Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02095041 |
| Other study ID # |
TOST |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 2014 |
| Est. completion date |
September 2015 |
Study information
| Verified date |
March 2021 |
| Source |
University of Calgary |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Oxygen is carried in the blood attached to hemoglobin molecules. Oxygen saturation is a
measure of how much oxygen hemoglobin is carrying as a percentage of the maximum it could
carry. Oxygen saturation can be measured non-invasively using pulse oximetry. On occasion,
term infants are admitted to the intensive care nursery for monitoring and show variability
in their oxygen saturation despite appearing well. As healthy newborns do not undergo routine
monitoring of oxygen saturation, health care team do not know the degree to which variability
in oxygen saturation are a normal phenomenon. With increasing interest in using pulse
oximetry as a screening tool to identify "at risk" newborns, it is important to have a clear
understanding of postnatal oxygen saturation trends and their variability in healthy babies.
In our study, Investigators will measure oxygen saturation on healthy newborns repeatedly and
for extended periods. This will allow us to describe both the variability in oxygen
saturations and the pattern of changes observed in oxygen saturations over time in healthy
newborns. To increase our confidence that babies included in our study were healthy at birth,
they will be followed for 8 weeks to identify indicators of perinatal disease that was missed
clinically. Any babies subsequently identified as having significant disease will be analyzed
separately from the main cohort of healthy babies. Furthermore, the oxygen saturation
readings will be obscured so as not to influence caregivers inappropriately. Lastly, pulse
oximetry measurements will be performed after discharge from hospital (on day 3 to 4),
potentially increasing the clinical utility of this study as it has repeatedly been stated in
the literature that the sensitivity of pulse oximetry to detect important underlying disease
increases significantly if performed several days after birth. This study will provide
important and novel normative data.
Description:
BACKGROUND:
The newborn period is a time of transition from the intrauterine to the extra-uterine
environment. Arterial fetal oxygen saturation before birth are approximately 65%. Within
minutes of delivery, and with the onset of respiration, the newborn's oxygen saturation rises
close to normal postnatal values.
In practice, oxygen saturation are measured continuously using a trans-cutaneous probe
connected to a pulse oximeter. The probe illuminates the local tissue and the true oxygen
saturation is estimated by measuring the wavelengths of light that are not absorbed. This
method of trans-cutaneous oxygen saturation measurement (SpO2) yields an accurate estimate of
the true oxygen saturation comparable to measurements made via co-oximetry using whole blood
(1,2).
Description of problem: Healthy newborns do not undergo routine monitoring of oxygen
saturation. Hence, health care team do not know if fluctuations in oxygen saturation are a
normal phenomenon. It is important to have a clear understanding of postnatal oxygen
saturation trends and their variability in healthy babies to help identify infants that
warrant further investigation or intervention, both in the neonatal intensive care unit
(NICU) and in the "normal" newborn nursery.
Identifying "At-Risk" Newborns:
Studies of oxygen saturation in apparently healthy babies describe a postnatal oxygen
saturation of 95-98% in the first few days after birth (3-5). There is a further small
increase in SpO2 of 2 to 3% over the next 72 hours following closure of the ductus
arteriosus. In these studies, oxygen saturation below a threshold value prompted further
investigation and/or treatment change. One study blinded the healthcare team to the oxygen
saturation values in only a small subset of the recruited patients (6). These studies defined
"normal" oxygen saturation based on whether significant pathology was discovered on further
investigation. By setting a threshold SpO2 value for determining the need for further
investigations or interventions and selectively targeting this group, investigators
potentially introduced bias.
It is often difficult to clinically identify babies in the early stages of potentially
serious diseases such as infection or critical congenital heart disease. Such babies may
appear well for several days after birth and therefore, are discharged home before a
diagnosis can be made. In these cases, there is a serious risk of rapid deterioration out of
hospital resulting in the baby returning to the emergency department with subsequent
readmission to hospital. Oxygen saturation screening before discharge home following birth
may help in identifying well-looking babies that have a serious underlying condition. For
these reasons, many centers are adopting a policy of performing screening SpO2 measurements
of all newborns. A recent systematic review of pulse oximetry screening for the detection of
critical congenital heart disease with 229421 newborns showed a sensitivity 76•5%,
specificity of 99•9% and false-positive rate of 0•14%(7). In this review there were 748 false
positive results, six times more than true positive tests. More importantly, 33 babies with
critical congenital heart disease were not identified. Positive predictive value for this
test was low (13%) because of the low prevalence of the disease and very high false positive
rate. The high false positive rate supports a need for high quality normative saturation data
before implementing these tests in the community. There is uncertainty in how to interpret
such information as current policies tend to set a single cutoff SpO2 value as a threshold
for further investigations, such as an echo-cardiogram. This may be an overly-simplistic
approach as it does not consider normal fluctuations in oxygen saturation that investigators
anticipate to occur in healthy newborns. Having high quality SpO2 values from healthy term
babies as a basis for comparison may lead to more accurate identification of "at-risk"
newborns.
Car Seat Testing:
Many babies admitted to the NICU undergo 90 minutes of continuous SpO2 recording while they
are positioned in their car seat prior to discharge home. The procedure, referred to a
car-seat testing, is meant to identify babies who are not able to tolerate the flexed body
position that results from sitting in a car seat. The 90-minute recording is presented as a
frequency histogram of SpO2 values so the clinician can identify babies who spend an
excessive proportion of time with oxygen saturations that are too low. The interpretation of
car seat testing results is largely subjective. By comparing testing results to SpO2
histograms from healthy babies, the clinician could more objectively identify babies that
"pass" or "fail" a car-seat test.
Oxygen Saturation Histogram Interpretation:
Preterm infants at 37 weeks corrected gestation who require ongoing mechanical ventilation,
continuous positive airway pressure or oxygen delivered via nasal prongs routinely have SpO2
frequency histograms created to help in deciding when they are ready for extubation or
transition off of continuous positive airway pressure. Currently there is no good-quality
SpO2 normative data to help in defining criteria for assessing SpO2 histograms to determine
if a baby is ready to transition off of respiratory support.
METHODS
STUDY DESIGN: Prospective, longitudinal, observational study.
STUDY CENTER: This study will be conducted in the city of Calgary, Alberta (altitude 1054
meters) in the postpartum wards of 3 geographically separate hospitals: Foothills Medical
Center, Rocky View General Hospital and Peter-Lougheed Hospital. Calgary has approximately
18,000 births per year.
In oxygen saturation reference studies conducted at different altitudes, postnatal oxygen
saturations at centers below 1500 meters were not significantly different to those measured
at sea level. Therefore, investigators expect that our results will be applicable to all
centers below 1500 meters in altitude.
As part of this study, Investigators are also conducting a pilot study of the same design in
Bogota, Columbia. Bogota is at an altitude of 2625 meters. The pilot study will examine if
patterns of oxygen saturation in healthy babies are the same at a high altitude as they are
in Calgary (altitude 1045 meters).
SUBJECT IDENTIFICATION & ENROLLMENT:
Investigators will review the electronic health records for babies admitted to the labor and
delivery wards on a daily basis to identify potential subjects. The electronic health record
displays the age of every patient. Newborns are identified by an age of 0 days. After staff
caring for the mother confirm her willingness to speak with us regarding our study, a local
co-investigator will approach the mother of potential subjects to request consent for study
enrollment. For enrolled infants, the notice of birth will have a label attached alerting the
Public Health Nurse that the baby is part of the study. For those parents who decline to
participate in the study, Investigators will request permission to follow up these infants
for 8 weeks to identify ER visits and hospital admissions. Comparing the data of these
infants with data of the other infants in the study will help us to detect bias in our
recruitment.
DATA TO BE COLLECTED Gestational age, age (Hours/ days of life), gender, birth weight,
multiples, mode of delivery, Group-B streptococci status, duration of rupture of membranes,
presence of labor, chorioamnionitis, maternal medical history & obstetrical history, maternal
smoking, gestational diabetes, pregnancy induced hypertension, antenatal ultrasound results,
amniocentesis/chorionic villous sampling results, Apgar scores, resuscitation details, and
cord blood gas results will be collected from the patient's electronic and paper health
record. Oxygen saturation data will be collected as outlined below.
OXYGEN SATURATION MEASUREMENTS:
Once enrolled, newborn infants will have oxygen saturations measured for 90 minutes using a
Masimo Radical 7 pulse oximeter. This pulse oximeter was chosen because of its resistance to
movement artifact and good performance in states of low perfusion (14,15). The pulse oximeter
will be set for normal sensitivity with 8 second averaging time and will save data points
every 2 seconds. One pulse oximeter probe will be placed on the right wrist (pre-ductal) and
the other probe will be placed on either foot (post ductal) to take continuous measurements
for 10 minutes, starting from the point at which the perfusion index, a measure of tissue
perfusion and signal quality, is acceptable (>1.0). This initial phase of recording will
occur under the supervision of a co-investigator in the nursery examination room with the
baby in a quiet state to ensure acquisition of accurate readings. Each infant's state of
alertness will be classified according to the March of Dimes' "States of the Term Newborn"
description (16).
The baby will be returned to the mother with one pulse oximeter still attached to the right
wrist for completion of the 90-minute recording period. During this 80 minute period,
investigators will record only preductal saturation as it will be inconvenient for the mother
to have two probes attached to the infant.
Another 15 mins of simultaneous pre and post-ductal SpO2 measurements will be performed in
the Public Health Nurse (PHN) clinic 2-3 days after discharge by a PHN trained in the use of
pulse oximetry.
NEONATAL STATE:
Neonatal state is a group of characteristic behaviors and physiological changes that recur in
a regular pattern (17). With each neonatal state there can be changes with heart rate, blood
flow, electroencephalographic and saturation changes (18-20) . Identification of the neonatal
state during oxygen saturation recording may help with the interpretation of the saturation
trends with the context of each neonatal state, and therefore, it will be controlled for in
the analysis. To categorize the infant's state, will use the "March of Dimes" states of the
term newborn (Ref: March of dimes)(see appendix). Even though this method has not been
validated by comparison with electro-physiological studies, it is simple and quick to
perform, non-invasive and does not require sophisticated equipment.
TIMING OF RECORDINGS:
Oximetry recordings will be performed every 12-24 hours prior to discharge during regular
working hours, with the first recording occurring between 6 and 24 hours after birth (21).
Recordings will not be performed prior to 6 hours of age to allow normal transition to the
extra-uterine environment to be completed. One further SpO2 recording will be performed by
the PHN 2 to 3 days after discharge in the Public Health Clinic. Note that, in Calgary, all
babies are routinely followed up by Public Health within a few days of discharge.
BLINDING:
Pulse oximeter readings will be obscured by fastening an opaque cover over the oximeter's
display. The perfusion index, a measure of the strength of the signal, will be left visible
so the investigator can ensure that a good quality signal is obtained. The beat to beat tone
function will be turned off and the high/low SpO2 alarms will be silenced as they are
indirect indicators of the oxygen saturation. In this manner, the investigators and staff
will be blinded to the oxygen saturation readings.
INTER OBSERVER AGREEMENT FOR ASSESSMENT OF NEONATAL STATE (MARCH OF DIMES):
With multiple investigators in our study, it is important to define the neonatal state
uniformly. With this simple method of assessment, investigators expect the inter-observer
agreement will be high. To estimate the inter-observer variability, the first 10 infants at
each site (Total 30 infants for 3 sites) who are recruited into the study will be observed
simultaneously by 2 investigators. Each observations will happen during the first 10 minutes
of recordings (in the normal newborn nursery) and will be recorded independently by the
investigators on preprinted forms.
Inter-observer variability will be determined using nominal kappa statistics with
bootstrapped bias corrected 95% confidence intervals. Kappa values can be classified as
follows: below zero=poor, zero to 0.20=slight, 0.21 to 0.4=fair, 0.41 to 0.6=moderate, 0.61
to 0.8=substantial, 0.81 to 1=almost perfect. Since the main purpose of this assessment is
not to validate the neonatal state assessment, but to understand the degree of variability
among the observations, investigators chose a convenience sample of 30 infants.
DATA MANAGEMENT:
Data is automatically recorded and stored in the pulse oximeter in real time. Prior to each
measurement, the co-investigator or Public Health Nurse, will record the date and time on the
pulse oximeter at the onset of SpO2 measurements. This will facilitate linking each patient
with their oximetry data when downloading the recorded information from the pulse oximeter.
The pulse oximeter stores 3 distinct types of data for each time point: oxygen saturation,
heart rate and a hexadecimal code which contains information regarding the quality of the
recording. The data will be imported from the pulse oximeter to Microsoft Excel using a
research laptop computer running a hyper terminal program. Each oximeter can accommodate all
of the measurements without exceeding its storage capacity. However, oximeter downloads will
occur shortly after collection to ensure the data is safely stored in a timely manner.
Study data will be collected and managed using REDCap(Research Electronic Data Capture), an
online research database.1 REDCap is a secure, web-based application designed to support data
capture for research studies, providing: 1) an intuitive interface for validated data entry;
2) audit trails for tracking data manipulation and export procedures; 3) automated export
procedures for seamless data downloads to common statistical packages; and 4) procedures for
importing data from external sources(22) . Identifying information will be kept in a study
binder and will not be entered into the REDCap database.
FOLLOW-UP OF BABIES:
Babies will be followed until 8 weeks of age, by reviewing their electronic health record, to
identify those who died, required readmission to hospital or visited the emergency room. For
these babies, investigators will review the hospital charts and electronic health records to
identify any important diagnoses that were made. Investigators will also review any
echo-cardiograms which were performed during the follow up period. Babies subsequently found
to have diagnosis of congenital heart disease, respiratory illness (congenital respiratory
disorders/ malformations), blood dyscrasia or intrauterine/perinatally acquired infection
(based on clinical features or microbiological evidence along with individual chart review)
will not have their data included in the nomogram. Infants with any of the above conditions
will be analyzed separately to determine if their oxygen saturations differed from those of
healthy babies.
SAMPLE SIZE:
Assuming mean oxygen saturation measurement are within a 0.25% margin of error and based on
published estimates of standard deviations for oxygen saturation measurements in this
population, investigators considered a standard deviation of 3.35. This will also serve to
estimate the average coefficient of variation within such margin of error. The actual sample
size calculation is 14. However, given our primary objective of creating a nomogram with
percentiles of oxygen saturations, it is necessary to enroll a larger number of babies.
Assuming a 10 to 15% drop out rate and 1-2% rate of babies excluded after discharge due to
diagnoses of heart disease, etc, investigators plan to enroll 625 babies to achieve a final
sample size of 500 babies.
ANALYSIS:
Investigators will analyze the trends in post-ductal SpO2, SpO2 variability and differences
between pre and post-ductal oxygen saturations for this initial phase. The "R project"
statistical computing package will be used for analyses under the supervision of one of our
co-investigators (A Nettel-Agguire, PhD statistician). Investigators will present descriptive
statistics for population characteristics. Categorical variables will be presented as
proportions and 95%CI, while numerical variables will be presented as mean (Standard
Deviation) or median (IQR) as appropriate.
For each baby, oxygen saturation means will be calculated along with SD (Standard Deviation)
and the coefficient of variation (SD/mean) for each time period (day 0, day 1, day 2, etc).
Sample means of these three parameters will be calculated with corresponding confidence
intervals.
Investigators will calculate oxygen saturation percentiles using LMS method
(skewness-median-coefficient of variation method) based on the individual means separately
for each day SpO2 measurements were made.
Investigators expect the SpO2 to remain stable over time. For assessing this, at least
graphically, Functional data analysis (FDA) on all the full individual profiles will be
performed. FDA creates a curve profile (via statistical penalized fitting of splines) for the
SpO2 data with respect to time for each individual. Hence a mean profile or mean curve can be
derived from all the subjects with their corresponding 95% confidence bands. This will be
done separately for Day 0 and day 1, day 2, etc.
Logistic regression will be done to assess the covariates of oxygen saturations, variability
of oxygen saturations, gestational age, birth weight and gender for the 8-week outcomes of
death, serious illness or hospital readmission.
NOVELTY OF STUDY:
This study adds to this field in the following ways:
1. To our knowledge, this is the first study to blind the healthcare team, co-investigators
and parents to the pulse oximeter readings for all enrolled infants. Blinding to the
pulse oximeter readings removes a potentially important source of bias.
2. Previous studies have provided either a single oxygen saturation value at a single point
in time or a single oxygen saturation value at multiple time points. Investigators will
be measuring continuous oxygen saturations on multiple occasions. This has 2 main
potential advantages:
1. Investigators will be able to construct SpO2 histograms of the minimum, mean,
standard deviation and coefficient of variation from the individual observed values
2. Performing pulse oximetry on more than one occasion will allow us to identify and
quantify changes in oxygen saturations over time
3. This study is unique in its definition of "healthy" which will be decided by the
infant's well-being at 8 weeks of age. This approach will allow investigators to
identify infants who appeared well at birth but subsequently were identified as "not
healthy".
4. Community oxygen saturation recording by the PHN is a novel concept of screening at a
different time point and at a time when critical congenital heart disease is more likely
to be detected by pulse oximetry as the ductus arteriosus normally closes within 72
hours of birth (23). A recent systematic review showed that the false positive rate
decreases 10 times if SpO2 measurements are made after 24 hours of age(7).
5. Measurement of both pre and post ductal SpO2 may increase the ability to detect illness
that is not clinically apparent (24).
ETHICS:
An ethics application has been submitted to the Conjoint Health Research Ethics Board.
Informed consent will be obtained prior to enrolling babies into the study. The use of pulse
oximetry with newborns in the NICU is routine. It is a safe procedure with no known harmful
effects. As the routine use of pulse oximetry is not currently standard of care in the
postpartum and labor and delivery wards, blinding the staff to the pulse oximeter readings
does not present ethical challenges. Furthermore, blinding the healthcare staff to the SpO2
readings may prevent potentially inappropriately changes to an infant's management based on
SpO2 readings.
