description of studies for safe oxygenation in preterms

2.  Extreme prematurity of less than 28 weeks'
gestation affects approximately 1% of births
 Although 80% of these infants are discharged
home alive , they often sustain severe
morbidity , including BPD, poor growth,
respiratory illness, hospital re-admissions,
visual deficits, cerebral palsy, sensori-neural
disability and cognitive, educational and
behavioural impairment.

3.  Oxygen is the most common therapy used in
the care of very preterm infants. It has been
associated with significant improvements in
neonatal survival and disability .
 However, preterm infants are highly sensitive
to the harmful biochemical and physiological
effects of supplemental oxygen.

4.  So hereby presenting few studies to confirm if
lower target saturation will indeed help in
minimizing complications.

5.  Less exposure to oxygen is a simple strategy
that could reduce oxidative stress and tissue
injury and prevent morbidity in very preterm
infants.
 In healthy preterm infants breathing air,
arterial oxygen saturation (SpO2) is 85-98%.
However, for infants requiring supplemental
oxygen, the optimum range of arterial oxygen
to minimise organ damage, without causing
hypoxic injury, remains unknown.

6.  The COT is a randomized and parallel double-
blind trial that was conducted in 25 hospitals in
Canada, the United States, Argentina, Finland,
Germany, and Israel.

7.  Enrollment began in December 2006 and ended
in August 2010. Follow-up assessments were
performed between October 2008 and August
2012.

8.  INCLUSION
Infants with gestational ages of 23 weeks 0 days
through 27 weeks 6 days were eligible for
enrollment during the first 24 hours after birth.

9.  EXCLUSION
 Infant not considered viable
 Persistent pulmonary hypertension
 Dysmorphic features or congenital
malformations that adversely affect life
expectancy or neurodevelopment
 Cyanotic heart disease
 Infant was unlikely to be available for long-
term follow-up.

10.  PRIMARY OUTCOMES
 Death
 Gross motor disability: Defined as a level of 2 or higher
according to the Gross Motor Function Classification
System
 Cognitive or language delay defined as composite
cognitive or language score of less than 85 (1 SD below
the mean of 100) on the Bayley Scales of Infant and
Toddler Development, Third Edition
 Severe hearing loss: Defined as the prescription of
hearing aids or cochlear implants
 Bilateral blindness: Defined as a corrected visual acuity
less than 20/200 in the better eye.

11.  SECONDARY OUTCOMES
ROP, brain injury, patent ductus arteriosus,
necrotizing enterocolitis (NEC),
bronchopulmonary dysplasia (BPD), and the
duration of use of positive airway pressure and
supplemental oxygen.

12.  INTERVENTION:
 Infants were placed on the modified Massimo
pulse oximeter. The oximeters were modified to
display and store oxygen saturations that were
either 3% higher or lower than the true values.
True values were displayed if the measured values
decreased below 84% or increased above 96%
 Caregivers were instructed to adjust the
concentration of oxygen to maintain saturation
values between 88% and 92%, which produced two
treatment groups with true target saturations of
85-89% or 91-95%

13.  Alarms were triggered when the displayed
saturations decreased to 86% or increased to 94%
 Study oximetry was continued until 36 weeks of
postmenstrual age even if an infant was not
receiving supplemental oxygen. Infants who were
receiving any respiratory support including
oxygen therapy at 35 weeks of postmenstrual age
were monitored with their assigned study
oximeter until a postmenstrual age of 40 weeks.
Study oximetry was stopped earlier if infants were
discharged home

14.  RESULTS
 The median of the individual study
participants` oxygen saturations on days with
more than 12 hours of oxygen was:
 Lower saturation group: 90.9% (IQR 89.6-
92.5%)
 Higher saturation group: 93.4% (IQR 92.7-
94.2%)
 Targeting lower compared with higher oxygen
saturations had no significant effect on the rate
of death or disability at 18 months.

15.  Secondary outcomes:
 Targeting lower compared with higher oxygen
saturations reduced the mean postmenstrual
age at the last oxygen therapy from 36.2 to 35.4
weeks (P = 0.03)
 There was no significant difference between the
groups in other outcome including ROP and
severe BPD

16.  In five randomized, masked trials with similar
protocols conducted in the United States,
Australia, New Zealand, Canada, and the
United Kingdom involving infants born before
28 weeks' gestation, investigators are
evaluating the effects of targeting a range of
oxygen saturation of 85 to 89%, as compared
with a range of 91 to 95%, on survival and
neurodevelopmental outcomes at 18 months to
2 years after the expected delivery date.

17.  Halfway through the trials, the oximeter-
calibration algorithm was revised.
 Recruitment was stopped early when an
interim analysis showed an increased rate of
death at 36 weeks in the group with a lower
oxygen saturation.

18.  RESULTS
1. DEATH:
Those in the lower-target group had a higher rate
of death than those in the higher-target group
before hospital discharge (23.1% vs. 15.9%;
relative risk in the lower-target group, 1.45;
95% confidence interval [CI], 1.15 to 1.84;
P=0.002).

19. 2. ROP: reduced rate in lower saturation group
3. BPD: no change
4. NEC: increased rate in lower saturation group
5. DURATION OF OXYGEN: Decreased in lower
saturation group

20.  In conclusion, preterm infants born before 28
weeks' gestation with a target oxygen
saturation of 85 to 89% had a significantly
higher rate of death than did those with a
target of 91 to 95% in a subgroup whose
treatment involved an oximeter-calibration
algorithm similar to that in current use. Our
findings strongly favor the avoidance of
targeting an oxygen saturation of less than 90%
among such infants, according to readings on
current oximeters

21.  Surfactant, Positive Pressure, and Oxygenation
Randomized Trial (SUPPORT), a controlled,
multicenter trial with a 2-by-2 factorial design,
to compare two target levels of oxygen
saturation and two ventilation approaches
(continuous positive airway pressure [CPAP]
initiated in the delivery room with a protocol-
driven strategy of limited ventilation vs.
intratracheal administration of surfactant with
a protocol-driven strategy of conventional
ventilation).

22.  The oxygen-saturation component of the trial
tested the hypothesis that a lower target range
of oxygen saturation (85 to 89%), as compared
with a higher target range (91 to 95%), would
reduce the incidence of the composite outcome
of severe retinopathy of prematurity or death
among infants who were born between 24
weeks 0 days of gestation and 27 weeks 6 days
of gestation.

23.  Patients
 Infants who were born between 24 weeks 0
days of gestation and 27 weeks 6 days of
gestation for whom a decision had been made
to provide full resuscitation were eligible for
enrollment at birth. Infants born in other
hospitals and those known to have major
congenital anomalies were excluded.

24.  PRIMARY OUTCOME:
Death before discharge occurred in 130 of 654
infants in the lower-oxygen-saturation group
(19.9%) as compared with 107 of 662 infants in
the higher-oxygen-saturation group (16.2%)
(relative risk with lower oxygen saturation,
1.27; 95% CI, 1.01 to 1.60; P=0.04; number
needed to harm, 27). The distribution of the
major causes of death did not differ
significantly between the two groups

25.  The rate of severe retinopathy among survivors
who were discharged or transferred to another
facility or who reached the age of 1 year was
lower in the lower-oxygen-saturation group
(8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37
to 0.73; P<0.001; number needed to treat, 11).

26.  SECONDARY OUTCOMES:
BPD: no change
DURATION OF OXYGENATION: decreased in
lower saturation group

27. A prospective meta-analysis (PMA) is one where
studies are identified, evaluated, and
determined to be eligible before the results of
any included studies are known or published,
thereby avoiding some of the potential biases
inherent in standard, retrospective meta-
analyses. This methodology provides the same
strengths as a single large-scale multicentre
randomised study whilst allowing greater
pragmatic flexibility.

28.  The NeOProM Collaboration protocol
(NCT01124331) has been agreed prior to the
results of individual trials being available. This
includes pre-specifying the hypotheses,
inclusion criteria and outcome measures to be
used.

29.  Participants:
Participants in the eligible trials will be infants
born before 28 weeks' gestation and enrolled
within 24 hours of birth.

30.  The primary outcome to be assessed is a
composite outcome of death or major disability
at 18 months - 2 years corrected age.

31.  Additional outcomes
 ROP treatment by laser photocoagulation or
cryotherapy (performed if Type I ROP or
threshold ROP occurs)
 measures of respiratory support, defined as (a)
supplemental oxygen requirement at 36 weeks'
postmenstrual age , (b) days of endotracheal
intubation (c) days of continuous positive
airway pressure (CPAP), (d) days of
supplemental oxygen, (e) days on home
oxygen

32.  patent ductus arteriosus diagnosed by
ultrasound and requiring medical treatment
 patent ductus arteriosus requiring surgical
treatment
 necrotising enterocolitis requiring surgery
 weight at birth, 36 weeks' postmenstrual age,
discharge home and 18-24 months corrected
age

33.  re-admissions to hospital up to 18-24 months
corrected age
 cerebral palsy with GMFCS level 2 or higher or
MACS level 2 or higher at 18-24 months
corrected age
 blindness (<6/60 vision, 1.3 logMAR in both
eyes)
 deafness requiring hearing aids
 quantitative Bayley III score

34.  The lower SpO2 range was associated with a
significant increase in the risk of death. There
was no significant difference between the two
target ranges in the rate of disability at 18-24
months, including blindness. A significant
difference between groups in the risk of the
composite primary outcome of death or
disability in favour of the higher SpO2 range
was mainly attributable to the difference
between groups in the risk of death.

35.  The lower target range did not reduce
bronchopulmonary dysplasia or severe visual
impairment, but it did increase the risk of
necrotizing enterocolitis requiring surgery or
causing death.

36.  The trials provide no reason to prefer SpO2
targets below 90% and indicate the importance
of more trials to see if a further survival
advantage can be identified. The safety of
targets above 95% has not been evaluated. The
five trials were designed to be similar to
facilitate an individual patient data meta-
analysis, and this Neonatal Oxygen Prospective
Meta-Analysis (NeOProM) may provide
further insights.

37.  Oxygen-Saturation Targets and Outcomes in
Extremely Preterm Infants
 By Lisa Marie
 In NEJM 2003