBI data from a 
preterm infant with apneic episodes. 
Zero on time axis represents the time 
of 
apnea 
event. 
(b) 
Average 
integrated power (black line) along 
with the 95% confidence interval (gray 
line). 
The 
average 
power 
is 
significantly different prior and post 
apnea events with p< 0.001 (From 
Indic et al. 2013). 
8 

Lung injury may be reduced by reducing volutrauma by a strategy of minimal ventilation and 
tolerance of higher PaCO2. We have shown earlier that a ventilatory strategy of mild permissive 
hypercapnia (PaCO2 45-55 mm Hg) compared to normocapnia (35-45 mm Hg) is associated with fewer 
very preterm infants on assisted ventilation during the first 96 hours after randomization, and without 
differences in mortality, air leaks, intraventricular hemorrhage, PDA or other complications (11). On the 
other hand, evaluation of a higher PaCO2 target of 55-65 mm Hg compared to 35-45 mm Hg during the 
first 7 postnatal days suggested that clinical outcomes were not improved with the hypercapnia  maybe 
because the duration or magnitude of hypercapnia were not sufficient (12).  
In the SAVE study, to determine whether minimal ventilation (PCO2 target >52 mm Hg) 
decreased death or BPD, compared to routine ventilation (PCO2 target <48 mm Hg), preterm infants 
(birth weight 501-1000g) and mechanically ventilated before 12h were randomly assigned to either 
minimal or routine ventilation strategies, along with a tapered dexamethasone course or placebo for 10 
days, using a 2x2 factorial design (13). After enrollment of 220 patients, the trial was halted because of 
nonrespiratory adverse events related to dexamethasone (spontaneous intestinal perforation). Despite 
the early termination of the trial, an important finding was that ventilator support at 36 weeks was 1% 
in the minimal versus 16% in the routine group (p <0.01). However, there was no difference in 
BPD/death at 36w (RR 0.93, 95% CI 0.77-1.12, p=0.43) due to the inclusion of moderate BPD and death 
in the outcome (13).  
More recently, in SUPPORT comparing CPAP and a protocol-driven limited ventilation strategy to 
early intubation, surfactant and conventional ventilation strategy, infants in the CPAP group had 
extubation criteria that included a PaCO2 <65 
mm Hg with pH>7.2 (14). On the other hand, 
the surfactant group had extubation criteria 
that included a PaCO2 <50 mm Hg with 
pH>7.3 (14). The primary outcome of death or 
physiological BPD at 36w PMA was not 
significantly different, but better secondary 
outcomes were noted in the CPAP group (e.g. 
lower mortality in the 24-25w pre-specified 
subgroup, 
fewer 
days 
of 
mechanical 
ventilation, less postnatal steroids) (14). 
However, apnea and instability in oxygenation 
were not specifically evaluated in this trial. We 
performed a secondary analysis of PaCO2 in 
relation to outcome in SUPPORT, and 
observed 
that 
severe 
IVH, 
BPD, 
and 
neurodevelopmental 
impairment 
were 
associated 
with 
hypercapnic 
infants 
(maximum PaCO2 in the highest quartile) and 
fluctuators (infants with both hypercapnia and 
hypocapnia – with maximum PaCO2 in highest 
quartile and minimum PaCO2 in lowest 
quartile) (15). Maximum PaCO2 was positively correlated with maximum FiO2 (rs 0.55, p<0.0001) and 
ventilator days (rs 0.61, p<0.0001), generally considered markers of illness severity, suggesting that high 
PaCO2 is a surrogate marker for respiratory illness severity (15). Of interest, the average PaCO2 even in 
infants without severe IVH was ≥48 mm Hg in the first two postnatal weeks with a relatively narrow IQR 
(∼10 mm Hg). Our data suggest clinical practices have evolved to maintain PaCO2 in the ‘permissive 
hypercapnia’ range (45–55 mm Hg)(15). 
Figure 4: Trend view of heart rate (HR), oxygen 
saturation (SpO2), respiratory rate (RR), and 
transcutaneous PCO2 (TcPCO2;~15 mmHg above 
PaCO2 in this infant) in a 2 week old preterm infant 
on low SIMV settings (rate 25, 15/4, FiO2 0.21-
0.25). SpO2 was more stable when the TcPCO2 
was higher. Note marked fluctuation in SpO2, and 
normal variability in HR, RR, and TCPCO2. 
9 

A current gap in our knowledge is whether maintenance of PCO2 at a higher level during the 
period of maximum risk of apnea after the first week or two (when the theoretical risk of IVH due to 
higher PaCO2 has also resolved) will keep the PaCO2 above the apneic threshold PCO2 (that is normally 
only 1 mm Hg below the baseline PaCO2)(10) and lower the rate of apnea. Mild permissive hypercapnia 
may elevate the PaCO2 sufficiently above the apneic threshold, improving stability of oxygenation. In our 
NICU, we frequently observe on trend analysis (12-hour trend view is standard, along with waveform 
and real-time values) that infants have fewer apnea and desaturations when they have a higher TcPCO2 
(Figure 4) but this phenomenon has not been systematically investigated. 
 
Aim 3:  
The goal of oxygen supplementation is to maintain stability of oxygenation, i.e., adequate 
oxygenation while minimizing episodes of hypoxemia and hyperoxemia. Preterm infants have 
respiratory instability which makes it challenging to target oxygen saturation in the desired range (16). 
As a consequence, preterm infants spend a considerable proportion of time outside (usually higher 
than) the targeted range (17). While avoiding hypoxemia is important, hyperoxemia can lead to 
oxidative injury. Intermittent hypoxemia in preterm infants is associated with episodic spontaneous 
transient hypoventilation. Caregivers often increase FiO2 during these episodes that may result in 
hyperoxemia, leading to a pattern of intermittent hypoxemia alternating with hyperoxemia. 
intermittent hypoxemic episodes are associated with worse short-term (e.g. increased 
respiratory support, retinopathy of prematurity, and time to full feeds)(18) and longer-term outcomes 
(e.g. neurodevelopmental impairment or NDI)(16). Using data from a subset of 115 preterm infants 
enrolled in the SUPPORT trial, Di Fiore et al.(19) found that infants randomized to the lower SpO2 target 
range (85-89%) had more episodes of intermittent hypoxemia [defined as ≤ 80 % for ≥ 10 seconds and ≤ 
3 minutes] in the 12 days after birth and beyond 57 days after birth compared to infants randomized to 
the higher oxygen saturation (91-95%) target range [p <0.05]. These episodes became shorter in 
duration but increased in severity with increasing postmenstrual age in both groups. Di Fiore et al. (18) 
had previously found that hypoxemic episodes are common [50-100/day] in infants at the lowest 
gestations and increase until 6 weeks after birth, followed by a decrease in weeks 6 through 8. 
Target oxygen saturations at UAB are based on data from the meta-analysis of randomized 
controlled trials of oxygen saturation targets which included data on 4911 infants from the SUPPORT, 
COT, and BOOST II trials (20). Targeting higher SpO2 [91-95%] increased the risk of severe retinopathy of 
prematurity [RR 0.74; 95 % CI, 0.59-0.92] while targeting lower SpO2 [85-89 %] increased the risk of 
death [1.41; 95 % CI 1.14-1.74] and necrotizing enterocolitis [RR 1.25; 95 % CI 1.05-1.49](20). Rates of 
BPD [RR 0.95; 95 % CI, 0.86-1.04] or other outcomes were not different between groups. Therefore, the 
higher oxygen saturation target (91-95% or 90-95% based on expert recommendations) is used at UAB. 
A prospective study followed 71 premature infants < 1500 g receiving O2 until they reached 31 
weeks’ PMA (21). Infants on nasal cannulae spent more time above the target range compared to 
infants on NIPPV/CPAP [Mean ± SD, 60 ± 14 v 41 ± 17%; p<0.002] indicating that O2 delivery modes may 
affect SpO2 targeting. O2 delivery at flows ≤ 1 liter through nasal cannulae, although common, is 
relatively unstudied and many infants receive an effective FiO2 <0.23 (22). Nasal cannulae allow 
entrainment of air with infant breaths (23, 24). The effective hypopharyngeal fraction of inspired O2 
[FiO2] can be calculated using formulae incorporating FiO2, cannula flow, and minute ventilation (24-27). 
However, effective O2 concentration is affected by the magnitude of mouth breathing as well as 
fluctuations in breathing rate, volume, and inspiratory time (28). At our NICU, the incubators are fitted 
with a servo-controlled system (Giraffe incubator with a Servo Control Oxygen System and Giraffe 
Omnibed) for inspired O2 administration that we have termed “oxygen environment”. Oxygen is 
pumped into the incubator and titrated to a set FiO2 via servo-control. This mode of O2 supplementation 
10 

may provide a more stable SpO2 in preterm infants that are receiving O2 therapy compared to nasal 
cannulae but this hypothesis has not been rigorously tested. 
Oxygen environment avoids the difficulty of needing to calculate effective O2 concentrations as 
the set O2 concentration is equal to the hypopharyngeal O2 concentration and there is no change in 
hypopharyngeal O2 concentration with mouth breathing or with fluctuations in respiratory effort. 
Oxygen environment and nasal cannulae are both commonly used methods of O2 delivery at UAB and 
worldwide. If one method is found to be more effective at maintaining the stability of oxygen 
saturations and decreasing episodes of intermittent hypoxemia this will be an important clinical finding. 
11 

SECTION 4. 
METHODS 
 
4.1. 
STUDY POPULATION 
 
 
4.1.1. Inclusion Criteria 
This study will enroll 120 neonates in our Regional NICU (RNICU) at UAB as follows: 
1. Inborn infants weighing 401-1,000 grams on admission and/or 220/7 to 286/7 (<29 weeks) 
inclusive completed weeks of gestation,  
2. Infants eligible for full care and resuscitation as necessary, and surviving beyond 24 h of age 
3. Enrollment at <1 week post-natal age 
4. Informed consent from parent/guardian 
Aim 2: This study will enroll the subset of infants from Aim 1 who are still intubated or on nasal IMV at 2 
weeks postnatal age, meet blood gas criteria (arterial or capillary arterialized blood gas values done q12-
24h, as most infants do not have an arterial line at 2 weeks: pH >7.25, PaCO2 >40 mm Hg), have TcCO2 
monitoring with TcCO2 values that trend and correlate appropriately with PaCO2, and are not judged too 
unstable by the Attending neonatologist. 
Aim 3: This study will enroll the subset of infants from Aim 1 who are receiving oxygen supplementation 
at 32w and 36w PMA, and are not judged too unstable by the Attending neonatologist. 
 
4.1.2. Exclusion Criteria 
 
1. Refusal or withdrawal of consent 
2. Major congenital malformations (e.g., not including patent ductus arteriosus, small hernia) 
 
4.2. 
DETAILED STUDY PROCEDURES 
 
4.2.1. Screening 
Clinical research coordinators will screen very preterm infants admitted to the neonatal intensive care 
unit for meeting inclusion criteria 
 
4.2.2. Consent Procedures 
 
Consent will be obtained after birth of the infant (postnatal consent) at <1 week postnatal age, using 
IRB-approved informed consent forms, by the clinical research coordinator or PI/designee. 
 
4.2.3. Randomization Procedures  
Aim 1: No randomization – this is an observational study on all enrolled infants 
 
Aim 2: Infants enrolled in Aim 2 will be randomized using a computer-generated random sequence 
generator to either (a) initially increase TcCO2 by 5 mmHg above baseline (max of 70 mm Hg; as long as 
pH >7.25) or (b) initially decrease TcCO2 by 5 mmHg below baseline (minimum of 40 mm Hg) 
 
12 

Aim 3: Infants enrolled in Aim 3 will be randomized using a computer-generated random sequence 
generator to either (a) initially administer oxygen by servo-controlled oxygen environment, or (b) 
initially administer oxygen by nasal cannula 
 
 
4.2.4. Study Intervention and Comparison  
 
 
Aim 1:  
This is a non-interventional observational study, in which we will use the data from the intensive 
multiparametric physiologic monitoring of 96 hour duration at each of the three time points of 2 weeks 
postnatal age, 32 weeks PMA, and 36 weeks PMA as well as the polysomnography at 36w PMA and 3 
months follow-up for this Aim. In addition, we will use a random sampling (3 continuous h/day of 2 days 
(Mon/Thurs) in each week of the infant’s hospital stay) of the continuous data recording of HR, RR, and 
SpO2 from enrollment to discharge. These data will be combined with clinical data during the hospital 
course as well as during follow-up, specifically data on respiratory or feeding support. 
Data used will include HR, RR, SpO2, ventilator/O2 supplementation, PETCO2 (end tidal CO2 by 
microcapnography), TCCO2 (transcutaneous CO2), rcSO2 (near-infrared cerebral oximetry), rsSO2 (near-
infrared somatic oximetry), and temperature. Data acquisition, band-pass filtering, and wavelet 
transforms of the signals will be done as described (2, 4, 6, 29).  
We will develop mathematical models of ventilatory patterns to predict apneic, 
hypoxemic and/or bradycardic episodes in individual infants before they occur. We will quantify 
the irregularity in breathing using the IBI and IBI variability as defined earlier (2, 4). The normal 
IBI is around 1 second, but due to the irregular breathing pattern in preterm infants, this may 
vary from <1s to 20s or longer. For this study, we will define eupnea as IBI <2s and apneic range 
as IBI>5s as done previously (29). The basic assumptions of the point process model for 
breathing are that peak inspiration (maximal inspiratory effort as recorded non-invasively) is a 
discrete event marked by neuronal inspiratory burst and that IBI dynamics are governed by 
multiple feedback and feed-forward loops modulating the respiratory oscillator. In addition to 
the respiratory signal, we will develop models using the ECG and SpO2 signals plus respiratory 
signals to determine if accuracy is improved. We have developed point process models for the 
evaluation of bradycardia and its severity. 
 
Aim 2: 
(a) 
We will use the data from the 96 hours of intensive multiparametric physiologic 
monitoring at 2 weeks postnatal age. The first 24h of the data collection will be the baseline 
data. Over the next 72h, we will evaluate 3 interventions in a cross-over manner, with the initial 
intervention randomly assigned (computer-generated): Intervention 1 (24-48h of data), 
Intervention 2 (48-72h), and Intervention 3 (72-96h). For example, Intervention 1 may be to 
increase TcCO2 by 5 mm Hg above baseline (at the time of capillary blood gas) and maintain at 
that level (by reducing IMV rate or pressures, by clinician decision) for 24h, and Intervention 2 
will be to decrease TcCO2 by 5 mm Hg back to initial values (by increasing IMV rate or pressures, 
by clinician decision) for the next 24h. Intervention 3 will be to repeat Intervention 1 (to 
increase TcCO2 by 5 mm Hg) to validate that results of Intervention 1 are due to increased PCO2 
and less likely to be random fluctuations. On the other hand, if Intervention 1 is to decrease 
13 

TcCO2 by 5 mm Hg (from baseline at time of capillary blood gas) and maintain at that level (by 
increasing IMV rate or pressures) for 24h, and Intervention 2 will be to increase TcCO2 by 5 mm 
Hg back to initial values (by decreasing IMV rate or pressures) for the next 24h. Intervention 3 
will be to repeat Intervention 1. These interventions are chosen so that we will be able to 
evaluate the effects of altering PaCO2 on respiratory irregularity while maintaining the pH at or 
above 7.2, generally regarded as a safe threshold. At the conclusion of interventions and data 
collection, infants will be managed according to the Clinician’s preference. 
 
Aim 3: 
For infants on oxygen supplementation at 32w PMA, we will use the data from the 96 hours 
of intensive multiparametric physiologic monitoring at 32w PMA. For infants on oxygen 
supplementation at 36w PMA, we will use the 96 hours of intensive multiparametric physiologic 
monitoring at 36w PMA as well as data from the sleep study 
(b) 
The first 24h of the data collection will be the baseline data. Over the next 72h, we will 
evaluate 3 interventions in a cross-over manner: Intervention 1 (24-48h of data), Intervention 2 
(48-72h), and Intervention 3 (72-96h). Initial intervention will be by random assignment 
(computer-generated). For example, Intervention 1 may be to switch the infant to the servo-
controlled O2 environment at a range necessary to maintain the optimal SpO2 (91-95%). As this 
may not be the same FiO2 as that by cannula, we will calculate the effective hypopharyngeal 
FiO2 using formulae incorporating FiO2, cannula flow, and minute ventilation (24-27) and adjust 
from this FiO2. The first 12h will be for identifying the appropriate FiO2 and stabilizing tracings, 
and the second 12 h will be data collected for analysis. Intervention 2 will be then be switching 
the infant back to the cannula at the FiO2 and flow rate the infant was receiving in the first 24h 
(unless the FiO2 or clinical status had markedly changed in the previous 24h and adjustments 
are necessary), with analysis of data in the second 12h after stabilization. Intervention 3 will be 
switching back to the servo-controlled O2 environment for 24h. Similarly, for infants for whom 
Intervention 1 is switching to a cannula, Intervention 2 will be back to the O2 environment, and 
Intervention 3 back to the cannula. At the conclusion of interventions and data collection, 
infants will be managed according to the Clinician’s preference. 
 
 
4.2.5. Blinding/Masking 
 
This is an unmasked study. 
 
4.2.6. Control or Monitoring of Co-interventions 
 
Medical interventions and ventilator management will be based upon clinician discretion. Evidence and 
consensus based guidelines are followed for uniformity in practice. No changes in management are 
required for this observational cohort study, except for the duration of the intensive multiparametric 
monitoring for 96 hours at 2 weeks postnatal age, 32 weeks PMA, and 36 weeks PMA, when 
interventions will be performed as described in Aims 2 (minor changes in TcCO2) or Aim 3 (Nasal 
cannula or Servo-controlled O2 environment). 
4.2.7. Primary Outcome 
 
14 

Hypoxemic episodes (defined as SpO2 <85% for >10s) will be determined by analysis of stored 
physiologic data.  
 
4.2.8. Secondary Outcomes (if applicable) 
 
1. Hypoxemia defined as SpO2 <85% 
2. Bradycardia defined as HR <100/min 
3. Bradycardic episode as HR <100/min for >10s  
4. Apnea defined as RR=0 for >20s, or RR=0 for >10s + SpO2 <85%  or HR <100/min  
5. BPD defined using physiologic definition at 36w PMA 
 
4.2.9. Additional Safety Outcomes (if applicable) 
 
Infants will be monitored for severe apnea/bradycardia episodes (defined as requiring bag and mask 
ventilation for >30 s or chest compression) associated with interventions in Aims 2 and 3. No such 
episodes were found to be associated with the interventions in pilot studies. 
 
4.2.10. Compliance Monitoring  
 
No specific protocol exists for Aim 1 (observational study). The PI or Research Coordinator or designee 
will initiate/stop or personally supervise the interventions in Aims 2 and 3. In pilot studies of 
interventions used in Aims 2 and 3, no issues with maintenance of compliance were noted.  
 
4.2.11. Study Specimens 
 
No biofluid specimens are required for the single-center study, but will be considered in the multicenter 
protocol. 
 
4.2.12. Post-hospital Procedures 
Reminder for follow-up and instructions for follow-up at 3 months will be sent to parents/caregivers. 
 
4.2.13. Follow-up at 3 Months 
 
Survivors to discharge will be followed-up at the 3 month follow-up visit for a sleep study 
(polysomnographic study)  at the Children’s of Alabama sleep center by the Pediatric pulmonologist. 
Respiratory outcomes as in SUPPORT Breathing Outcomes study (30) will be evaluated at the 3 month 
follow-up visit in addition to the Sleep study. 
 
4.2.14. Additional Follow-up Assessments 
This will be decided upon by regular clinical team. Most infants enrolled in this study are eligible for 
follow-up by the Newborn Follow-Up clinic, and some are also eligible for follow-up by the BPD follow-
up clinic.  
 
4.3. 
POTENTIAL RISKS AND BENEFITS TO SUBJECTS 
 
Potential Risks:  
15 

This study is primarily an observational study (Aim 1), and comparative effectiveness research 
(Aims 2 and 3), and is hence of low risk. Infants enrolled in this study are intrinsically at high risk, as they 
are born extremely preterm with a risk of death exceeding 20% and death or disability exceeding 50%, 
but participation in this study adds only minimally to the underlying risk. 
For Aim 1, we will collect physiologic data from patient monitors, and clinical data on patient 
characteristics, illness severity, and outcomes from the medical records of the 120 enrolled infants. The 
primary risks are those of loss of confidentiality and privacy. Results and their linked clinical data will 
then be assigned an unique identifying code and anonymized to minimize risks to confidentiality. Only 
the PI and research coordinator will have access to patient data before anonymization. No patient 
identifiers will therefore remain in the data set that will be transmitted to the Data Coordinating Center.  
For Aim 2, we will enroll a subset of infants from Aim 1 to determine if mild permissive 
hypercapnia (trying to increase blood carbon dioxide concentrations 5 mm Hg from baseline) leads to 
improved control of breathing in preterm infants. While extreme hypercapnia associated with pH <7.15 
is generally avoided, mild hypercapnia with pH maintained >7.2 is usual practice in most centers, 
including UAB, and is considered safe. These infants will be monitored using continuous pulse oximetry 
and transcutaneous CO2 monitoring, and the fluctuations in blood carbon dioxide concentrations of 5 
mm Hg from baseline are expected to alter blood pH by less than 0.05, and these fluctuations are much 
less than normally noted in routine care (fluctuations of up to 30 mm Hg or more over a day are often 
seen). We will not include infants with extreme blood carbon dioxide concentrations (blood PCO2 of less 
than 40 mm Hg or more than 70 mm Hg as indicated by transcutaneous monitoring, after adjustment for 
skin-blood PCO2 difference on most recent blood gas analysis). This Aim is intent-to-treat, and it is 
possible that we will not see any statistical differences over time with regards to blood carbon dioxide 
concentrations despite our intent to increase or decrease the level by 5 mm Hg, as there are large 
fluctuations in routine care, due to inherent variation in respiratory drive and other clinical variables. 
Even more extreme transient elevations of blood carbon dioxide at 2 weeks of age are unlikely to cause 
clinical problems as the risk period of IVH (the main concern with elevated blood carbon dioxide in 
preterm infants) is mainly in the first few days after birth. Hypocapnia or very low blood carbon dioxide 
concentrations may reduce brain blood flow, but we are evaluating infants with levels in the upper end 
of the normocapnia range or mild permissive hypercapnia, and excluding infants with more extreme 
values. Infants with hypocapnia generally have spontaneous hyperventilation rather than due to 
clinician intervention, as the goal is minimal ventilation and not overventilation.   
For Aim 3, we will evaluate the effects of oxygen administration using a servo-controlled oxygen 
environment as compared to nasal cannula on control of breathing and stability of blood oxygen levels. 
Both methods are in common use in our NICU, and are not known to have any major risks. Minor risks of 
using a nasal cannula include accidental dislodgement with movement of the infant. Minor risks of 
oxygen environment include a drop in oxygen concentration if caregivers leave port-holes open for too 
long by accident, allowing the oxygen to exit the incubator. However, as infants are being carefully 
monitored using continuous pulse oximetry and ECG monitoring, any desaturation or bradycardia 
episode will immediately lead to an audible and visible alarm.  
We also plan to develop a biorepository using remnant samples, as required by the multicenter 
collaborative (no invasive sampling will be done specifically for this study). 
There is no financial risk from participation in this study. 
A potential risk is of psychological harm to parents during the informed consent process, as they 
become aware of the high risk of death or handicap to their very preterm infant. However, this risk is 
the same, whether or not the parents are in the study, as they all receive counseling regardless of being 
in this or other studies.  
Risk:           
 
 
 
 
   Frequency            Severity                 Reversibility 
1. Loss of confidentiality and privacy         Very low (anonymized data)   Low      Not applicable 
16 

2. Mild increases or decreases in PCO2   Common (happens often routinely)   Low     Reversible 
3.  Nasal cannula dislodgement 
        Common (happens often routinely) Low   Reversible 
4. Oxygen environment open to air       Common (happens often routinely)   Low   Reversible 
5. Psychological harm to parents             Common (all parents at risk)       Low      Not applicable 
This study is an observational study (Aim 1) and comparative effectiveness study (Aims 2 and 3), and the 
risks that the infants are exposed to are those that are normally present and happen often in usual 
neonatal intensive care. As this study involves more intensive monitoring than usual, the expectation is 
that these infants will be at even lower risk as compared to infants who are monitored only using 
standard equipment. The minor risks in Aims 2 and 3 occur frequently in infants during usual intensive 
care, and are likely to be unchanged in this study compared to usual care, but harm may occur if nursing 
staff do not respond to monitoring alarms (as in usual care). The more intensive monitoring may help 
reduce these risks.  
 
Potential benefits: 
 
There is a potential of direct benefit to study participants from participating as Aim 1 is based on 
intensive multi-parametric monitoring of multiple variables only some of which are routinely monitored. 
As the monitoring is not masked to caregivers, nurses and clinicians may become aware of changes in 
the monitored variables and intervene more quickly for abnormal cardiorespiratory events and prevent 
apnea or bradycardia duration in the infants who are enrolled and being monitored, as compared to 
infants who are not enrolled.  
Aims 2 and 3 are comparative effectiveness research studies done in a cross-over fashion, so infants are 
not likely to have a persistent benefit from one intervention. If caregivers note that one intervention 
seems to be associated with better oxygen saturation stability, fewer apneic episodes etc, it is possible 
that these infants may benefit by the better intervention being used after the period of evaluation for 
Aim 2 or 3. 
The results of this study will be published in the peer-reviewed literature and then deposited in PubMed 
Central to make the manuscript freely available, which may benefit other investigators in the field as 
well as interested parents and family. 
Development and validation of mathematical models of personalized ventilatory patterns based on 
multiparametric vital signs monitoring and signal analysis methods will enable the scientific community 
to gain greater insight into the pathogenesis of respiratory disorders in extremely preterm infants and 
discover targets for new prevention and treatment strategies to improve outcomes for very vulnerable 
children at the beginning of life 
17 

SECTION 5. 
ANALYTICAL PLAN 
 
5.1. 
STATISTICAL ANALYSIS PLAN 
 
It should include a plan for analysis of primary and secondary outcomes, subgroup analyses if planned, 
and for handling of missing data and subjects who die or are lost to follow-up.  
Primary Outcome:  
Hypoxemic episode (SpO2 <85% for >10s) frequency 
Secondary Outcome(s)  
Frequency of Hypoxemia (SpO2<85%), Bradycardia (HR<100/min), Bradycardia episode (HR<100/min for 
>10s); Apnea (RR=0 for >20s, or RR=0 for >10s + SpO2 <85% or HR<100/min); BPD defined using 
physiologic definition at 36w PMA  
Aim 1: Statistical calculations will be performed using SPSS. Parametric tests will be used for analyses of 
all continuous variables except for comparisons involving the incidences of specified ranges of IBIs, 
which is a skew distribution. Nonparametric tests will also be used for analyses of ordinal datasets. The 
Kolmogorov-Smirnov (one-sample) and Friedman's and Wilcoxon signed-rank tests will be used for the 
nonparametric analyses. For factorial analyses of parametric data, separate repeated-measures ANOVAs 
will be used. For factors with more than two levels, the Greenhouse-Geisser correction will be used, and 
ε with unadjusted degrees of freedom will be reported. Where a main effect was observed for factors 
with more than two levels, post hoc tests using the Bonferroni adjustment will be done. Values will be 
expressed as means and SD, and p values (2-tailed) of <0.05 considered statistically significant. Pearson 
product-moment correlation coefficient analysis will be used to establish the association between 
pathological pauses in breathing and breathing stability. 
Aims 2 and 3: As in Aim 1, we will quantify IBI and IBI variability as defined earlier (2, 4). Also as in Aim 1, 
other outcomes will include (i) hypoxemic time –the % time with SpO2 <90%, (ii) moderate hypoxemic 
time with SpO2 <80% and severe hypoxemic time with SpO2 <60% (iii) bradycardic time – % time with HR 
<100, (iv) severe bradycardic time – % time with HR <60, (iv) hypoxemic, bradycardic, or apneic episodes 
– the number of episodes of  SpO2 <90%, SpO2 <80%,  SpO2 <60%,  HR<100, HR<60, or RR=0, 
respectively, for >10 seconds, with the episode length defined as the number of seconds of data values 
below the threshold, (v) cerebral hypoxemic episodes (decrease in rcSO2 <50% or of 20% from baseline 
for >1 minute) and somatic hypoxemic episodes (decrease of 20% from baseline in peri-renal area). 
 
5.2. 
SAMPLE SIZE AND POWER ESTIMATES 
 
Aim 1: A sample size of 100 infants per group is sufficient to detect a 20% change in a parameter related 
to an outcome using standard parametric or nonparametric tests (e.g. Wilcoxon signed-rank) at 80% 
power, α=0.05, with expected standard deviation of change of 50%. We plan to enroll 120 to account for 
attrition due to early death. Statistical power of 80% for detecting 20% difference in parameters is 
maintained even if the incidence of outcome (e.g. BPD) is only 20% of enrolled (24 of 120) infants if the 
standard deviation is 40% or less (as is expected to be, based on preliminary studies). 
Aim 2: A sample size of 16 infants  is sufficient to detect a 30% change in a parameter related to an 
outcome using standard parametric (e.g. paired t-test) or nonparametric tests at 80% power, α=0.05, 
with expected standard deviation of change of 40%. Hence, enrollment of 25 patients will be sufficient, 
even if there is attrition of up to 5 patients due to death, and data from 4 patients has technical issues 
with usability. 
18 

Aim 3: As in Aim 2, 16 infants are sufficient to detect a 30% change in a parameter related to an 
outcome by standard parametric (e.g. paired t-test) or nonparametric tests at 80% power, α=0.05, with 
expected standard deviation of 40%. Hence, enrollment of 25 patients will enable detection of even 
minimal changes, or of changes in parameters with much variation. 
 
5.3. 
AVAILABLE POPULATION 
 
We have an estimated available population of 200 extremely preterm infants each year admitted to the 
RNICU. The limitation of sample size to 120 is due to costs associated with study (NIRS sensors, sleep 
studies) rather than with limitation in the number of available infants.  
5.4. 
PROJECTED RECRUITMENT TIME 
 
We plan to enroll at least 40 infants per year during years 2-4 of the study (120 in total), with additional 
enrollment possible in early Year 5. As infants will require a sleep study 3 months post-discharge, we will 
cease enrollment by mid-Year 5 to ensure all infants have all necessary data available by end of study 
funding in end-Year 5. 
 
5.5. 
STUDY MONITORING PLAN 
Study monitoring plan is as reported in plan submitted to OSMB, and will be consistent with monitoring 
at all study centers for adverse events. SAEs will be reported to OSMB and IRB as required. Aim 1 is 
primarily observational, and Aims 2 and 3 are comparative effectiveness studies evaluating interventions 
that are routinely used in the NICU. No SAEs attributable to the study interventions are hence 
anticipated, or have been noted in preliminary studies, even though study monitoring is in place.  
 
19 

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