Articles

Permissive hypercapnia in extremely low birthweight

infants (PHELBI): a randomised controlled multicentre trial
Ulrich H Thome, Orsolya Genzel-Boroviczeny, Bettina Bohnhorst, Manuel Schmid, Hans Fuchs, Oliver Rohde, Stefan Avenarius,
Hans-Georg Topf, Andrea Zimmermann, Dirk Faas, Katharina Timme, Barbara Kleinlein, Horst Buxmann, Wilfried Schenk, Prof Hugo Segerer,
Norbert Teig, Corinna Gebauer, Roland Hentschel, Matthias Heckmann, Rolf Schlsser, Jochen Peters, Rainer Rossi, Wolfgang Rascher,
Ralf Bttger, Jrgen Seidenberg, Gesine Hansen, Maria Zernickel, Gerhard Alzen, Jens Dreyhaupt, Rainer Muche, Helmut D Hummler, for the
PHELBI Study Group*

Summary
Lancet Respir Med 2015;
3: 53443
Published Online
June 16, 2015
http://dx.doi.org/10.1016/
S2213-2600(15)00204-0
See Comment page 499
*Members listed in the appendix
Division of Neonatology,
University Hospital for Children
and Adolescents, University of
Leipzig, Leipzig, Germany
(Prof U H Thome MD,
C Gebauer MD); Division of
Neonatology, Dr. von Hauner
University Childrens Hospital,
Ludwig Maximilian University
of Munich, Munich, Germany
(Prof O Genzel-Boroviczeny MD);
Division of Pediatric
Pneumology, Allergology and
Neonatology, Hannover
Medical School, Hannover,
Germany (Prof B Bohnhorst MD,
Prof G Hansen MD); Division of
Neonatology and Pediatric
Critical Care, University
Hospital for Children and
Adolescents, University of Ulm,
Ulm, Germany (M Schmid MD,
M Zernickel MSc,
Prof H D Hummler MD); Division
of Neonatology and Pediatric
Critical Care, University
Hospital for Children and
Adolescents, Albert Ludwigs
University Freiburg, Freiburg,
Germany (H Fuchs MD,
Prof R Hentschel MD); Division
of Neonatology and Pediatric
Critical Care, Elisabeth
Childrens Hospital, Klinikum
Oldenburg, Medical Campus,
Carl von Ossietzky University
of Oldenburg, Oldenburg,
Germany (O Rohde MD,
J Seidenberg MD); Hospital for
General Pediatrics and
Neonatology, Otto von
Guericke University
Magdeburg, Magdeburg,
Germany (S Avenarius MD,
R Bttger MD); Division of
Neonatology, University
Hospital for Children and

534

Background Tolerating higher partial pressure of carbon dioxide (pCO) in mechanically ventilated, extremely low
birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test
the hypothesis that higher target ranges for pCO decrease the rate of bronchopulmonary dysplasia or death.
Methods In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany
with birthweight between 400 g and 1000 g and gestational age 2328 weeks plus 6 days, who needed endotracheal
intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or
control group. The high target group aimed at pCO values of 5565 mm Hg on postnatal days 13, 6070 mm Hg on
days 46, and 6575 mm Hg on days 714, and the control target at pCO 4050 mmHg on days 13, 4555 mm Hg
on days 46, and 5060 mm Hg on days 714. The primary outcome was death or moderate to severe bronchopulmonary
dysplasia, dened as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age.
Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the
ISRCTN registry, number ISRCTN56143743.
Results Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving
179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359).
The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not dier signicantly
from the control group (54/180 [30%]; p=018). Mortality was 25 (14%) in the high target group and 19 (11%; p=032)
in the control group, grade 34 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=030), and the rate of
severe retinopathy recorded was 20 (11%) and 26 (14%; p=036).
Interpretation Targeting a higher pCO did not decrease the rate of bronchopulmonary dysplasia or death in ventilated
preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not dier between groups.
These results suggest that higher pCO targets than in the slightly hypercapnic control group do not confer increased
benets such as lung protection.
Funding Deutsche Forschungsgemeinschaft.

Introduction
Extremely preterm infants who survive often develop
bronchopulmonary dysplasia, which is characterised by
severely impaired alveolarisation, which in turn results
in a markedly reduced area for gas exchange.1 Infants
with bronchopulmonary dysplasia often need long-term
oxygen supplementation and frequent hospital readmissions,2 with consequent high morbidity and healthcare costs. Ventilator-induced lung injury is deemed one
of the main pathogenic factors for the development of
bronchopulmonary dysplasia and is mainly related to the
magnitude of tidal volume.3,4 Reduction of tidal volumes
might result in alveolar hypoventilation with increased
blood partial pressure of carbon dioxide (pCO), which
might be benecial.5 The intentional reduction of the
intensity of mechanical ventilation and allowing pCO
values above 45 mmHg is referred to as permissive
hypercapnia.

Increased respiratory drive through higher pCO has

been used for decades to wean infants o mechanical
ventilation. Early use of permissive hypercapnia in
newborn preterm infants from the rst day of life has
been controversial, because it might increase cerebral
perfusion, which can enhance oxygen delivery to the
brain, but also increases the risk of intracranial
haemorrhage.6 Furthermore, young rats have developed
retinopathy when exposed to very high pCO values
(roughly 100 mm Hg).7 Instead, because the susceptibility
to ventilator-induced lung injury might be highest soon
after birth,4 the reduction of tidal volumes with resultant
permissive hypercapnia could be most benecial when
applied early.
Data from some retrospective analyses suggest an
association between higher arterial pCO (PaCO) values
during the rst days of life in preterm infants and a
reduced incidence of bronchopulmonary dysplasia,8,9
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Articles

Research in context
Evidence before this study
Data from animal experiments suggested that permissive
hypercapnia could be benecial for subjects requiring
mechanical ventilation because of lower tidal volumes and
additional biochemical eects. We hypothesised that such
benets might also apply to preterm infants. We searched
PubMed from 1960 until 2014 for English language articles
with the following search terms: preterm infant, permissive
hypercapnia, and minimal ventilation. We also searched the
reference lists of previous review articles. Several retrospective
analyses were inconclusive. Three randomised trials were
identied in which ventilator-dependent extremely low
birthweight infants were allocated to dierent partial pressure
of carbon dioxide (pCO) targets. Two were small and
monocentric and the third, the SAVE trial, was prematurely
terminated for reasons unrelated to the mechanical ventilation.
All three used dierent PCO targets and the pCO dierences
between the randomly allocated groups were small. None of the
trials showed reduced incidence of bronchopulmonary dysplasia
associated with permissive hypercapnia. One of the
monocentric trials reported faster weaning o mechanical
ventilation, the other, however, a worse neurodevelopmental
outcome. Investigators of the SAVE trial reported a smaller
number of infants requiring long-term mechanical ventilation
beyond a postmenstrual age of 36 weeks. Results of a metaanalysis encompassing all three trials with 334 infants were
calculated which showed trends but no signicant dierences

whereas others do not.10,11 Furthermore, ndings of a

randomised trial12 comparing two dierent tidal volume
settings in adults with acute respiratory distress syndrome
showed increased survival and decreased morbidity in
patients randomly assigned to the lower tidal volume,
who also had higher PaCO.
Several trials have assessed how strategies to avoid
mechanical ventilation can improve outcomes for
preterm infants.13 For this approach to be successful,
investigators need to accept higher than normal pCO
values, but it is not clear whether lung protection is
due more to the use of non-invasive support than to
increased pCO. In preterm infants already on mechanical ventilation, results of four previous randomised
trials1417 of permissive hypercapnia and a meta-analysis18
did not show reduced incidences of bronchopulmonary
dysplasia. However, two of these trials had small sample
sizes,14,15 and in the third with 220 infants, the PaCO
dierence between the groups was only 4 mm Hg.16 In
the fourth trial, management diered between
treatment groups in several aspects other than pCO
target ranges.17 However, no signicant increases in
adverse events, especially the rate of intracranial
haemorrhage, associated with permissive hypercapnia
were reported, and some secondary analyses of the
www.thelancet.com/respiratory Vol 3 July 2015

between the results of dierent pCO targets. In another very

large randomised trial, management diered between
treatment groups in several aspects other than pCO target
ranges.
Retrospective analyses also suggested an increased risk of
intracranial haemorrhage that was not substantiated by the
randomised trials. Animal experiments suggested an increased
risk of retinopathy of prematurity associated with severe
hypercapnia. Whether this risk also applied to human beings
was unknown.
Added value of this study
With a sample size of 359, this multicentre trial did not show
increased lung protection and improved outcomes associated
with higher pCO targets, despite lower ventilator pressures. On
the contrary, higher pCO targets were associated with an
increased incidence of bronchopulmonary dysplasia or death in
the subgroup of infants with the worst lung disease.
Furthermore, there was an unexpected increased incidence of
necrotising enterocolitis, but no increase in the incidence of
intracranial haemorrhage or retinopathy of prematurity.
Implications of all available evidence
Mildly hypercapnic pCO targets as used in the control group of
this trial and the hypercapnia group of the SAVE trial seem to be
safe and are likely to be associated with small health benets.
Higher pCO targets as used in the high target group of this trial
do not increase these benets, and might cause harm.

prematurely terminated SAVE trial17 suggest some

benecial eects.
In their eorts to improve outcome, many neonatologists
have accepted permissive hypercapnia as their standard of
care,19 despite the absence of clearly proven benecial
eects. Consideration has been given to even higher pCO
targets as being of even greater benet. Hence permissive
hypercapnia has spread in todays neonatal intensive care
without sucient supporting evidence,20 with the
optimum PaCO target range for ventilated preterm
infants still to be established. This situation led us to do a
large multicentre trial comparing two markedly dierent
PaCO target ranges in extremely low birthweight infants.
We aimed to study whether a higher pCO target range
would reduce the rate of moderate to severe
bronchopulmonary dysplasia 21 or death in extremely low
birthweight infants needing mechanical ventilation.
Furthermore, we aimed to nd out whether hypercapnia
would be most benecial to the infants requiring the most
ventilatory support.

Methods
Study design and patients

Adolescents, FriedrichAlexander University Erlangen,

Erlangen, Germany
(H-G Topf MD, W Rascher MD);
Mutter-Kind-Zentrum,
Klinikum rechts der Isar,
Technical University of Munich,
Munich, Germany
(A Zimmermann MD);
University Hospital for General
Pediatrics and Neonatology,
Justus Liebig University
Giessen, Giessen, Germany
(D Faas MD); Division of
Neonatology, Hospital for
Children and Adolescents,
Vivantes-Hospital Neuklln,
Berlin, Berlin, Germany
(K Timme MD, Prof R Rossi MD);
Hospital for Children and
Adolescents, Childrens
Hospital of the Third Order,
Munich, Germany
(B Kleinlein MD,
Prof J Peters MD); Division of
Neonatology, University
Hospital for Children and
Adolescents of the J.W. Goethe
University Frankfurt am Main,
Frankfurt am Main, Germany
(H Buxmann MD,
Prof R Schlsser MD); Hospital
for Children and Adolescents,
Central Hospital Augsburg,
Augsburg, Germany
(W Schenk MD); St. Hedwig
Hospital, University of
Regensburg, Regensburg,
Germany (Prof H Segerer MD);
Department of Neonatology
and Pediatric Intensive Care,
Katholisches Klinikum, Ruhr
University Bochum, Bochum,
Germany (N Teig MD); Division
of Neonatology and Pediatric
Critical Care, University
Hospital for Children and
Adolescents, Ernst Moritz
Arndt University Greifswald,
Greifswald, Germany
(Prof M Heckmann MD);
Division of Pediatric Radiology,
University Hospital of the
Justus Liebig University
Giessen, Giessen, Germany
(Prof G Alzen MD); and Institute
of Epidemiology and Medical
Biometry, University of Ulm,
Ulm, Germany
(J Dreyhaupt PhD, R Muche PhD)
Correspondence to:
Prof Ulrich Thome, Division of
Neonatology, Department of
Womens and Childrens
Medicine, University Hospital of
Leipzig, 04103 Leipzig, Germany
uhthome@web.de
See Online for appendix

In this randomised multicentre trial, infants were

recruited from 16 tertiary care perinatal centres in
535

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1534 patients screened

430 not on assisted

ventilation

362 randomly
assigned
3 dropouts

179 high target group

411 no consent
4 chromosomal
anomaly
24 malformation
1 hydrops
14 asphyxia
40 palliative care
52 outborn
196 other

180 control target group

25 died before
36 week PMA

19 died before
36 week PMA

40 on O2 or
mechanical
support at
36 week PMA

35 on O2 or
mechanical
support at
36 week PMA

Figure 1: Trial prole

PMA=postmenstrual age. Infants not receiving invasive assisted ventilation
within 24 h of birth were not eligible for the study. Randomisation had to be
done within 12 h of intubation. The main reason for non-enrolment for some
eligible infants was that parents declined consent. Further reasons for this were
language barriers with some parents, or unavailability of parents able to give
consent within 12 h of birth.

High target
group (n=179)
Gestational age (weeks)
Birthweight (g)

256 14
713 156

Control group
(n=180)
257 13
709 153

Boys

105 (59%)

99 (55%)

Antenatal steroids (any)

162 (91%)

157 (87%)

PPROM >24 h

45 (25%)

35 (20%)

Apgar score at 5 min

7 (19)

8 (19)

Age at intubation (h)

0 (022; 21)

Intubation age 1 h

55 (31%)

0 (021; 13)
57 (32%)

Surfactant replacement

172 (96%)

175 (97%)

Total surfactant (mg/kg)

188 (65774)

183 (55829)

Methylxanthine treatment

168 (94%)

168 (94%)

Data are mean SD, median (minmax); mean, or n (%). PPROM=preterm

premature rupture of the membranes.

Table 1: Demographic data for study infants

Germany (appendix p 11). All infants who weighed 1000 g

or less at birth were screened. Inborn infants with a
gestational age of 2328 weeks plus 6 days, weighing
4001000 g and receiving endotracheal intubation and
mechanical ventilation within 24 h of birth were eligible.
Exclusion criteria were birth outside the prenatal centres
delivery ward, chromosomal anomalies, congenital
malformations requiring early surgery or otherwise
536

compromising respiratory care or outcome, hydrops

fetalis, air leaks before randomisation, severe birth
asphyxia, or a decision to provide compassionate care
only. The trial was approved by each centres institutional
review board and written informed consent was obtained
from the parents or legal guardians of all infants. The
trial was approved by the institutional review boards of
all participating centres. On-site monitoring was done by
the Interdisciplinary Centre for Clinical Trials (IZKS),
University Medical Centre, Mainz, Germany. An
independent data safety monitoring board (DSMB)
consisting of four experienced neonatologists and one
biostatistician evaluated critical safety issues as well as
the protocol amendment to enable the interim analysis
(appendix p 11). A database was programmed and all data
were entered in duplicate.

Patient allocation and masking

Infants were randomly assigned (1:1) with a secure webbased randomisation system (e-randomixer, IZKS), and
randomisation results were applied immediately. Randomisation was done by a block randomisation scheme
with variable block sizes (26) stratied by site and
birthweight (three strata: 400499 g, 500749 g,
7501000 g). It was not feasible to mask caregivers and
parents because of the many clinically indicated blood gas
determinations and ventilator adjustments required in
neonatal intensive care.

Procedures
Endotracheally intubated and mechanically ventilated
infants were randomly allocated to two dierent target
ranges of pCO. In both groups, an age-dependent pCO
increase was permitted to make weaning easier. In the
high target group (experimental intervention) the PaCO
target range was 5565 mm Hg from 13 days of life
(072 h postnatal age), 6070 mm Hg from days 46
(73144 h), and 6575 mm Hg from days 714 (145336 h).
In the control target group the PaCO target range was
4050 mm Hg from days 13 (072 h), 4555 mm Hg
from days 46 (73144h), and 5060 mm Hg from
days 714 (145336 h).
Postnatal age was counted from birth, and infants were
entered into the schedule when they were randomly
assigned. Randomisation and assignment to the
randomised target range had to be completed within 12 h
of endotracheal intubation, and was applied as long as
the infants remained intubated or until the end of day 14.
Extubation could be attempted if the PaCO was
maintained within or below the target range assigned
with a rate of less than 30 breaths per min and FiO was
less than 05. After extubation, no pCO targets were
dened by the study protocol. In the case of re-intubation
before day 14, the target range according to the
randomised group assignment and actual postnatal age
was resumed. Blood pCO was to be measured in at least
12-h intervals, or more frequently if clinically indicated or
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when measurement results outside the target range

occurred. Both arterial and capillary pCO measurements
were accepted, because routine care in several of the
study centres did not include arterial line placement in
all infants, and there was consensus that arterial lines
should not routinely be left in place for 14 days. The study
protocol allowed waiving of all management restrictions
in the case of severe complications.
To minimise volutrauma, a high ventilation rate
(6080 per min) was favoured over high tidal volumes in
both groups. Initial ventilator settings comprised a rate of
6080 per min or greater, inspiratory time of 025035 s,
positive end-expiratory pressure 36 mbar, and a peak
inspiratory pressure resulting in minimal to moderate
chest rise. The rate was allowed to be decreased only if the
peak inspiratory pressure was 14 mbar or lower.
Synchronised ventilation or forms of volume control were
allowed to be used at the discretion of the clinicians in
charge of patient care. Because the administration of
sodium bicarbonate has been linked to increased lung
damage,22,23 its use was discouraged. Furthermore, we
attempted to prevent inconsistent use between the two
study groups to avoid it becoming a confounder. Therefore,
bicarbonate administration to correct a low pH in
combined acidosis was linked to the base decit rather
than the pH or pCO and allowed only if the base decit
exceeded an arbitrary level of 8 mmol/L, independent of
pH and pCO. We used high frequency ventilation only as
a rescue method. The rst dose of natural surfactant was
generally given immediately after intubation as a standard
treatment in all participating centres. However, this was
not governed by the trial protocol since intubation
occurred before enrolment. Further doses were to be
given to all enrolled infants suering from respiratory
distress syndrome and requiring at least a fraction of
inspired oxygen (FiO) of 03. Up to two additional doses
were given within 24 h if the FiO requirement exceeded
03, unless there were contraindications. Caeine was
recommended for all participating infants.

High target group

(n=179)

Control group
(n=180)

p value

65 (36%)

54 (30%)

018

Mortality to 36 weeks postmenstrual age

25 (14%)

19 (11%)

032

Moderate or severe bronchopulmonary dysplasia at

36 weeks postmenstrual age

40 (22%)

35 (19%)

044
029

Moderate or severe bronchopulmonary dysplasia or

death at 36 weeks postmenstrual age*

Death before day 28

22 (12%)

16 (9%)

O or positive pressure for 28 days

147 (82%)

150 (83%)

044

Mild bronchopulmonary dysplasia (consensus

denition)

104 (62%)

112 (63%)

026

Moderate bronchopulmonary dysplasia (consensus

denition)

18 (10%)

23 (13%)

Severe bronchopulmonary dysplasia (consensus

denition)

22 (12%)

12 (7%)

Intraventricular haemorrhage all grades

50 (28%)

55 (31%)

046

9 (5%)

8 (4%)

063

Severe intraventricular haemorrhage (grade 34)

26 (15%)

21 (12%)

030

Severe intraventricular haemorrhage (grade 34)

present on day 1 without progress

7 (4%)

3 (2%)

048

Combined death or moderate to severe

bronchopulmonary dysplasia or intraventricular
haemorrhage (grade 34)

82 (46%)

67 (37%)

009

Intraventricular haemorrhage present on day 1

without progress

Periventricular leukomalacia

16 (9%)

11 (6%)

031

Hydrocephalus internus

24 (16%)

27 (17%)

076

8 (4%)

7 (4%)

078

93 (52%)

79 (44%)

Hydrocephalus internus with shunt

Infants who received bicarbonate treatment
Bicarbonate dose cumulative over the entire hospital
stay, in infants who received bicarbonate (mmol/kg)
Extubated within the rst 14 days of life
Re-intubated within the rst 14 days of life
Days of sedative use per infant
Pulmonary interstitial emphysema
Pneumothorax
pCO targets waived in response to a severe
complication
Days pCO targets waived
Postnatal dexamethasone treatment
Cumulative dexamethasone dose (mg)

58 (05462)

63 (07380)

137 (77%)

137 (77%)

51 (29%)

51 (29%)

2 (014)

25 (014)

013
029
10
10
059

25 (14%)

32 (18%)

032

8 (5%)

13 (7%)

027

32 (18%)

26 (14%)

038

4 (110)

3 (113)

045

30 (17%)

29 (16%)

081

065 (00648)

066 (010300)

38 (22%)

Outcomes

Cumulative hydrocortisone dose (mg)

88 (06219)

The primary outcome of the trial was death or

bronchopulmonary dysplasia before 36 weeks postmenstrual age according to the physiological denition
of bronchopulmonary dysplasiaie, requiring mechanical pressure support or supplemental oxygen at
36 weeks postmenstrual age within 2 days, including
an oxygen reduction test for infants requiring less than
03 FiO (bronchopulmonary dysplasia or death).24 The
bronchopulmonary dysplasia part of this denition also
represents moderate to severe bronchopulmonary
dysplasia according to the National Institute of Child
Health and Development (NICHD) consensus definition.21 Bronchopulmonary dysplasia status was established independent of caregiver assessments by a
computer algorithm, which applied the above denition
to collected clinical data as part of the statistical analysis.

Retinopathy of prematurity

78 (47%)

78 (47%)

Severe retinopathy grade 3

20 (11%)

26 (14%)

036

Necrotising enterocolitis grade 2

20 (12%)

8 (5%)

002

www.thelancet.com/respiratory Vol 3 July 2015

50 (28%)

09

Postnatal hydrocortisone treatment

58 (0590)

017
031
092

Weight at 36 weeks postmenstrual age (g)

1943 (12003120)

2000 (10002830)

076

Weight gain to 36 weeks postmenstrual age (g)

1244 (3252384)

1250 (2002030)

059

Data are n (%) with 2 test, median with Mann-Whiney U test (minmax), unless stated otherwise. *Primary outcome
of trial, p value by group sequential analysis. One additional patient with severe bronchopulmonary dysplasia died
1 day after completing 36 postmenstrual weeks. As diagnosed by the study radiologist; high target (n=178), one
ultrasound exam missing. One infant was transferred and no follow-up cranial ultrasound scans were available.

Table 2: Overall outcome indicators

Major secondary outcomes included the severity of

bronchopulmonary dysplasia according to the consensus
denition,21 and the incidence and severity of intracranial
haemorrhage according to Papile and colleagues.25
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600

Control target
High target

70

500

60

400

50

300

40

200

30

100

20
0

7
8
Day of life

10

11

12

13

14

mm Hg

80

Figure 2: Daily mean values of the partial pressure of carbon dioxide (pCO2) in all patients who were intubated
at the time of measurement
Error bars indicate standard deviations, lower bars indicate numbers of patients contributing data. Shaded areas
indicate the target ranges of the high target and control groups. The pCO2 values were signicantly higher in
patients randomly assigned to the high target group than in those in the control target group (linear mixed eects
regression model; p<00001), although the high target range was frequently not achieved because of the patients
own respiratory eorts. The main reason for absent data was extubation.

600

Control target
High target

735

500

730

400

725

300

720

200

715

100

710
0

pH

740

0
1

10

11

12

13

14

Day of life

Figure 3: Daily mean values of the pH in all patients who were intubated at the time of measurement
Error bars indicate standard deviations, lower bars indicate numbers of patients contributing data. The pH values
were signicantly lower in patients randomly assigned to the high target group than in those in the control target
group (linear mixed eects regression model; p<00001). The main reason for absent data was extubation.

Cranial ultrasound examinations were done on the rst

day of life, at 1214 days, and at 36 weeks postmenstrual
age and were evaluated centrally by one masked
paediatric radiologist (GA). Retinopathy of prematurity
was routinely screened for and classied according to the
International Classication.26 Necrotising enterocolitis
was diagnosed when the clinical and radiological ndings
corresponded to stage II or higher according to the
staging criteria of Bell and colleagues.27

Statistical analysis
The sample size was calculated for the test according to
a group sequential design,28 allowing earlier termination
of enrolment in case a signicant dierence was detected
during scheduled interim analyses. A pre-trial primary
538

outcome rate of death or bronchopulmonary dysplasia

incidence of 47%, showing a 20% relative reduction (from
50% to 40%) with a power of 80% and a signicance level
of 5%, using a two-sided group sequential test with two
interim analyses, required a maximum sample size of
830 patients.
Predened secondary analyses were done by tests,
Students t tests, Mann-Whitney U tests, survival analyses,
and, for repeated measures, linear mixed eects regression
models. Subgroup analyses were done to test the hypothesis
that hypercapnia is of most benet to infants at the highest
risk of poor outcomes, by analysing interactions29 with loglinear Poisson regression with robust estimation of error
variance.30 The predened subgroups were infants in the
three birthweight strata, small for gestational age infants
dened (according to published German reference data31)
as birthweight less than 10th percentile for the gestational
age, and infants with more severe lung disease (FiO >04
or mean airway pressure >10 mbar for >4 h). Sex was added
post hoc to the subgroup analyses because of its importance
as a highly relevant risk factor.32
All analyses were done on an intention-to-treat basis. A
p value of less than 005 was deemed signicant. Sample
size calculation and interim and nal analyses of the
primary outcome were done with the software East
(Cytel Software Corporation, Cambridge, MA, USA) and
Addplan (Aptiv Solutions, Reston, VA, USA). For all other
analyses, SAS software (SAS Institute, Cary, NC, USA)
was used.
Early in 2012, an amendment of the study protocol was
developed to allow for the interim analysis requested by
the review board of the funding agency. The sequential
designs boundaries had not been exceeded at that time (ie,
there were no detectable signicant dierences). The study
design was changed from a three-stage group sequential
design into a two-stage adaptive group sequential design
with one interim analysis. The amendment was approved
by the DSMB and the lead investigators responsible
institutional review board. The interim analysis was based
on 312 completed infants and carried out by an independent
statistician (BM; appendix p 10). The results were presented
to the DSMB, which recommended terminating
enrolment. The funding agencys review board concurred
with this recommendation and it was implemented by the
study coordinator.
This trial is registered with the ISRCTN registry, number
ISRCTN56143743.

Role of the funding source

The funding agencys review board requested the interim
analysis early in 2012, when it became clear that the
recruitment rate would remain below the original
projections. Apart from this request, the funding agency
had no role in data collection, analysis, and interpretation,
nor in writing the report. Access to the raw data was
limited to the data manager (MZ) and the statistician
(JD). The corresponding author (UHT) had full access to
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all of the data and ultimate responsibility for submission

for publication.

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Proportion of intubated infants (%)

Between March 1, 2008, and July 31, 2012, we screened

1534 infants and recruited 362, of whom three had to be
excluded: two because parental consent was withdrawn
and one after being mistakenly randomly assigned despite
meeting an exclusion criterion (malformation), leaving
359 patients (179 in the high target group, 180 in the
control group) for the intention-to-treat analysis (gure 1).
Table 1 shows baseline demographic and clinical
characteristics of the two groups.
The primary endpoint of bronchopulmonary dysplasia or
death was met in 36% of patients in the high target group
and 30% in the control group, which was not a signicant
dierence according to the Addplan analysis (table 2).
Looking separately at the components of the composite
primary outcome (ie, requirement for mechanical support
or supplemental oxygen and mortality, either at an age of
28 days or at 36 weeks postmenstrual age), there were no
signicant dierences. Comparisons of bronchopulmonary
dysplasia severity according to the consensus denition21
were also inconclusive.
Day-by-day mean values of pCO and pH diered
signicantly between study groups (gures 2 and 3).
The pCO dierence peaked at 7 mm Hg on day 4 and
the mean dierence between days 2 and 11 was
62 mm Hg. Furthermore, infants in the high target
group had signicantly lower values for peak inspiratory
pressure (appendix p 5), suggesting increased weaning
eorts in the high target group. Tidal volumes were not
measured at all centres, and no signicant dierences
were detectable (appendix p 6).
The incidence of intraventricular haemorrhage was
similar in both groups, as were the incidence of
retinopathy of prematurity, periventricular leukomalacia,
hydrocephalus, and air leaks (table 2). Infants in the high
target group had a signicantly higher rate of necrotising
enterocolitis. Weight gain was similar in both groups.
Typical for modern neonatal care, we used dierent
ventilation methods across dierent study sites (appendix
p 7); the choice of ventilation modes did not dier
signicantly between study groups. However, nal
independence from the ventilator and supplemental
oxygen was not accelerated by the high target (gures 4
and 5).
We noted no signicant interactions of risk factors with
the primary outcome of bronchopulmonary dysplasia or
death. In the predened analyses, we did not identify a
subgroup that might have beneted from the high target
(table 3). Furthermore, all interactions were nonsignicant. However, in infants with severe lung disease,
the high target was associated with a higher incidence of
bronchopulmonary dysplasia or death.
The signicantly increased incidence of necrotising
enterocolitis prompted another unplanned subgroup

High target
Control target
Censored

75

50

25

0
0

20

40

60

80

100

Day of life

Figure 4: Kaplan-Meier analysis of weaning from invasive mechanical

ventilation
There was no signicant dierence between groups (p=018, log-rank test).
Circles indicate censored datapoints. Censoring generally occurred in patients
who were still intubated on day of life 99 or in patients who died.
100

Proportion of infants
on supplemental oxygen (%)

Results

100

High target
Control target
Censored

75

50

25

0
0

20

40

60

80

100

Day of life

Figure 5: Kaplan-Meier analysis of weaning from supplemental oxygen

There was no signicant dierence between groups (p=025, log-rank test).
Circles indicate censored datapoints. Censoring generally occurred in patients
who were still on positive pressure or supplemental oxygen on day of life 99 or
in patients who died.

analysis, which showed an association between the

incidence of necrotising enterocolitis and the high target
in infants with severe lung disease (p=006) and in
infants with 500749 g birthweight (p<001; table 4).
During the follow-up, there were three additional
deaths. Of these, two of the infants (one in the high
target group, one in the control group) had been
classied for the primary outcome as having
bronchopulmonary dysplasia and died within the rst
year. The third, in the high target group, had not met
our bronchopulmonary dysplasia criteria and died at
2 years corrected age.

Discussion
The high pCO target did not reduce the primary outcome.
Our results should be interpreted in view of the protocol
specications for this trial. Infants were only eligible
539

Articles

High target group Control group

(n=179)
(n=180)
Overall

Risk ratio (95% CI) pinteraction

65 (36%)

54 (30%)

121 (090163)

400499

14/22 (64%)

10/18 (56%)

115 (068193)

500749

39/83 (47%)

32/90 (36%)

132 (092189)

7501000

12/74 (16%)

12/72 (17%)

097 (047202)

Small for gestational age

(birthweight <10th percentile)

21/35 (60%)

18/41 (44%)

137 (088212)

Appropriate for gestational age

(birthweight 10th percentile)

44/144 (31%)

36/139 (26%)

118 (081171)

Infants with severe lung disease

37/64 (58%)

29/72 (40%)

144 (101204)*

Infants without severe lung disease

28/115 (24%)

25/108 (23%)

105 (066168)

Boy

40/105 (38%)

36/99 (36%)

105 (073150)

Girl

25/74 (34%)

18/81 (22%)

152 (091255)

Groups according to birthweight (g)

074

Infants small for gestational age

062

Severe lung disease

030

Sex

024

Data are n (%). Eect of intervention according to baseline characteristics (log-linear Poisson regression with robust
estimation of error variance for bronchopulmonary dysplasia or death).*Signicantly increased risk associated with the
high target (p=004).

Table 3: Subgroup analyses for eect on moderate or severe bronchopulmonary dysplasia or death at
36 weeks postmenstrual age

High target
group

Control
group

p value

More severe lung disease

10/61 (16%)

4/68 (6%)

006

Less severe lung disease

10/113 (9%)

4/106 (4%)

012

Birthweight (g)
400499

2/21 (10%)

1/17 (6%)

039

500749

14/79 (18%)

5/89 (6%)

p<001

7501000

4/74 (5%)

2/68 (3%)

068

Data are n (%) with test.

Table 4: Subgroup analyses for necrotising enterocolitis stage 2

when they needed endotracheal intubation and invasive

mechanical ventilation because pCO control is very
limited in non-intubated infants. In combination with
increasing clinical eorts to avoid invasive mechanical
ventilation altogether,17,33,34 eligible infants were only a
minor fraction of the admitted extremely low birthweight
infants, and this markedly slowed enrolment. However,
including only intubated infants led to the selection of less
stable infants who were more likely to have pronounced
respiratory distress syndrome, and thus to a highly
relevant trial population with regard to the questions
under investigation. Enrolment, initially projected for
3 years, was terminated after the interim analysis done in
the fourth year. Several considerations played a part in this
decision. First, the interim analysis showed no benet,
and a possible trend favouring the control rather than the
high target group. This nding suggested that it was futile
to continue recruitment because a benet to the high
target group showing over the remainder of the trial had
540

become extremely unlikely. Second, proving the opposite,

a worse outcome in the high target group, would not
change current standard of care. Third, ethical concerns
were raised about the need to randomly assign hundreds
of additional patients to achieve the original sample size
with limited further scientic gain, whereas other
multicentre trials poised to test important hypotheses
were held back. Fourth, too many changes to clinical
standards can confound trial results if patient recruitment
exceeds more than 35 years.
Although the study nished prematurely, the sample
size was still higher than the sum of all three previously
published trials, in which investigators had enrolled only
intubated infants and randomly assigned them into
dierent pCO target groups.1416 Furthermore, we
recorded higher pCO dierences between groups.
Despite the preference for higher risk infants who needed
mechanical ventilation in settings in which non-invasive
support was the rule, the overall rate of bronchopulmonary
dysplasia or death was lower in our trial, perhaps because
of continuous improvements in care. However, the
results of the three previous trials, an older meta-analysis
of two of these trials,18 and this trial, were similar, showing
no dierences in the rates for primary outcome between
the study groups.
Dierent pCO targets were also used in the very large
SUPPORT trial,17 which enrolled 1316 infants and
compared a strategy favouring non-invasive continuous
positive airway pressure and an upper pCO limit of
65 mm Hg for intubation and extubation with a strategy
of using primary intubation, surfactant administration,
and an upper pCO limit of 50 mm Hg. However, there
were no lower limits for the pCO and actual pCO values
were not reported. Like previous trials of hypercapnia and
our trial, the SUPPORT trial found no dierence in the
primary outcome. However, time spent on mechanical
ventilation was shorter in the continuous positive airway
pressure and hypercapnia group, which is probably the
result of the study protocol favouring extubation to
continuous positive airway pressure in this group.
Available data suggest that the encouraging trend towards
a better outcome in the continuous positive airway
pressure group of the SUPPORT trial might be more
related to favouring continuous positive airway pressure
and avoiding mechanical ventilation13 than to favouring
hypercapnia. Nasal continuous positive airway pressure
could have intrinsic benets, which might include full
control of expiratory braking by the vocal cords and a
large leak to discharge excessive air quickly if necessary.
Several considerations led to the selection of the pCO
targets for this trial. No optimum pCO target range has
ever been dened. Data from bench research and clinical
trials in adults suggested the benecial eects of
hypercapnia and hypercapnic acidosis.5,35 In preterm
infants, secondary and subgroup analyses of the
prematurely terminated SAVE multicentre trial suggested
reduced need for prolonged mechanical ventilation was
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Articles

associated with mild hypercapnia16 as compared with

normocapnia, without adverse eects. Mild hypercapnia
has since been increasingly introduced into routine care,
and discussion centred on how high to increase the pCO
goal to maximise benets. Additionally, the risk of
accidental hypocapnia fell.36 Consequently, a control
group with a normocapnic pCO target of 3545 mm Hg
seemed unethical and a mildly hypercapnic target range
was chosen. Because previous trials had been criticised
for their small pCO dierences, the high target group
was planned with much higher pCO targets to increase
the dierence in pCO between the groups, although it
was anticipated that these targets might not always be
achieved because of increased respiratory eorts by the
patients. Furthermore, we assumed that lung protection
might be increased with higher pCO goals, because
ventilator requirements and mechanical forces are
decreased, and biochemical benets of a high pCO
might depend on its concentration.37 Finally, stepwise
increases of the target ranges of both groups were
included because this was standard practice in the
participating units to help with weaning o mechanical
ventilation. We kept the planned dierence between
groups constant. Therefore, our trial is a comparison of
two dierent ranges of hypercapnia, one higher than the
other, particularly after the rst 3 days of life.
In view of these considerations, our results are
surprising. Signicantly lower ventilator pressures in the
high target group did not translate into better outcomes.
Furthermore, the most important outcomes tended to
favour the control group rather than the high target group,
arguing against the benets of a high target that might
have been missed because of the smaller-than-intended
sample size or the smaller-than-intended pCO dierence.
To explain the negative results, we hypothesised that
only infants who were extremely ill beneted from the
high target. The predened subgroup analyses had been
designed to address this hypothesis, but had low power
owing to limited sample sizes. However, our results
suggested that there was no benecial eect associated
with the high target for even the smallest infants,
consistent with subgroup analyses of the SUPPORT
trial.17 Furthermore, in infants with more severe lung
disease, the high target might have been associated with
detrimental eects, according to our data. Similarly, a
reanalysis of the SUPPORT trial showed associations
between high pCO values and adverse outcomes.38
Lung protective ventilation is a complex issue, and the
pCO is just one factor. Low ventilator pressure might be
lung protective, or lead to increased lung injury if
atelectasis formation is not prevented. However, the
most important determinant is a low tidal volume,3 and a
higher pCO might be a surrogate marker for lower tidal
volumes when other ventilatory parameters are kept
constant. As shown in experimental models,39,40 additional
lung protection can arise from the biochemical eects of
higher pCO and lower pH. On the other hand, high
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pCO and corresponding low pH values might also have

harmful side-eects that outweigh any benets, and this
could explain why the high pCO target was not
associated with an improved outcome in this trial.5,41,42
Indeed, there were no pH limits, rstly because lower
pH limits for premature infants have not been dened,
and, second, the only way to correct a low pH while
maintaining hypercapnia is by bicarbonate infusion,
which itself can have negative side-eects22,23 and thus be
a possible confounder. To prevent such a confounding
eect and promote equal bicarbonate use in both study
groups, we used bicarbonate administration to correct
the pH when the base decit rather than the pH exceeded
a limit. Consequently, the varying use of bicarbonate was
not signicantly dierent between the two study groups,
but resulted in lower pH values in the high target group.
Therefore, important enzymes could have been too far
outside their optimum pH to function as needed in the
high target group, which could have, along with other
eects, impaired wound repair in injured lungs43,44 and
alveolar uid clearance45 under hypercapnic conditions.
In this case, the most severely injured lungs would be
most aected, as suggested by the respective subgroup
analysis. Similar eects of hypercapnic acidosis could
also have impaired the function of intestinal cells and
might have caused the signicantly higher rate of
necrotising enterocolitis in the high target group,
because an association between acidosis and NEC has
already been described.46 Alternatively, the diering NEC
rate might be an incidental nding because we did
several univariate analyses.
As in general neonatal care, we used dierent ventilation
modes. Most of the newer modes have not been proven to
be more benecial in rigorous large-scale clinical trials.
Additionally, the measurement of tidal volume or
synchronisation of ventilation with an in-line ow sensor
at the expense of a higher dead space, possibly increasing
the need for mechanical support, has not been shown to
reduce lung injury and lead to better outcomes in extremely
low birthweight infants. Therefore, some centres in our
study group avoided using ow sensors (appendix p 7).
The use of ow sensors did not have a signicant eect on
the outcomes of this trial (data not shown).
We noted no increases of intraventricular haemorrhage
or retinopathy of prematurity attributable to the high
target. The rate of IVH might seem high, but only the
less stable infants with the highest risk for IVH were
eligible for this trial. Severe IVH (grade 3 or 4) might
seem slightly more frequent in the high target group, but
there were already a few more cases of severe IVH
present on day 1ie, before the protocol specications
had been fully enforced. Likewise, ndings of previous
trials did not show an increased incidence of IVH
associated with permissive hypercapnia.1417,47 Data from
previous retrospective analyses had already suggested
that uctuations of pCO2 were more strongly associated
with IVH than sustained high values.48,49
541

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The main limitation of this trial is probably its

premature cessation, reducing statistical power to answer
the pertinent questions. Furthermore, the pCO values
were lower than intended in the high target group, which
could be attributed either to the patients own respiratory
drive, or to insucient adherence to the protocol by the
clinicians. The signicantly lower peak inspiratory
pressure values in the high target group probably reect
the clinicians attempts to minimise ventilation and let
the pCO rise in accordance with the protocol. Clinical
decisions on choosing ventilator settings were not only
driven by pCO targets but tended to be more complex.
Looking at the collected data on ventilator settings, these
decisions did not always follow the study protocol.
However, our trial represents a pragmatic comparison of
two management strategies in daily clinical care.
In any case, all ndings should be interpreted with
appropriate caution. Previous trials also failed to fully
achieve pCO targets in the high target groups,1416 which
suggests that the target ranges in the high target group
were impossible to achieve in most infants most of the
time and probably should not be attempted either
clinically or in future studies.
In summary, we recorded no signicant dierence in
the primary outcome of bronchopulmonary dysplasia or
death between the two pCO target groups in infants
requiring intubation and mechanical ventilation. We
conclude that managing extremely low birthweight
infants with pCO targets according to the high target
group, as compared with the control group, is not
associated with improved outcomes. Moreover, the high
target might be associated with an increased incidence
of necrotising enterocolitis, and in infants with more
severe lung disease, with an increased incidence of
bronchopulmonary dysplasia or death, and therefore
cannot be recommended.
Contributors
UHT was the study coordinator and lead investigator and wrote the
grant application and institutional review board application, developed
and drafted the study protocol, co-developed the statistical analysis plan,
recruited patients, gathered data, and wrote the manuscript, and
generated gures; OG-B developed the study protocol, recruited patients,
gathered data, and edited the manuscript; BB developed the study
protocol, recruited patients, gathered data, edited the manuscript; MS,
HF, OR, SA, DF, AZ, BK, HB, WS, HS, NT, and RH developed the study
protocol, recruited patients, gathered data, and edited the manuscript;
HF developed the study protocol, recruited patients, gathered data, and
edited the manuscript; H-GT, KT, and CG recruited patients, gathered
data, and edited the manuscript; MH, RS, JP, RR, and JS developed the
study protocol, recruited patients, and edited the manuscript; WR and
GH developed the study protocol, and edited the manuscript; RB
recruited patients, gathered data, and edited the manuscript; MZ
programmed the study database, managed data and queries, entered
data into the database, and edited the manuscript; GA developed the
study protocol, analysed all cranial ultrasound exams, selected chest
radiographs, and edited the manuscript; JD developed the nal statistical
analysis plan and the protocol amendment, carried out the statistical
analyses, generated gures, and edited the manuscript; RM developed
the study protocol, initial statistical plan, sample size calculation, and
edited the manuscript; and HDH had the initial idea to do this study,
edited the grant application, developed the study protocol, recruited
patients, gathered data, and edited the manuscript.

542

Declaration of interests
We declare no competing interests.
Acknowledgments
This trial was funded by the Deutsche Forschungsgemeinschaft
(German Research Foundation, DFG, project number Th626/5-1),
which is taxpayer funded. The trial underwent extensive review by
anonymous expert reviewers before funding was approved by the
funding agencys review board. We thank the parents of our infants for
their consent and support of this project, which was given at a very
dicult time; all physicians and nurses who worked in the participating
units, many without being directly involved in this project, for their
support; and Waldemar A Carlo, Namasivayam Ambalavanan, and
Frank Pohlandt for their invaluable advice in developing the study
protocol and writing this manuscript; Sabine Schmid for entering data,
and Evelyn Killick for language editing.
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severe intraventricular hemorrhage in preterm infants.
Pediatrics 2007; 119: 299305.
McKee LA, Fabres J, Howard G, Peralta-Carcelen M, Carlo WA,
Ambalavanan N. PaCO2 and neurodevelopment in extremely low
birth weight infants. J Pediatr 2009; 155: 21721.

543

Comment

Arg117His-CFTR status has direct relevance to newborn

screening programmes for cystic brosis. Inclusion of
Arg117His-CFTR in screening panels leads to identication
of infants who have a very low likelihood of developing
cystic brosis lung disease, at least during childhood.
Removing the Arg117His-CFTR mutation from newborn
screening panels has been advocated.9 This position will
need to be reassessed in view of Moss and colleagues
results,6 since ivacaftor will probably play an important
part in treating Arg117His/5T-CFTR and might well be of
benet in those few patients with Arg117His/7T-CFTR
who have lung disease.
These data6 are therefore an important contribution to
the medical literature, since they provide clear support
for the treatment of patients with Arg117His-CFTR. The
results also show CFTR activity in children as well as in
adults, providing a rationale for the treatment of some
children. Whether patient-specic response to ivacaftor
can be predicted from specimens studied ex vivoeg,
nasal epithelial cells or intestinal organoidsremains
to be claried.10 Long-term studies to assess the safety
and ecacy of ivacaftor in general are also needed. In
this respect, evidence that the drug can modify the
rate of decline in lung function or the development of
structural injury will be important. Finally, the results
from Moss and colleagues study reinforce the notion of
mutation-specic treatment of CFTR dysfunctionan
important step on the road to personalised care for all
individuals with cystic brosis.

Frank J Accurso
University of Colorado and Childrens Hospital Colorado, Aurora,
CO 80045, USA
Frank.Accurso@ucdenver.edu
I have served on the Cystic Fibrosis Foundation Therapeutics, Inc./Vertex
Pharmaceuticals, Inc. Joint Development Committee since 2003. The purpose
of this committee is to improve the communication between the two groups.
I represent Cystic Fibrosis Foundation Therapeutics, Inc. in these discussions
and have no ties, nancial or otherwise, with Vertex Pharmaceuticals, Inc.
I receive reimbursement from Cystic Fibrosis Foundation Therapeutics, Inc. for
the twice a year in-person committee meetings only for plane fare, lunch, and
parking. I do not receive any remuneration from Cystic Fibrosis Foundation
Therapeutics, Inc. for time or eort. I receive no remuneration at all from
Vertex Pharmaceuticals, Inc.
1
2
3

8
9

10

Rowe SM, Miller S, Sorscher EJ. Cystic brosis. N Engl J Med 2005;
352: 19922001.
Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic brosis lung disease.
N Engl J Med 2015; 372: 157475.
Van Goor F, Hadida S, Grootenhuis, et al. Rescue of CF airway epithelial cell
function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA
2009; 106: 1882530.
Ramsey BW, Davies J, McElvaney NG, et al. VX08-770-102 Study Group.
A CFTR potentiator in patients with cystic brosis and the G551D
mutation. N Engl J Med 2011; 365: 166372.
De Boeck K, Munck A, Walker S, et al. Ecacy and safety of ivacaftor in
patients with cystic brosis and a non-G551D gating mutation. J Cyst Fibros
2014; 13: 67480.
Moss RB, Flume PA, Elborn JS, et al, on behalf of the VX11-770-110
(KONDUCT) Study Group. Ecacy and safety of ivacaftor in patients with
cystic brosis who have an Arg117His-CFTR mutation: a double-blind,
randomised controlled trial. Lancet Respir Med 2015; 3: 52433.
Kiesewetter S, Macek M Jr, Davis C, et al. A mutation in CFTR produces
dierent phenotypes depending on chromosomal background. Nat Genet
1993; 5: 27478.
Witt DR, Schaefer C, Hallam P, et al. Cystic brosis heterozygote screening
in 5161 pregnant women. Am J Hum Genet 1996; 58: 82335.
Thauvin-Robinet C, Munck A, Huet F, et al. The very low penetrance of
cystic brosis for the R117H mutation: a reappraisal for genetic counselling
and newborn screening. J Med Genet 2009; 46: 75258.
Dekkers JF, van der Ent CK, Beekman JM. Novel opportunities for
CFTR-targeting drug development using organoids. Rare Dis 2013;
1: e27112.

Permissive hypercapnia in preterm infants: the discussion

continues
During the past decade the threshold of viability in
extremely preterm infants has shifted to the lower
gestational age of younger than 26 weeks postmenstrual
age with subsequent improved survival. As a
consequence, more of the survivors have to be treated
for typical co-morbidities of extreme prematurity such
as brochopulmonary dysplasia. The latter is associated
with extreme prematurity and ventilator-induced lung
injury. Data from small studies have suggested that
permissive hypercapnia might reduce the incidence
of lung injury, and as a result the German multicentre
PHELBI study group1 embarked on a large randomised
www.thelancet.com/respiratory Vol 3 July 2015

controlled study of 830 extremely low birthweight

infants testing two levels of partial pressures of
carbon dioxide (PCO2) during the rst 2 weeks of life.
The study was stopped prematurely after an interim
analysis of 359 (23%) of 1534 infants screened in
53 months, in which investigators noted no dierence
in the primary outcome of death or moderate to severe
bronchopulmonary dysplasia between groups.
We would like to commend the authors and the
journal for publishing the no dierence ndings as the
report contains lessons to be learned. The study included
preterm infants from 23 to 28 weeks gestation onwards.

Published Online
June 16, 2015
http://dx.doi.org/10.1016/
S2213-2600(15)00240-4
See Articles page 534

499

Roger Job/Reporters/Science Photo Library

Comment

The incidence of bronchopulmonary dysplasia is highest

in infants younger than 28 weeks and therefore this
was an appropriate target population. Of note is the
long duration of recruitment of more than 4 years.
Clinical practice might have changed during this time
especially with the increasing use of non-invasive means
of respiratory support to wean or avoid intratracheal
ventilation altogether.2 During non-invasive ventilator
support PCO2 concentrations are established by the
breathing eorts of newborn babies and clinicians are
less able to aect the concentrations directly. Future
studies will need to consider this growing group of
patients and would benet from new non-invasive
techniques such as plethysmogram analysis of pulse
oximetry traces to measure spontaneous breathing
rates together with PCO2 concentrations.3
In the PHELBI study, PCO2 target concentrations were
aimed at three increasing levels in the rst 14 days
of life.1 The study design might have inadvertently
aected the clinicians decision to ventilate newborn
babies to achieve the PCO2 targets during the study
period. It was not possible to mask the clinicians to
group allocations. After 14 days, 25% of infants were
still ventilated. In the present trend of neonatal clinical
care to wean to non-invasive ventilation as soon as
possible, many tertiary care centres would consider this
intubation rate to be high.2
The PHELBI study group targeted the lung injury
aspect of bronchopulmonary dysplasia by using low
tidal volume ventilation strategies without controlling
500

for it with volume-targeted ventilation methods that

help to reduce lung injury. Results of recent animal
studies have also shown that lung injury starts early at
resuscitation at birth and could be improved by allowing
redistribution of placental blood through delaying cord
cutting and initiating lung expansion rst.4 Findings of
the study by Polglase and colleagues4 in preterm lambs
showed a smoother transition to extrauterine life after
birth if the lambs were given ination breath with their
cord intact. This method enabled a smooth increase in
pulmonary blood ow with expansion of lung alveoli.4
Benets of redistribution of placental blood in preterm
infants such as better adaptation after birth, less need
for blood transfusion, less incidence of intraventricular
haemorrhage and necrotising enterocolitis have
been widely described and therefore have been
incorporated into international guidelines on newborn
resuscitation.58
The PHELBI study group did not collect information
about whether the recruited infants received standardised delivery room management and subsequent
stabilisation to minimise lung injury, including any
means of redistribution of placental blood before
enrolment into the study. Future studies of the
reduction of lung injury and the development of
bronchopulmonary dysplasia should include this aspect
of resuscitation of the preterm infant. This approach
would need antenatal consent to enrol the preterm
infant into the trial. Findings of a recently published
qualitative study of parents showed a positive attitude
towards enrolling their unborn preterm baby into
a randomised trial to study two dierent ways of
enhancing redistribution of placental blood at birth.9,10
Increasing data seem to suggest that the lower the
gestational age the more varying practices between
hospitals will aect the outcome of preterm infants.11
With the participation of many centres in increasingly
larger randomised controlled trials over a long time
(like the PHELBI study), accounting for comparative
eectiveness between centres (ie, alternative standards
of care, assessing outcomes important to individuals,
and incorporating varied settings and participants)
becomes an important part of outcome assessment.12
Much still needs to be learnt about lung injury and
the development of bronchopulmonary dysplasia
in extremely low birthweight infants. The pattern
of respiratory distress syndrome in these infants has
www.thelancet.com/respiratory Vol 3 July 2015

Comment

changed over the past 10 years. The introduction

of antenatal steroids has changed the incidence of
severe respiratory distress syndrome. Researchers can
now look at other preventive measures at the time of
resuscitation at birth,5 which might have more eect
than PCO2 concentrations in the rst day of life or
dierent ventilation strategies such as low volume
ventilation or patient synchronised ventilation. The
PHELBI study provides the basis for further discussions
on how to design future study protocols. Optional
antenatal consent will probably increase recruitment
in trials of extremely low birthweight infants of 23 to
28 weeks gestation.

Heike Rabe, Jose Ramon Fernandez-Alvarez

Brighton and Sussex Medical School and University Hospitals,

Academic Department of Paediatrics, Royal Alexandra Childrens
Hospital, Brighton BN2 5BE, UK
Heike.Rabe@bsuh.nhs.uk

10

We declare no competing interests.

11

Thome UH, Genzel-Boroviczeny O, Bohnhorst B, et al, for the PHELBI Study

Group. Permissive hypercapnia in extremely low birthweight infants
(PHELBI): a randomised controlled multicentre trial. Lancet Resp Med 2015;
published online June 16. http://dx.doi.org/10.1016/S22132600(15)00204-0.

12

Fernandez-Alvarez R, Gandhi RS, Amess PN, et al. Heated humidied high

ow nasal cannula versus low ow nasal cannula as weaning mode from
nasal CPAP in infants 28 weeks gestation. Eur J Pediatr 2014; 173: 9398.
Wertheim D, Olden C, Symes L, et al. Monitoring respiration in wheezy
preschool children by pulse oximetry plethysmogram analysis.
Med Biol Eng Comput 2013; 51: 96570.
Polglase GR, Dawson JA, Kluckow M, et al. Ventilation onset prior to
umbilical cord clamping (physiological-based cord clamping) improves
systemic and cerebral oxygenation in preterm lambs. PLoS One 2015;
10: e0117504.
Sweet D, Carnielli V, Greisen G, et al. European Consensus Guidelines on the
management of neonatal respiratory distress syndrome in preterm infants:
2010 Update. Neonatology 2010; 97: 40217.
The American College of Obstetricians and Gynecologists. Committee on
Obstetric Practice. Timing of umbilical cord clamping after birth.
Obstet Gynecol 2012; 120: 152226.
The National Institute for Health and Care Excellence. Intrapartum care:
care of healthy women and their babies during childbirth. December, 2014.
http://www.nice.org.uk/guidance/cg190 (accessed Feb 25, 2015).
WHO. Every Newborn: an action plan to end preventable deaths.
http://www.everynewborn.org/Documents/Full-action-plan-EN.pdf
(accessed March 10, 2015).
Ayers S, Sawyers A, During C, et al. Parents report positive experiences
about enrolling babies in a cord-related trial before birth. Acta Pediatr 2015;
104: e164e170.
Rabe H, Jewison A, Fernandez Alvarez R, et al. Milking compared with
delayed cord clamping to increase placental transfusion in preterm
neonates. A randomized controlled trial. Obstet & Gynecol 2011;
117: 20511.
Rysavy MA, Li L, Bell EF, et al. Between-hospital variation in treatment and
outcomes in extremely preterm Infants. New Engl J Med 2015;
372: 180111.
Lagatta J, Uhing M, Panepinto J. Comparative eectiveness and practice
variation in neonatal care. Clin Perinatol 2014; 41: 83345.

About 510% of patients on mechanical ventilation

will have persistent respiratory failure necessitating
prolonged mechanical ventilation.1 This condition is part
of the larger syndrome of chronic critical illness, in which
critically ill patients have continuing organ failures
leading to protracted periods of organ support.2 Both
prolonged mechanical ventilation and chronic critical
illness are important public health problems. In the
USA, for example, more than 380 000 individuals are
estimated to have chronic critical illness every year, with
costs exceeding US$50 billion annually.3
A meta-analysis of studies reporting clinical outcomes
in prolonged mechanical ventilation published in
The Lancet Respiratory Medicine further highlights the
challenges posed by these patients.4 Emily Damuth and
colleagues4 systematically reviewed 124 studies from
16 dierent countries worldwide, with sobering results.
Pooled mortality at hospital discharge was 26%, 57% of
www.thelancet.com/respiratory Vol 3 July 2015

patients were liberated from mechanical ventilation by

the end of their hospital stay, and 22% of patients were
discharged home. Perhaps most concerning was that
59% of patients were dead at 1 year.
These ndings should serve as a wake-up call to
clinicians, hospital administrators, and health policy
makers involved in the care of patients with prolonged
mechanical ventilation. Eorts are urgently needed
to increase liberation rates and improve survival.
Unfortunately, the way to proceed in this area is not
at all clear. Despite the increasing recognition of
the immense clinical and nancial burden chronic
critical illness puts on health systems, evidence-based
strategies to guide clinical care in this population
are lacking. This situation is the real wake-up call
not that outcomes must be improved, but that how
to improve them is simply not known. Immediate,
targeted research is needed to ll this knowledge gap

Jade/Blend Images/Corbis

Improving outcomes in prolonged mechanical ventilation:

a road map

Published Online
May 21, 2015
http://dx.doi.org/10.1016/
S2213-2600(15)00205-2
See Articles page 544

501