Elective high frequency oscillatory ventilation versus

conventional ventilation for acute pulmonary dysfunction in

preterm infants (Review)

Henderson-Smart DJ, Cools F, Bhuta T, Offringa M

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2007, Issue 4

http://www.thecochranelibrary.com

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 1
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 TABLE OF CONTENTS

ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . . 3
SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . . 3
METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Characteristics of ongoing studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Comparison 01. HFOV vs CV (all trials) . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Comparison 02. HFOV vs CV subgrouped by volume strategy on HFOV . . . . . . . . . . . . . . . 22
Comparison 03. HFOV vs CV subgouped by use of surfactant . . . . . . . . . . . . . . . . . . . 23
Comparison 04. HFOV vs CV subgrouped by type of HFO ventilator . . . . . . . . . . . . . . . . 23
Comparison 05. HFOV vs CV subgrouped by lung protective (LPS) CV strategy . . . . . . . . . . . . . 23
Comparison 06. HFOV vs CV subgrouped by age at randomisation . . . . . . . . . . . . . . . . . 24
Comparison 07. HFOV vs CV subgrouped by I:E ratio on HFOV . . . . . . . . . . . . . . . . . . 24
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Analysis 01.01. Comparison 01 HFOV vs CV (all trials), Outcome 01 Death by 28-30 days . . . . . . . . . 26
Analysis 01.02. Comparison 01 HFOV vs CV (all trials), Outcome 02 Mechanical ventilation at 28 - 30 days in survivors 26
Analysis 01.03. Comparison 01 HFOV vs CV (all trials), Outcome 03 Oxygen at 28-30 days in survivors . . . . 27
Analysis 01.04. Comparison 01 HFOV vs CV (all trials), Outcome 04 CLD at 28-30 days (O2 + xray) in survivors . 27
Analysis 01.05. Comparison 01 HFOV vs CV (all trials), Outcome 05 Death or CLD at 28-30 days . . . . . . 28
Analysis 01.06. Comparison 01 HFOV vs CV (all trials), Outcome 06 Death by 36-37 weeks or discharge . . . . 28
Analysis 01.07. Comparison 01 HFOV vs CV (all trials), Outcome 07 CLD at 36-37 weeks PMA or discharge in 29
survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 01.08. Comparison 01 HFOV vs CV (all trials), Outcome 08 Death or CLD at 36-37 weeks PMA or discharge 30
Analysis 01.09. Comparison 01 HFOV vs CV (all trials), Outcome 09 Any pulmonary air leak . . . . . . . . 31
Analysis 01.10. Comparison 01 HFOV vs CV (all trials), Outcome 10 Gross pulmonary air leak . . . . . . . 32
Analysis 01.11. Comparison 01 HFOV vs CV (all trials), Outcome 11 Intraventricular hemorrhage - all grades . . 32
Analysis 01.12. Comparison 01 HFOV vs CV (all trials), Outcome 12 Intraventricular hemorrhage - grd 3 or 4 . . 33
Analysis 01.13. Comparison 01 HFOV vs CV (all trials), Outcome 13 Periventricular leukomalacia . . . . . . 34
Analysis 01.14. Comparison 01 HFOV vs CV (all trials), Outcome 14 Retinopathy of prematurity (grd 2 or more) in 35
survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 02.01. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 01 Death by 36-37 36
weeks or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 02.02. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 02 CLD at 36-37 37
weeks PMA or discharge in survivors . . . . . . . . . . . . . . . . . . . . . . . . . .
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants i
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 02.03. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 03 Death or CLD 38
at 36-37 weeks PMA or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 02.04. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 04 Gross pulmonary 39
air leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 02.05. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 05 Intraventricular 40
hemorrhage - grd 3 or 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 02.06. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 06 Periventricular 41
leukomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 03.01. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 01 Death by 36-37 weeks or 42
discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 03.02. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 02 CLD at 36-37 weeks PMA 43
or discharge in survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 03.03. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 03 Death or CLD at 36-37 44
weeks PMA or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 03.04. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 04 Gross pulmonary air leak 45
Analysis 03.05. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 05 Intraventricular hemorrhage 46
- grd 3 or 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 03.06. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 06 Periventricular leukomalacia 47
Analysis 04.01. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 01 Death by 36-37 48
weeks or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 04.02. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 02 CLD at 36-37 weeks 49
PMA or discharge in survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 04.03. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 03 Death or CLD at 50
36-37 weeks PMA or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 04.04. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 04 Gross pulmonary air 51
leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 04.05. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 05 Intraventricular 52
hemorrhage - grd 3 or 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 04.06. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 06 Periventricular 53
leukomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 05.01. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 01 Death by 54
36-37 weeks or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 05.02. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 02 CLD at 56
36-37 weeks PMA or discharge in survivors . . . . . . . . . . . . . . . . . . . . . . .
Analysis 05.03. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 03 Death or 57
CLD at 36-37 weeks PMA or discharge . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 05.04. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 04 Gross 59
pulmonary air leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 05.05. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 05 60
Intraventricular hemorrhage - grd 3 or 4 . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 05.06. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 06 61
Periventricular leukomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 06.01. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 01 Death by 36-37 weeks 63
or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 06.02. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 02 CLD at 36-37 weeks 64
PMA or discharge in survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 06.03. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 03 Death or CLD at 36- 65
37 weeks PMA or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 06.04. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 04 Gross pulmonary air 66
leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 06.05. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 05 Intraventricular 67
hemorrhage - grd 3 or 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants ii
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 06.06. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 06 Periventricular 68
leukomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 07.01. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 01 Death by 36-37 weeks 69
or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 07.02. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 02 CLD at 36-37 weeks 70
PMA or discharge in survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 07.03. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 03 Death or CLD at 36-37 71
weeks PMA or discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 07.04. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 04 Gross pulmonary air leak 72
Analysis 07.05. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 05 Intraventricular 73
hemorrhage - grd 3 or 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 07.06. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 06 Periventricular 74
leukomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants iii
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Elective high frequency oscillatory ventilation versus
conventional ventilation for acute pulmonary dysfunction in
preterm infants (Review)

Henderson-Smart DJ, Cools F, Bhuta T, Offringa M

This record should be cited as:

Henderson-Smart DJ, Cools F, Bhuta T, Offringa M. Elective high frequency oscillatory ventilation versus conventional ventilation for
acute pulmonary dysfunction in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000104. DOI:
10.1002/14651858.CD000104.pub2.

This version first published online: 18 July 2007 in Issue 3, 2007.

Date of most recent substantive amendment: 14 May 2007

ABSTRACT
Background
Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive
pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease
(CLD). Conventional IPPV is provided at 30-80 breaths per minute, while a newer form of ventilation called high frequency oscillatory
ventilation (HFOV) provides ’breaths’ at 10 - 15 cycles per second. This has been shown to result in less lung injury in experimental
studies.
Objectives
The objective of this review is to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared
to conventional ventilation (CV) in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS), on the
incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation.
Search strategy
Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references,
abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in
the English language. The search was updated in April 2007.
Selection criteria
Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly
due to RDS, who were given IPPV. Randomisation and commencement of treatment needed to be as soon as possible after the start
of IPPV and usually in the first 12 hours of life.
Data collection and analysis
The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative
risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. For all
measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text.
Meta-analysis was performed using a fixed effects model. Where heterogeneity was over 50%, the random effects RR is also given.
Main results
Fifteen eligible studies of 3,585 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on
mortality at 28 - 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup
analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction
was of borderline significance overall. Subgroups of trials showed a significant reduction in CLD with HFOV when high volume
strategy for HFOV was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 1
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
randomisation occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-
analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group.

In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The
subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 intraventricular haemorrhage
and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not
in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group.

Authors’ conclusions
There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to
treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the
evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective
HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating
HFOV and CV, and report important long-term neurodevelopmental outcomes.

PLAIN LANGUAGE SUMMARY

Insufficient evidence exists to support the routine use of high frequency oscillatory ventilation (HFOV) instead of conventional
ventilation for preterm infants with lung disease who are given positive pressure ventilation.

High frequency oscillatory ventilation is a way of providing artificial ventilation of the lungs that theoretically may produce less injury
to the lungs and therefore reduce the rate of chronic lung disease. This review of the evidence from fifteen randomised controlled trials
showed variable results between studies and no clear overall benefit or harm resulting from HFOV.

BACKGROUND
Pulmonary disease continues to be the major cause of morbidity
and mortality in very preterm infants. Although assisted ventila-
tion with intermittent positive pressure ventilation (IPPV) has de-
creased mortality, morbidity from lung injury is high. Acute injury
such as pulmonary air leak was common prior to the availability
of surfactant. Chronic lung disease (CLD) develops in up to one
third of preterm infants with the respiratory distress syndrome
(RDS) who receive IPPV (Northway 1992; Ehrenkrantz 1992).
In addition to immaturity, over distention of the lung and oxygen
toxicity are thought to be important factors in the pathogenesis of
CLD (Jobe 2000).
In order to avoid distortion of the lung caused by the large swings
in pulmonary pressures during conventional ventilation (CV) at
rates of 30 - 80, high frequency oscillatory ventilation (HFOV) at
rates of 600 - 800 per minute was developed. In animal models,
the use of HFOV results in more uniform lung inflation, improves
oxygenation and reduces the severity of lung pathology produced
by IPPV (Truog 1984; de Lemos 1987).
As discussed by Clark 2000, there are strategies that reduce lung
injury with both HFOV and CV. Animal studies show that lung
volume maintenance with HFOV prevents lung injury (McCul-
loch 1988). The effectiveness of HFOV might also be enhanced by
the use of more powerful piston driven ventilators compared with
those that generate the oscillations by flow interruption (Jouvet
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
1997), and even by certain settings with the same type of ventilator
(inspiratory/expiratory ratio of 1/1 versus 1/2, Pillow 1999). Var-
ious strategies with CV appear to reduce acute lung injury. These
include avoiding high tidal volumes, using positive end expiratory
pressure (PEEP) and using short inspiratory times and faster rates.
Allowing carbon dioxide to rise (permissive hypercapnoea) rather
than increasing ventilation may also reduce lung injury in preterm
infants (Woodgate 2006). Many of these treatment strategies and
their effects on lung injury are based on pathophysiological stud-
ies in animal models (increased cytokine release with higher tidal
volumes and reduced PEEP, Meredith 1989) or trials in adults
with RDS (Petrucci 2006). There is evidence in preterm infants
that strategies to synchronise ventilation (higher rates and patient
triggered ventilation) reduce the rate of pneumothorax and the
duration of ventilation (Greenough 2003), although there is no
evidence that these strategies reduce CLD at 36 weeks postmen-
strual age.
OBJECTIVES
The objective of this review is to determine the effect of the elective
use of high frequency oscillatory ventilation (HFOV) when com-
pared to conventional ventilation (CV) in preterm infants who
are mechanically ventilated for RDS on the incidence of chronic
lung disease, mortality and other complications associated with
prematurity and assisted ventilation.
2
The following subgroup analyses pre-specified:
(1) Management of HFOV: A strategy to maintain lung volume
has the potential for better alveolar recruitment compared to a
strategy to maintain one of low volume, and thus might result
in better outcomes in terms of CLD. A ’high volume strategy’
(HVS) with HFOV was defined as one in which two or more of
the following treatment approaches were explicitly stated in the
methods: initial use of a higher mean airway pressure than on CV;
initial weaning of fractional inspired oxygen before mean airway
pressure; and use of alveolar recruitment manoeuvres.
(2) Surfactant replacement: Surfactant replacement therapy would
increase alveolar recruitment, attenuate RDS, and lead to less lung
injury and CLD. A similar pulmonary benefit could occur in in-
fants whose mothers received antenatal corticosteroids.
(3) Birth weight and gestational age: Outcomes might differ in
groups of infants born at different weights and gestational ages.
Infants born at very low gestation and/or with very low birth
weight have a higher incidence of CLD and may benefit more from
HFOV. On the other hand, these infants are more susceptible to
neurological complications such as intraventricular haemorrhage
(IVH) and periventricular leukomalacia (PVL).
In order to explain persisting heterogeneity in the meta-analyses in
previous versions of this review, the following subgroup analyses
were added for the 2007 update:
(4) Type of HFOV ventilator: True (piston) HFO ventilators
might be more effective in maintaining lung volume and lead to
different effects compared with those that use flow interruption.
Also, differences in inspiratory:expiratory times on HFOV may
affect lung injury.
(5) Management of CV: Lung protective strategies on CV (short
inspiratory times, rates of ≥60/minute, PEEP of 4 - 6 cms H2 0,
limiting tidal volume, patient triggering or permissive hypercap-
noea) may affect the differences between HFOV and CV.
(6) Duration of ventilation prior to randomization or age at ran-
domization: The treatment that infants receive prior to randomi-
sation could alter outcomes and this could be measured by dura-
tion of ventilation prior to randomisation and/or age at randomi-
sation.
CRITERIA FOR CONSIDERING
STUDIES FOR THIS REVIEW
Types of studies
Randomised or quasi-randomised controlled trials.
Types of participants
Preterm or low birth weight infants with pulmonary dysfunction,
mainly due to RDS, who were considered to require IPPV.
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Types of intervention
Elective HFOV vs. CV, with randomisation early in the course of
RDS soon after mechanical ventilation was begun. Such trials were
classified as ’ elective’. Trials were classified as ’rescue’, and therefore
excluded from this review, when patients were randomised after
failure to adequately ventilate on CV or when complications of
CV developed or were likely to develop. The use of HFOV as
rescue therapy and the use of elective high frequency jet ventilation
are the subjects of other reviews (Bhuta 2005; Bhuta 2003). Trials
were not eligible if cross-over of interventions were mandatory.
Types of outcome measures
Outcomes from trials were not eligible if there was a 20% or greater
rate of missing or unreported data.
Primary
1. Mortality at 28 - 30 days and at term equivalent age
2. Chronic lung disease
Oxygen dependency at 28 - 30 days (with and without chest x-
ray changes)
Oxygen dependency or use of assisted ventilation at 36 - 37 weeks
postmenstrual age (PMA) or discharge
3. Death or chronic lung disease
Secondary
4. Failure of allocated treatment to maintain gas exchange, leading
to cross over to alternate treatment
5. Pulmonary air leak syndromes - all [including pulmonary inter-
stitial emphysema - (PIE) and gross extrapulmonary air leak (such
as pneumothorax)]
6. Intraventricular haemorrhage
All grades
Grades 3 (ventricles distended with blood) or 4 (parenchymal
involvement)
7. Periventricular leukomalacia
8. Retinopathy of prematurity (ROP) - grade 2 or more
9. Use of hospital resources (length of hospital stay, duration of
IPPV)
10. Long term growth and neurodevelopment
SEARCH METHODS FOR
IDENTIFICATION OF STUDIES
See: methods used in reviews.
Searches were made of the Oxford Database of Perinatal
Trials, Cochrane Controlled Trials Register (CENTRAL, The
Cochrane Library Issue 2, 2007, MEDLINE and EMBASE
(using MeSH headings ’high-frequency-ventilation’ and
’infant, preterm’ from 1983 to April 2007), previous reviews
including cross references, abstracts, conferences and symposia
proceedings, expert informants, journal hand searching by the
Cochrane Collaboration, mainly in the English language. Expert
3
informant’s search in the Japanese language was made by Prof. Y.
Ogawa in 1996. Abstracts of the annual meetings of Society for
Pediatric Research (1996 - 2006 inclusive) were also searched.
METHODS OF THE REVIEW
The standard methods of the Cochrane Collaboration and the
Cochrane Neonatal Review Group (CNRG) were used to evaluate
the methodological quality of each trial. Trials were reviewed
independently by each author for eligibility. Data were extracted
separately by each author, then compared and any differences
resolved.
Additional information was obtained from Ogawa 1993;
Gerstmann 1996; Rettwitz-Volk 1998; Thome 1998; Plavka
1999; Moriette 2001 and Johnson 2002 regarding trial
methodology. Schreiber 2003 re-analysed their trial data on
use of nitric oxide to evaluate outcomes related to HFOV/CV
to which the infants were also randomised. Clark 1992 and
Plavka 1999 provided information on infants excluded post-
randomisation, which allowed for an intention to treat analysis.
Plavka 1999; Moriette 2001 and Van Reempts 2003 provided
additional outcome information from their trials (see Table of
Included Studies for details).
Results for outcomes requiring survival to a given age are reported
with survivors as the denominator (IPPV, CLD ). Survival was
used as the denominator for ROP, where the number examined
was not given (HIFI 1989; Schreiber 2003, Van Reempts 2003).
The standard method of the CNRG was used to analyse the data.
Treatment effects were expressed using relative risk (RR) and risk
difference (RD). From 1/RD the number needed to treat (NNT)
to produce one outcome was calculated. For each measure the
95% confidence intervals (CI) are routinely given. In subgroup
analyses the 99% CIs are also given for summary RRs in the text.
Meta-analysis was performed using a fixed effects model. Where
heterogeneity was over 50%, the random effects RR is also given.
DESCRIPTION OF STUDIES
Overall, 20 randomised controlled trials of HFOV vs. CV were
found, of which 15 met eligibility criteria and full trial data
were available. Details of each of these included studies (HIFI
1989; Clark 1992; Ogawa 1993; Gerstmann 1996; Rettwitz-Volk
1998; Thome 1998; Plavka 1999; Moriette 2001; Durand 2001;
Courtney 2002; Johnson 2002; Van Reempts 2003; Craft 2003;
Schreiber 2003; Vento 2005) are given in the Table of Included
Studies.
The study by Froese 1987 has not been included because after ran-
domisation of infants (unknown gestation range) with presumed
RDS, 5 of 11 in the HFOV group and an unknown number from
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
the CV group were excluded from the comparisons between treat-
ments. Only data on infants < 29 weeks with RDS were reported.
Lombert 1996 has been excluded because there was 22% loss after
randomisation. Cambonie 2003 was not included as the trial only
examined haemodynamic status during HFOV compared to CV
and clinical outcomes were not reported.
Two other studies have been excluded from the review. HiFO
1993 was excluded since HFOV was used as rescue therapy. This
study is included in a separate review of HFOV (Bhuta 2005).
The study by Ramanathan 1995, which has only been published
in abstract form, was excluded because there was a mandatory
crossover from HFOV to CV at 96 hours of age. Some information
from these latter two trials concerning rates of IVH is considered
in the discussion.
Participants
All but three (Clark 1992; Plavka 1999; Van Reempts 2003) of
the included studies were multicentre. The total number of in-
fants randomised in each study varied from 40 (Craft 2003) to
673 (HIFI 1989). All studies included preterm infants, although
the upper limit for birth weight or gestation differed. This upper
limit for birth weight was 1001 g in one (Craft 2003) 1200 g
in two (Courtney 2002; Durand 2001) 1500 g in two (Rettwitz-
Volk 1998; Plavka 1999), 1750 g in one (Clark 1992), 2000 g in
two (HIFI 1989, Ogawa 1993). Upper gestational age limits were
35 weeks in one (Gerstmann 1996), 34 weeks in one (Schreiber
2003), 32 weeks in one (Van Reempts 2003), 30 weeks in two
(Thome 1998, Moriette 2001) and 29 weeks in one (Johnson
2002). The average age at randomisation varied from less than
one hour (Thome 1998; Johnson 2002) to 12 hours (Schreiber
2003). Each trial stratified infants at randomisation by weight or
gestational age, although few data are reported by these subgroups.
Prenatal corticosteroid use was not reported in two trials (HIFI
1989; Ogawa 1993); they were used in a minority of women in
two trials (Clark 1992; Gerstmann 1996) and used in 50 - 92%
of women in the remaining seven trials.
Interventions
Different ventilators were used to deliver HFOV. Four trials used
the Sensormedics 3100 (Clark 1992; Gerstmann 1996; Plavka
1999; Courtney 2002), two used the Hummingbird (HIFI 1989;
Ogawa 1993), one used a Stephan piston oscillator (Rettwitz-
Volk 1998), one used an Infant Star ventilator (Thome 1998),
one used a French piston oscillator (Moriette 2001), one (Van
Reempts 2003) used either Sensormedics 3100 (71%) or Infant
Star (29%) and one (Johnson 2002) used a variety of ventilators
(Sensormedics, SLE, Draeger). HFOV was delivered at 10-15 Hz
in 12 trials and at 15-20 Hz in one (Rettwitz-Volk 1998).
The three criteria used to define a high volume strategy (HVS) with
HFOV are given in the objectives. All 13 trials with a HVS used
a higher mean airway pressure (MAP) on HFOV than on CV. In
addition, two trials (Thome 1998; Moriette 2001) used both alve-
4
olar recruitment manoeuvres and weaning of FiO2 prior to wean-
ing MAP, while Gerstmann 1996; Clark 1992 and Van Reempts
2003 used weaning of FiO2 first and Ogawa 1993 used alveolar
recruitment manoeuvres. Two trials (HIFI 1989; Rettwitz-Volk
1998) did not use a HVS for HFOV.
In all trials, CV was administered using time cycled, pressure lim-
ited ventilators. There was a large variation in the specific meth-
ods of administration of CV that might provide lung protection.
Details are given in the Table of Included Studies.
Surfactant therapy with animal derived extracts was used as therapy
for RDS in the majority of participants in all but two trials (HIFI
1989; Clark 1992).
Postnatal corticosteroids for CLD were used in 41 - 61% of infants
in three trials (Rettwitz-Volk 1998; Thome 1998, Courtney 2002),
in 20% of infants in one trial (Johnson 2002) and in less than
eight per cent of infants in two trials (Moriette 2001; Van Reempts
2003). Plavka 1999 reported cumulative dosage and Courtney
2002 reported mean days of therapy in infants in each group. In
all studies, the usage of postnatal steroids was similar in the two
treatment groups. In the Vento 2005 trial, corticosteroids were
administered to 35% of survivors in the HFOV group and to 60%
of survivors in the CV group.
In Durand 2001 and Courtney 2002 prophylactic indomethacin
was given routinely to all infants.
Outcomes
Not all outcomes were reported in each study. The definitions of
CLD ’at 28 days’ differed between studies. CLD was assessed at 28
days of age in six studies (HIFI 1989; Ogawa 1993; Rettwitz-Volk
1998; Thome 1998; Moriette 2001; Van Reempts 2003; Schreiber
2003) and 30 days of age in the other two (Clark 1992; Gerstmann
1996). In five studies, the definition of CLD at 28 days of age
was based on oxygen therapy alone (Rettwitz-Volk 1998; Thome
1998; Plavka 1999; Moriette 2001; Schreiber 2003) while in the
remainder both oxygen therapy and an abnormal chest x-ray were
required.
’Late’ CLD at term equivalent age varied from 36 weeks PMA
(Clark 1992; Thome 1998; Plavka 1999; Moriette 2001; Court-
ney 2002; Johnson 2002) or 37 weeks PMA (Rettwitz-Volk 1998)
to ’at discharge’ [Gerstmann 1996, mean PMA 37.1 (36.5, 37.9)
weeks in HFOV group and 37.5 (36.6, 38.0) weeks in CV group].
The criteria for CLD at term equivalent age was based on use of
oxygen therapy in nine trials, on clinical score (oxygen plus signs)
in one trial (Plavka 1999), on oxygen or use of assisted ventilation
in two trials (Courtney 2002; Van Reempts 2003) and on oxygen
use plus an abnormal chest Xray in one trial (Schreiber 2003).
In each trial, cross-over to the other treatment was allowed when
pre-determined failure criteria were reached. These criteria (hy-
poxaemia and/or hypercarbia) were similar in each trial and for
each treatment group, but the decision to cross over was left to
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
the clinician. In two trials (Clark 1992; Rettwitz-Volk 1998), the
additional criterion for cross-over of severe pulmonary interstitial
emphysema was applied only to the CV group. Because of the
variable definition of ’failure of assigned treatment’ between treat-
ment groups, this outcome has not been included in the meta-
analysis. When cross-over occurred, the subjects were analysed the
groups as randomised.
METHODOLOGICAL QUALITY
Details of the methodological quality of each study are available
in the Table of Included Studies.
Randomisation: there were adequate efforts to conceal treatment
assignment in each study.
Blinding of treatment: not possible in any study.
Exclusions after randomisation: minimal for primary outcomes
(all less than 8%).
Blinding of outcome assessment: variable between outcomes and
studies. Assessment of chest x-rays for the diagnosis of CLD was
blinded as to treatment group in studies by Clark 1992; Ogawa
1993; Plavka 1999 and Moriette 2001; Schreiber 2003. Blinded
head ultrasound assessments were carried out in the HIFI 1989,
Clark 1992, Ogawa 1993, Moriette 2001; Durand 2001;Courtney
2002; Johnson 2002; Van Reempts 2003 and Schreiber 2003 trials.
RESULTS
Fifteen trials involving 3585 infants were included.
Mortality
There were no significant differences in the rates of mortality by
28 - 30 days [outcome 01-01, 2060 infants in nine trials, summary
RR 1.09 (95% CI 0.88, 1.35)] or in the rates of mortality by 36
- 37 weeks PMA or discharge [Comparison 01-06, 2820 infants
in 13 trials, summary RR 0.98 (95% CI 0.83, 1.14)], either in
any individual trial or in the overall analyses . Subgroup analyses
including use of volume recruitment on HFOV, routine use of
surfactant , use of piston oscillators, use of lung protective strategies
on CV and inspiratory:expiratory ratio on HFOV also failed to
show any significant differences in mortality rates.
Chronic lung disease at 28-30 days
The use of oxygen therapy at 28 - 30 days was reported for 1043
infants in six trials. There was no significant difference between
the HFOV and CV groups in the individual trials, or in the meta-
analysis [Comparison 01-03, summary RR 0.98 (95% CI 0.88,
1.10)].
CLD in survivors at 28-30 days of age, based on the use of oxygen
or mechanical ventilation and the presence of an abnormal chest
5
x-ray, was reported for 820 infants in four trials (outcome 01-04).
Two trials (Clark 1992; Gerstmann 1996) showed a significantly
lower incidence of this outcome in the HFOV group and there
was a trend towards a reduced incidence in the overall analysis
[summary RR 0.86 (95% CI 0.74, 1.01)]. This latter meta-analysis
showed significant heterogeneity (I2 = 71.3% ) and when a random
effects model was used the summary RR is 0.66 (95% CI 0.41,
1.07).
Five trials involving 1160 infants reported both mortality and
CLD at 28 - 30 days (outcome 01-05). Two showed a significant
decrease of this combined outcome in the HFOV group (Clark
1992; Gerstmann 1996). In the overall analysis, there was a non-
significant trend towards a reduced risk of ’death or CLD at 28-
30 days’ in the HFOV group [summary RR 0.94 (95% CI 0.85,
1.04)] .
CLD at 36 - 37 weeks postmenstrual age (PMA) in survivors
CLD in survivors at 36 - 37 weeks PMA or at discharge was
reported for 2310 infants in 13 trials (outcome 01- 07). Four
trials (Clark 1992; Gerstmann 1996; Durand 2001; Vento 2005)
found a significant decrease in the HFOV group. In the overall
analysis using a fixed effects model, there was a reduction of CLD
in the HFOV group [summary RR 0.89 (95% CI 0.81, 0.99), RD
0.04 (95% CI -0.08, -0.01)] of borderline significance. There was
significant heterogeneity in this meta-analysis (I2 = 63.2%) and
using a random effects model gave a summary RR of 0.83 (95%
CI 0.68, 1.03), which is not significant.
Subgroup analyses
The analysis of the subgroup of 12 trials (2223 infants) using a
high volume strategy (HVS) on HFOV (outcome 02-02) did not
differ from the overall analysis because only one trial reporting
CLD at 36 weeks PMA did not use a HVS, and it had no cases of
CLD to contribute to the overall analysis.
In the subgroup analysis by use of routine surfactant, (outcome 03-
02) only one small trial of 51 infants (Clark 1992) reporting CLD
at 36 weeks did not use surfactant. This trial showed a significant
reduction in the HFOV group [RR 0.23 (95% CI 0.07, 0.73)].
This result was significantly different from the subgroup analysis
of the 12 trials involving 2259 infants in which surfactant was
used. The latter result is similar to the overall analysis of CLD at
36 weeks PMA [summary fixed effects RR 0.91 (95% CI 0.82,
1.01)] with persisting heterogeneity (I2 =58.5%).
Subgroups by use of different types of oscillator (flow interrupters,
true piston oscillators or both) showed no statistical difference
(overlapping 95% confidence intervals) between the summary RRs
of the subgroups (outcome 04-02). For the subgroup of eight
trials of 1353 infants that used of HF piston oscillators, there was
a significant reduction in CLD in the HFOV group [summary
RR 0.76 (95% CI 0.65, 0.90), RD -0.13 (95% CI -0.23, -0.02),
NNT 8 (95% CI 4, 54)]. The summary RR remained significantly
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
reduced when the 99% CI was used (99% CI 0.65, 0.95). There
was significant heterogeneity (I2 = 68.2%). Using a random effects
model, the RR was still significantly reduced [summary RR 0.67
(95% CI 0.47, 0.94)] but not when both random effect model
and 99% CI was used [summary RR 0.67 (99% CI 0.42, 1.05)].
Some subgroups based on lung protective strategies (LPS) on CV
(outcome 05-02) were different (95% confidence intervals do not
overlap) between the summary RRs when a fixed effects model was
used. Three of the four subgroups showed a moderate amount of
heterogeneity (I2 greater than 50%). Using a random effects model
no significant difference between the groups was demonstrated.
In the two trials of 174 infants in which there was ’definitively
no LPS on CV’ criteria, there was a significant reduction in CLD
in the HFOV group with moderate heterogeneity [summary RR
0.48 (95% CI 0.31, 0.75), RD -0.42 (95% CI -0.08, -0.01), I2 =
53.5%]. The difference remained significant when the 99% CI
was used (99% CI 0.26, 0.87), but not when a random effects
model was used due to wider confidence intervals [summary RR
0.42 (95% CI 0.18, 1.02)].
Subgroups by age at randomisation (less than 2 hrs, 2 - 6 hrs,
greater than 6 hrs) showed no statistical difference (overlapping
95% confidence intervals) between the summary RRs of the sub-
groups (Comparison 06 - 02). The group of four trials of 782
surviving infants who were randomised at two to six hours of age
showed a significant overall reduction in the risk of CLD with
minimal heterogeneity [summary RR 0.72 (95% CI 0.59, 0.87),
(99% CI 0.56, 0.92), I2 =23.3%].
Subgroups by inspiratory:expiratory time ratio on HFOV (I:E =
1:1, 1:2 or variable / unknown) showed no statistical difference
(overlapping 95% confidence intervals) between the summary RRs
of the subgroups (Comparison 07 - 02). The group of six trials of
829 surviving infants who were given HFOV using an I:E of 1:2
showed a significant overall reduction in the risk of CLD but with
considerable heterogeneity [fixed effects summary RR 0.76 (95%
CI 0.64, 0.90), (99% CI 0.61, 0.95), I2 =73.6%]. The random
effects summary RR was also significantly reduced in the HFOV
group at the 95% CI level (95% CI 0.41, 0.95) but not at the
99% level (99% CI 0.36, 1.09).
Death or CLD at 36 weeks postmenstrual age
There was a small reduction of the risk of the combined outcome
of ’death or CLD at 36-37 weeks PMA or discharge’ in the HFOV
group [outcome 01-08, summary RR 0.93 (95% CI 0.86, 1.00)]
which is of borderline significance using the fixed effects model.
In view of moderate heterogeneity (I2 =57.7%), a random effects
model was also used, yielding a nonsignificant difference in the
summary RR [0.89 (95% CI 0.77, 1.03)].
Subgroup analyses
There was no statistically significant difference in death or CLD
at 36 weeks postmenstrual age between the different categories
6
within each of the subgroups (95% CIs overlap), except the one
comparing inspiratory (I:E) ratios on HFOV. In this latter sub-
group, the use of an I:E ratio of 1:2 was associated with a sig-
nificantly lower rate of death or CLD [summary RR 0.08 (0.07,
0.91)] than was seen in the group with variable or unknown I:E
ratio [summary RR 1.01 (092, 1.11)], but was not significantly
different when compared with the group in which 1:1 ratio was
used [summary RR 0.96 (0.72, 1.26)]. Within subgroups, some
individual categories show significant effects and these are outlines
below.
As for the outcome CLD alone, there was a significant overall
reduction in death or CLD in the subgroup of trials using true
piston oscillators [fixed effects summary RR 0.83 (95% CI 0.74,
0.94), RD -0.08 (95% CI -0.13, -0.03), NNT 12 (95% CI 8,
34)]. However, there was a persisting moderate heterogeneity (I2
= 56.8%), with a random effects summary RR of 0.78 (95% CI
0.63, 0.97).
In the subgroup of 2 trials of 190 infants with no lung protective
strategy on CV, there was a significant reduction of death or CLD
with HFOV [summary RR 0.56 (95% CI 0.38, 0.81), summary
RD -0.221 (95% CI -0.36, -0.05), NNT 5 (95% CI 3, 19), I2
=0%].
In the subgroup analysis of age at randomisation, in the group of
four trials of 944 infants with randomisation occurring at two to
six hours of age there was a significant reduction in death or CLD
with HFOV [summary RR 0.79 (95% CI 0.68, 0.91), summary
RD -0.14 (95% CI -0.24, -0.04), NNT 7 (4, 26)] with nonsignifi-
cant heterogeneity (I2 =34.5%). The summary RR remains signif-
icantly reduced when the 99% CI was used (99% CI 0.65, 0.95).
In the subgroup of 6 trials involving 984 infants that used an I:E of
1:2 for HFOV, there was a significant reduction of death or CLD
in the HFOV group [summary RR 0.80 (95% CI 0.70, 0.91, RD
-0.11, (95% CI -0.17, -0.04, NNT 9 (95%CI 5, 23), I2 + 67.1%].
This difference was still significant using a random effects model
[summary RR 0.72 (95% CI 0.54, 0.95)]
Duration of oxygen therapy
The duration of oxygen therapy was reported in seven trials. The
statistical reporting of this outcome differed substantially between
trials so meta-analysis was not undertaken.
Gerstmann 1996 found no significant difference in the duration
of oxygen therapy in infants with birth weights of one kilogram
or less, but a shorter duration of oxygen therapy in HFOV infants
with birth weights over one kilogram [median days (95% CI), 13.2
(6.6, 24.3) vs. 27.6 (14.3, 37.7), P = < 0.05]. Van Reempts 2003
reported mean and standard deviations for days of oxygen that
were similar in the two groups [HFOV 23.6 (28.2) vs. CV 22.7
(28.5)]. No significant difference in the median days of oxygen
therapy between treatment groups was found in the three other
studies [Thome 1998, 36 vs. 39.5; Plavka 1999, 20 (95% CI
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
1, 86) vs. 29 (95% CI 4, 107); Moriette 2001 22 (IQR 47) vs.
22 (IQR 41). Craft 2003 reported mean (and range) for days of
oxygen therapy for the two subgroups by birthweight; 500 - 750 g,
HFOV 75.5 (3 - 136) vs. CV 95.1 (3 - 196); 751 - 1000 g, HFOV
59.9 (1 - 119) vs. CV 53.0 (27 - 93). These differences were not
statistically different. Vento 2005 reported the mean (SD) hours
of oxygen therapy that was significantly lower in the HFOV group
[760 (473) ] compared with the CV group [1445 (1297)], P =
0.03.
Use of mechanical ventilation
The use of mechanical ventilation at 28 - 30 days was reported in
three studies and was not significantly different in individual trials
or in the meta-analysis.
Seven trials reported the total duration of mechanical ventilation
(MV). Overall, the trend was for shorter durations of ventilation
in the HFOV groups, but no individual trials showed a significant
difference. These data have not been combined in meta-analysis
because of differences in the statistical reporting between trials.
In the Gerstmann 1996, trial the median (95% confidence inter-
vals) days on MV in those with a birth weight less than 1 kg was
24.7 (95% CI 3.7, 61.4) in the HFOV group and 53.7 (95% CI
28.4, 103) in the CV group, a trend that was not significantly
different. In this trial, there was also a similar median duration of
MV in infants with birth weights over 1 kg [4.1 days (1.7, 6) in
the HFOV group vs. 4.5 days (95% CI 3, 6.1) in the CV group].
Clark 1992 reported medians and ranges for the days on MV for
all infants entered in the study that were not significantly different
between the HFOV group [16 (95% CI 1.8, 67)] and the CV
group [30.3 (0.5, 222)]. Ogawa 1993 reported similar mean (+/-
SD) days of mechanical ventilation in the HFOV group (17.3 +/-
24.4) and CV group (13.5 +/- 21). Plavka 1999 reported means
with 95% confidence intervals for duration of mechanical venti-
lation and no difference between HFOV and CV groups [5 (95%
CI 1,70) vs. 7 (95% CI 3, 52)] was shown. Moriette 2001 found
similar mean (interquartile range, IQR) duration of mechanical
ventilation between HFOV and CV groups [9 (17) vs. 9 (16)].
Van Reempts 2003 reported similar mean and standard deviations
of days of MV in the two groups [HFOV 7.7 (9.7) vs. CV 4.9
(9.1)]. Craft 2003 reported mean (and range) for days of mechan-
ical ventilation for the two subgroups by birthweight; 500 - 750 g,
HFOV 43.3 (1 - 136) vs. CV 59 (3 - 133); 751 - 1000 g, HFOV
37.7 (1 - 83) vs. CV 20.1 (1 - 56). These differences were not
statistically different. Vento 2005 reported the mean (SD) hours
of mechanical ventilation that were not significantly different be-
tween the HFOV group, 310 (313) and the CV group, 656 (981),
P 0.15.
Failed treatment
Two trials reported failure to maintain gas exchange with the al-
located treatment. Thome 1998 reported a non-significant trend
towards more infants failing based on oxygenation index criteria
7
in the HFOV group (7/140 vs. 4/144), while Gerstmann 1996
reported more failures with CV (1/64 vs. 9/64, P = 0.008).
Six trials reported crossover to the alternate treatment, a decision
that was left to the judgement of individual clinicians. In the HIFI
1989 trial there was a significant increase of treatment failures
(failure to maintain adequate gas exchange) in the HFOV group
leading to crossover of treatment (85/346 in the HFOV group
and 60/327 in the CV group, P = 0.01). Moriette 2001 reported
a switch in ventilator mode for fewer infants assigned to HFOV
than to CV [(15% vs. 29%), OR 0.43 (95% CI 0.24, 0.78)].
Johnson 2002 found the same rate of failure of assigned treatment
(10% in each group), while Courtney 2002 reported that more
infants exited the assigned mode of treatment in the CV group
compared to the HFOV group (52/254 vs. 31/244 respectively,
P = 0.02). Van Reempts 2003 reported 17 (11.6%) failures in
the HFOV group and 10 (6.5%) failures in the CV group, a
nonsignificant difference. In Durand 2001, two infants crossed
over from HFOV and seven infants crossed over from CV at the
discretion of clinicians. In Craft 2003, one infant crossed over
from HIFI and none crossed over from SIMV. These data have
not been combined in a meta-analysis as there were differences in
definitions between trials and possibly in clinician uptake of the
option to cross over.
Two trials had the additional failure criterion of PIE in the CV
group. These trials reported crossover to be similar between groups
(Rettwitz-Volk 1998, 8/46 vs. 9/50) or to be more common in the
CV group (Clark 1992, 5/30 vs. 9/26, P = 0.01).
Pulmonary air leak syndromes
Ten trials involving 2726 infants reported ’any pulmonary air leak’
(outcome 01-09). Two trials showed a significant increase in any air
leak in the HFOV group [Thome 1998, RR 1.38 (95% CI 1.01,
1.89), Schreiber 2003, RR 1.67 (95% CI 1.15, 2.43)]. Overall
analysis of the ten trials shows a small but significant increase in
the HFOV group [summary RR 1.19 (95% CI 1.05, 1.34), RD
0.05 (95% CI 0.01, 0.08)].
Gross pulmonary air leak (excluding PIE alone) is reported for
1804 infants in nine trials (outcome 01-10). No individual trial
showed a difference, but overall there is an increase in the HFOV
group of borderline significance with no heterogeneity [summary
RR 1.32 (95% CI 1.00, 1.72), RD 0.03 (95% CI 0.00, 0.06),
NNT 35 (95% CI 18, 1000), I2 = 0%].
Subgroup analyses of gross pulmonary air leak
In the subgroup of eight trials of 908 infants using a HVS for
HFOV, there was a significant increase in gross pulmonary air leak,
[summary RR 1.36 (95% CI 1.03, 1.79)] with no heterogeneity
(I2 = 0%). This difference did not reach significance when the
99% CI is used (0.94, 1.95). In the other subgroup analyses, there
was no significant difference between subgroups (outcome 02-04).
Intraventricular haemorrhage (IVH)
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Ten trials involving 2971 infants reported all grades of IVH (out-
come 01 - 11). There was no significant difference in the rate of
IVH of all grades between the treatment groups in individual trials
or in the overall analysis [summary RR 1.05 (95% CI 0.96, 1.15)].
Fifteen trials involving 3585 infants reported the rates of the more
severe grades of IVH, Grade 3 or 4 (outcome 01 - 12, subgroup).
Two trials reported significantly higher rates in the HFOV group;
the large HIFI 1989 study, which contributed most weight in the
overall analysis [RR 1.41 (95% CI 1.06, 1.88)], and the trial by
Moriette 2001 [RR 1.73 (95% CI 1.04, 2.87)]. Moriette 2001
reported an increased rate of severe IVH in the HFOV group, both
in infants born at less than 28 weeks gestation (HFOV 26/81 vs.
CV 15/72) and in infants born at 28 or 29 weeks gestation (HFOV
8/58 vs. CV 4/61). Overall, there was no significant difference in
the rates of more severe grades of IVH between the HFOV and
CV groups [summary RR 1.11 (95% CI 0.95, 1.30)].
In the subgroup the analyses of severe grades 3 or 4 IVH, no sta-
tistically significant differences were apparent between any of the
categories within the groups. Some individual groups within the
subgroup analyses showed increases in the rates of severe IVH.
In the subgroup by use of high volume strategy for HFOV (out-
come 02 - 05), the two trials (HIFI 1989; Rettwitz-Volk 1998)
in which HVS was not used showed a significant increase in the
risk of severe IVH [summary RR 1.45 (95% CI 1.09, 1.93), RD
0.074 (95% CI 0.02, 0.13), NNT 14 (95% CI 56, 8)]. The RR is
of borderline significance when the 99% CI is used (1.00, 2.11).
There was a significant increase in the rate of grade 3 or 4 IVH in
the subgroup analysis of two trials (HIFI 1989; Clark 1992) not
using surfactant replacement therapy [summary RR 1.36 (95%
CI 1.03, 1.79), RD 0.07 (95% CI 0.01, 0.13), NNH 15 (95%
CI 143, 8)]. Most of the weight in these latter two analyses was
contributed by HIFI 1989.
Periventricular leukomalacia ( PVL)
PVL was reported for 3474 infants in 13 studies. There was a
nonsignificant trend towards an increased rate with HFOV in the
HIFI 1989 [RR 1.61 (95% CI 0.99, 2.60)], but no significant
difference overall [summary RR 1.10 (95% CI 0.85, 1.43)] (out-
come 01 - 13).
In the subgroup analyses, there were no significant differences
between categories within the subgroups (95% CIs overlap).
In the subgroup by use of high volume strategy for HFOV (out-
come 02 - 06), the two trials (HIFI 1989; Rettwitz-Volk 1998) in
which HVS was not used show a significant increase in the risk
of PVL [summary RR 1.64 (95% CI 1.02, 2.04)]. This was not
significant at the 99% CI level (0.88, 3.06).
In the subgroup of 2 trials in which lung protective strategies on
CV were not used (HIFI 1989, Gerstmann 1996), there was a
significant increase in PVL in the HFOV group [RR 1.57 (95%
CI 0.99, 2.48)]. This was not significant at the 99% CI level (0.86,
2.86).
8
Most of the weight in these latter two analyses was contributed by
HIFI 1989.
Retinopathy of prematurity (ROP)
Ten trials with 2367 surviving infants report significant ROP
(grade 2 or more). The overall analysis showed a significant de-
crease in the HFOV group with no heterogeneity [summary RR of
0.85 (95% CI 0.74, 0.99), RD 0.04 (95% CI 0.07, 0.01), NNT
30 (15, 357), I2 = 0%] (outcome 01 - 14).
Pulmonary function tests, symptoms and growth at follow-up.
No significant differences in pulmonary function test results were
found during the neonatal period (Abbasi 1991) or at discharge
(Gerhardt 1989) in subgroups of infants from individual centres
in the HIFI 1989.
Long-term follow-up assessments (in 82% of survivors), includ-
ing pulmonary function tests (in 43% of survivors from seven of
the ten centres), were carried out at nine months corrected age in
infants from HIFI 1989 (The HIFI Study Group 1990a). There
were no significant differences in respiratory function tests (com-
pliance, resistance, lung volumes) or in the incidence of respiratory
tract infections, hospital re-admissions, respiratory symptoms and
signs (retractions and episodes of wheezing) or in growth.
Twelve month follow-up of patients in the Ogawa 1993 trial
showed persistence of abnormal fibrous or emphysematous shad-
ows on chest x-ray in two of the infants in the HFOV group and
four in the CV group.
Eighty seven percent of the infants in Gerstmann 1996 were fol-
lowed up at a mean age of 6.4 years. Improved respiratory func-
tion tests (decreased peak expiratory flow, increased residual lung
volume, maldistribution of ventilation) were found in the HFOV
group, but there were no significant differences in symptoms (pul-
monary illness, asthma, hospitalisation) between the groups.
Of 185 survivors from 12 centres in Johnson 2002, 149 were in-
vited for respiratory function tests and these were successfully car-
ried out in 76 at 11 - 14 months of age (Thomas 2004). No differ-
ences were found between the HFOV and CV groups in any of the
measures (functional residual capacity, inspiratory and expiratory
resistance, respirator rate). Respiratory symptoms, treatments and
growth were assessed at two years of age (Marlow 2006) and there
were no differences between the HFOV and CV groups.
A two years of age assessment of 138 (82%) of survivors in the
NOVA study (Schreiber 2003 - re-analysed by type of ventilation)
revealed no difference in the mean height, weight or head circum-
ference between the HFOV and CV groups.
Neurodevelopmental outcomes at follow up.
Neurodevelopmental status at follow-up was reported for six stud-
ies (HIFI 1989; Ogawa 1993; Gerstmann 1996; Johnson 2002;
Van Reempts 2003; Schreiber 2003). The age and methods of as-
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
sessment varied between studies so the results are presented in the
text and not analysed by meta-analysis.
Neurodevelopmental status was assessed at 16 to 24 months cor-
rected age in 77% of survivors of the HIFI 1989 study (185 HFOV
& 201 CV) using Bayley psychometric tests and central nervous
system examinations (The HIFI Study Group 1990b). The rate of
moderate to severe abnormality (Bayley’s scores more than one SD
below the mean or neurological abnormality) was higher in the
HFOV group [RR 1.28 (95% CI 1.02, 1.60)]. The rate cerebral
palsy was 11% in both groups. There was an increase in the rate
of hydrocephalus in the HFOV group [RR 2.08 (95% CI 1.07,
4.06)]. Using logistic regression, abnormal neurological status was
shown to be associated with the increased rate of severe grades 3
or 4 IVH in this study.
One year follow-up in the trial by Ogawa 1993 showed no signif-
icant difference in motor and/or mental development, although
the method of neurological assessment was not given.
Gerstmann 1996 reported neurodevelopmental status at a mean
of 6.4 years for 87% of the infants. Assessment of mental function,
using the Wechsler Scale for Children, and motor function, using
the Bruinink-Oseretsky test showed no significant difference in
mean scores between the two groups.
Johnson 2002 reported neurodevelopmental outcomes at 22 - 28
months (corrected for prematurity) based paediatric report for
73% of survivors and on parent questionnaires for 49% of sur-
vivors. No difference between HFOV and CV groups were found.
Van Reempts 2003 followed up a subgroup of infants who were
less than 30 weeks gestation or 1250 grams at birth, or had in-
tracranial lesions on ultrasound. This included 70 infants in the
HFOV group and 68 in the CV group, representing 57% and
51% respectively of survivors in the whole trial. Bayley motor and
mental developmental indices, as well as motor diagnoses, were
assessed at seven to twelve months corrected age. There was no
significant difference between the groups, with 60% of HFOV
infants and 70% of CV infants being completely normal. Follow-
up of only the ’abnormal’ infants at 18 - 24 months corrected age
revealed none of the infants in the HFOV group and four of the
infants in the CV group were persistently abnormal, which was
not statistically different.
Schreiber 2003 re-analysed the follow-up data from the NOVA
study according to mode of ventilation. Of the 168 survivors to
two years of age (84 in each group), data were available for 66
(78.6%) of those in the HFOV group and 72 (85.7%) in the CV
group. Based on blinded assessments using Bayley’s Scales (mean
scores and number with scores < 70) and Pediatric neurological
assessment, there were no differences between the groups.
Length of stay and hospital costs
The total hospital costs from a subgroup of patients from one
centre in Gerstmann 1996 suggested that the median hospital costs
9
were less in 42 patients randomised to HFOV compared with 41
in the CV group. In this trial, similar differences were found for
those infants with birth weights of one kilogram or less and those
of more than one kilogram. There were no significant reductions
in the median length of hospital stay or in median duration of
IPPV in this trial nor in Rettwitz-Volk 1998 and Clark 1992,
although the trend in each case was towards a reduction in the
HFOV group. Johnson 2002 reported similar median and range of
days hospital stay in survivors between treatment groups (HFOV
94, 73-114; CV 89, 70-112 ).
Other outcomes
Outcomes by birth weight and gestational age have been variably
reported in the trials. This important subgroup analysis will be at-
tempted in a future update, following author contributions to an
individual patient data analysis that is currently underway (prin-
cipal investigator Filip Cools).
Use of surfactant was not a prespecified outcome in this review.
Three trials (Gerstmann 1996; Plavka 1999; Moriette 2001) re-
ported less use of surfactant in the group receiving HFOV. In four
trials there was no significant difference in surfactant use (Durand
2001; Courtney 2002; Johnson 2002, Van Reempts 2003).
DISCUSSION
In this review, the search revealed 15 trials that met prespecified
eligibility criteria, four trials that were excluded, one new trial
awaiting full assessment and another yet to be published. It is
possible that there are other trials that have not been published
or were published in a language not covered by this systematic
review. The reviewers would be most interested in hearing of other
published, unpublished or ongoing trials.
Limitations of this review
The studies have been carried out over a long time period (20
years) during which changing obstetric and neonatal practices may
have influenced the conditions under study such as RDS, IVH
and CLD. Participants in early trials could be up to 34 weeks
gestational age or 2000 g birth weight, whereas recent trials have
been confined to infants of less than 30 weeks gestational age or
less than 1200 g birth weight.
Interventions varied by type of ventilator and strategy used for
HFOV and CV. Over time it more likely that HFOV was deliv-
ered using a HVS, which would be likely to improve the effect of
HFOV, while CV is more likely to be delivered using lung pro-
tective strategies, which could reduce the comparative effective-
ness of HFOV. Lung protective strategy on CV to prevent CLD
is difficult to define. There are variable maneuvers that principally
affect acute lung injury rather than CLD. In this review, four cat-
egories were used to evaluate trials that used most strategies (’defi-
nite LPS’) compared with the other extreme of none (’definitively
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
no LPS’) and two intermediate groups. This summary data is based
on mixed, soft evidence and might be able to be explored further
in the proposed individual data analysis currently under way.
The quality of the studies was generally high, as all attempted
to conceal the randomisation process. However, the interventions
were not blinded in any study and this could be associated with
bias regarding the use of co-interventions and the ascertainment of
outcomes, such as duration of mechanical intervention and oxygen
therapy. Ascertainment of outcomes was generally complete or
made so by author clarification. Since the treatment could not
be blinded in any study, outcomes that were caregiver dependent,
such as the duration of oxygen therapy or diagnosis of CLD, may
be less valid.
Pulmonary outcomes
The overall analysis of CLD at 28 - 30 days is dominated by the
HIFI 1989 trial, which is the largest. Soon after the completion
of this study, it was criticized because the methodology used to
apply HFOV did not include methods to recruit lung volume
(Froese 1991). This criticism is partly supported by the results
of subsequent trials that used a high volume strategy where there
was a significant reduction in CLD at 28 - 30 days of age (Clark
1992; Gerstmann 1996). HIFI 1989 did not report the rates of
CLD at term equivalent age or discharge and overall analysis of the
remaining trials showed no significant reduction in this outcome
with HFOV.
The interventions (treatment and control) varied from trial to trial.
Jouvet (Jouvet 1997) found that HFOV generated by a ventila-
tor using flow interruption (e.g. Drager Babylog) was less pow-
erful than HFOV generated by a ventilator using a piston (e.g.
Sensormedics), so that there was an inability to increase tidal vol-
ume when pressure amplitude was increased above 50%. None of
the studies using flow interruption rather than piston oscillation
found a difference in the incidence of chronic lung disease.
Although there were no statistically significant differences in the
other subgroup analyses of CLD, there were some specific groups
of trials which showed a significant reduction in CLD with HFOV.
The explanations for this may not be clear. For example, randomi-
sation at 2 - 6 hrs of age compared with 0 - 2 hrs may have included
infants with more definite lung disease, rather than a mixed group
including those with hypoventilation at birth. Many factors may
have been interacting, such as use of antenatal corticosteroids, use
of surfactant, use of piston oscillators for HFOV, use of high vol-
ume strategy, use of lung protective strategies on CV, and use of
inspiratory:expiratory ratio of 1:2. Although there may be biolog-
ical plausibility for these factors more research is required to clar-
ify the effectiveness of HFOV. The individual patient data review
could examine these multiple variables.
Although there were no significant differences in any individual
trials, overall, pulmonary air leaks occurred more frequently in the
HFOV group.
10
Other reviews of the evidence of effectiveness of HFV (both oscil-
lation and jet ventilation) also found that CLD was not reduced
when HVS was not used for HFV and/or LPS was used on CV
(Bollen 2003; Thome 2005).
Neurodevelopmental outcomes.
Increases rates of IVH or PVL occurred in some individual trials
but not overall. The pathophysiological factors that might have led
to an increased rate of IVH or PVL are not certain. The authors of
HIFI 1989 suggested that the nearly constant high mean airway
pressure during HFOV might restrict venous return, increase in-
tracranial venous pressure, and decrease cerebral blood flow. How-
ever, animal studies (Kinsella 1991) and human studies (Laub-
scher 1996) failed to show these cardiovascular changes. The latter
study reported that cardiac output fell when on HFOV. In a single
centre involved in the study of Johnson 2002, echocardiography
was carried out in 45 infants (Osborn 2003). Superior vena cava
flow was reduced (< 50 ml/kg/min) in more HFOV (48%) than
CV (20%) infants, but this difference was not significant. Cam-
bonie 2003 examined the haemodynamic changes during HFOV
vs. CV and found no difference in cardiac function but did find
a lower end diastolic velocity and a higher resistance index in the
anterior cerebral artery.
The tendency for higher rates of IVH or PVL found in this review
in association with failure to use HVS was also shown in two other
reviews of the evidence of effectiveness of HFV (both oscillation
and jet ventilation, Bollen 2003; Thome 2005) and in a review of
elective jet ventilation vs. CV (Bhuta 2003). Failure to recruit lung
volume and the consequent cardiorespiratory instability has been
implicated (Froese 1991). Whether it was one of these mechanisms
or just lack of experience with a new technology at the time is
difficult to say. The large HIFI 1989 dominated this analysis.
In five of the six trials reporting long term neurodevelopmental
outcome, no difference was apparent although in some studies
there was considerable loss to follow-up.
Research questions raised by this review include:
1. Are there differences in pulmonary outcomes and adverse effects
by type of ventilator used to generate HFOV? The question would
be answered best by a head to head trial of HFOV using a true
oscillator vs. a flow interrupter.
2. What is the long term growth and development of infants treated
with HFOV vs. CV? This could be answered by follow-up of
infants enrolled in existing trials.
3. Are there differences in the costs compared to benefits of HFOV?
One small study (Gerstmann 1996) suggested that HFOV reduced
costs of care.
4. Despite increasing the number of subgroup analyses in this up-
date of summary data from trials, marked heterogeneity persists.
To further explore the comparison of HFOV and CV, a collabora-
tive study is underway to review individual patient data obtained
from the trials using a prespecified protocol for analysis. If you
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
have randomised controlled trial data on this topic and wish to join
the collaboration, contact Filip Cools (filip.cools@az.vub.ac.be).
AUTHORS’ CONCLUSIONS
Implications for practice
There is no clear evidence that elective HFOV compared with CV
offers important advantages when used as the initial ventilation
strategy to treat preterm infants with acute pulmonary dysfunc-
tion. There is no evidence of a reduction in death rate. There may
be a small reduction in the rate of CLD with HFOV use, but
the evidence is weakened by the inconsistency of this effect across
trials and is not significant overall. Adverse effects on short term
neurological outcomes have been observed in some studies, but
these effects are not significant overall. Most trials reporting long-
term outcome have not identified any difference.
Implications for research
Any future trials on elective HFOV should target those infants
who are at most risk of CLD (extremely preterm infants), compare
different strategies for generating HFOV, and report important
long-term pulmonary and neurodevelopmental outcomes. Eco-
nomic analysis should also be incorporated.
POTENTIAL CONFLICT OF
INTEREST
None
ACKNOWLEDGEMENTS
Authors of the following trials Clark 1992; Ogawa 1993; Ger-
stmann 1996; Rettwitz-Volk 1998; Thome 1998; Plavka 1999;
Moriette 2001; Johnson 2002; Van Reempts 2003, kindly
provided additional information about their studies. Michael
Schreiber kindly re-analysed the data from the NOVA study
(Schreiber 2003) and its follow up results according type of ven-
tilation.
SOURCES OF SUPPORT
External sources of support
• No sources of support supplied
Internal sources of support
• Royal Prince Alfred Hospital, Sydney AUSTRALIA
• Department of Neonatology, Royal North Shore Hospital, Syd-
ney AUSTRALIA
11
• Department of Neonatology, Academic Medical Centre, Ams-
terdam NETHERLANDS
• Centre for Perinatal Health Services Research, University of
Sydney AUSTRALIA
REFERENCES
References to studies included in this review
Clark 1992 {published and unpublished data}
Clark RH, Gerstmann DL, Null DM, deLemos RA. Prospective ran-
domized comparison of high-frequency oscillatory and conventional
ventilation in respiratory distress syndrome. Pediatrics 1992;89:5–
12.
Courtney 2002 {published data only}
∗
Courtney SE, Durand DJ, Asselin JM, Hudak ML, Aschner JL,
Shoemaker CT. High-frequency oscillatory ventilation versus con-
ventional mechanical ventilation for very-low-birth-weight Infants.
New England Journal of Medicine 2002;347:643–652.
Durand DJ, Asselin JM, Hudak ML, Aschner JL, McArtor RD,
Cleary JP, VanMeurs KP, Stewart DL, Shoemaker CT, Wiswell TE,
Courtney SE. Early high frequency oscillatory ventilation versus
synchronized intermittent mandatory ventilation in very low birth
weight infants: a pilot study of two ventilation protocols. Journal of
Perinatology 2001;21:221–229.
Craft 2003 {published data only}
Craft SP, Bhandari V, Finer NN. The sy-fi study: a randomized
prospective trial of synchronized intermittent mandatory ventilation
versus a high-frequency flow interrupter in infants less than 1000 g.
Journal of Perinatology 2003;23:14–19.
Durand 2001 {published data only}
Durand DJ, Asselin JM, Hudak ML, Aschner JL, McArtor RD,
Cleary JP, et al. Early high-frequency oscillatory ventilation versus
synchronized mandatory ventilation in very low birth weight infants:
a pilot study of two ventilation protocols. Journal of Perinatology
2001;21:221–229.
Gerstmann 1996 {published and unpublished data}
Gerstmann DR, Minton SD, Stoddard RA. Results of the provo mul-
ticenter surfactant high frequency oxcillatory ventilation controlled
trial. Pediatric Research 1995;37:333A.
Gerstmann DR, Minton SD, Stoddard RA, Meredith KS. The use
of early high-frequency oscillatory ventilation in respiratory distress
syndrome. Clinical Research 1994;42:109A.
Gerstmann DR, Minton SD, Stoddard RA, Meredith KS, Bertrand
JM. Results of the Provo multicenter surfactant high frequency oscil-
latory ventilation controlled trial. Pediatric Research 1995;37:333A.
∗
Gerstmann DR, Minton SD, Stoddard RA, Meredith KS, Monarco
F, Bertrand JM, Battisti O, Langhendries JP, Francois A, Clark RH.
The Provo multicenter early high-frequency oscillatory ventilation
trial: Improved pulmonary and clinical outcome in respiratory dis-
tress syndrome. Pediatrics 1996;98:1044–1057.
Gerstmann DR, Wood K, Miller A, Steffen M, Ogden B, Stoddard
RA, Minton SD. Childhood outcome after early high-frequency os-
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
cillatory ventilation for neonatal respiratory distress syndrome. Pedi-
atrics 2001;108:617–623.
HIFI 1989 {published data only}
Abbasi S, Bhutani VK, Spitzer AR, Fox WW. Pulmonary mechan-
ics in preterm neonates with respiratory failure treated with high-
frequency compared with conventional mechanical ventilation. Pe-
diatrics 1991;87:487–493.
Gerhardt T, Reifenberg L, Goldberg RN, Bancalari E. Pulmonary
function in preterm infants whose lungs were ventilated convention-
ally or by high-frequency oscillation. Journal of Pediatrics 1989;115:
121–126.
∗
The HIFI study group. High frequency oscillatory ventilation com-
pared with conventional mechanical ventilation in the treatment
of respiratory failure in preterm infants. New England Journal of
Medicine 1989;320:88–93.
The HIFI study group. High frequency oscillatory ventilation com-
pared with conventional mechanical ventilation in the treatment of
respiratory failure in preterm infants: assessment of pulmonary func-
tion at 9 months of corrected age. Journal of Pediatrics 1990a;116:
933–41.
The HIFI study group. High frequency oscillatory ventilation com-
pared with conventional mechanical ventilation in the treatment of
respiratory failure in preterm infants: neurodevelopmental status at
16 to 24 months of postterm age. Journal of Pediatrics 1990b;117:
939–46.
Johnson 2002 {published data only}
Johnson AH, Peacock JL, Greenough A, Marlow N, Limb ES,
Marston L, Calvert SA. High-frequency oscillatory ventilation for
the prevention of chronic lung disease of prematurity. New England
Journal of Medicine 2002;347:633–42.
Osborn DA, Evans N. Randomized trial of high-frequency oscillatory
ventilation versus conventional ventilation: effects on systemic blood
flow in very preterm infants. Journal of Pediatrics 2003;143:192–8.
Thomas MR, Rafferty GF, Limb ES, Peacock JL, Clavert SA, Marlow
N, Milner AD, Greenough A. Pulmonary function at follow-up of
very preterm infants from the United Kingdom oscillation study.
American Journal of Respiratory and Critical Care Medicine 2004;169:
868–72.
Moriette 2001 {published data only}
∗
Moriette G, Paris-Llado J, Walti H, Escande B, Magny J-F, Cam-
bonie G, Thiriez G, Cantagrel S, Lacaze-Masmonteil T, Storme L,
Blanc T, Liet J-M, Andre C, Salanave B, Breart G. Prospective ran-
domized multicenter comparison of high-frequency oscillatory ven-
tilation and conventional ventilation in preterm infants of less than
12

30 weeks with respiratory distress syndrome. Pediatrics 2001;107:
363–372.
Moriette G, Walti H, Salanave B, Chagnot D, Magny J-F, Cambonie
G, Pauchard JY, Cantagrel S, Lacaze T, Storme L, Blanc T, Liet J-
M, Lebouedec S, Paris-Llado J, Breart G. Prospective randomized
multicenter comparison of high-frequency oscillatory ventilation
(HFOV) and conventional ventilation (CV) in preterm infants < 30
weeks gestational age (GA) with RDS. Pediatric Research 1999;45:
212A.
Ogawa 1993 {published data only}
∗
Ogawa Y, Miyasaka K, Kawano T, Imura S, Inukai K, Okuyama
K, Oguchi K, Togari H, Nishida H, Mishina J. A multicentre ran-
domised trial of high frequency oscillatory ventilation as compared
with conventional mechanical ventilation in preterm infants with
respiratory failure. Early Human Development 1993;32:1–10.
Plavka 1999 {published data only}
Plavka R, Kopecky P, Sebron V, Svihovec P, Zlatohlavkova B, Janus
V. A prospective randomized comparison of conventional mechani-
cal ventilation and early high frequency oscillatory ventilation in ex-
tremely premature newborns with repiratory distress syndrome. In-
tensive Care Medicine 1999;25:68–75.
Rettwitz-Volk 1998 {published and unpublished data}
Rettwitz-Volk W, Veldman A, Roth B, Vierzig A, Kachel W, Varnholt
V, Schlosser R, von Loewenich V. A prospective, randomized, multi-
centre trial of high-frequency oscillatory ventilation compared with
conventional ventilation in preterm infants with respiratory distress
syndrome receiving surfactant treatment. Journal of Pediatrics 1998;
132:249–254.
Schreiber 2003 {published and unpublished data}
Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurode-
velopmental outcomes of premature infants treated with inhaled ni-
tric oxide. New England Journal of Medicine 2005;353:23–32.
∗
Schreiber MD, Gin-Mestan K, Marks JD, Hou D, Lee L, Srisuparp
P. Inhaled nitric oxide in premature infants with respiratory distress.
New England Journal of Medicine 2003;349:2099–107.
Schreiber MD, Gin-Mestan K, Srisuparp P, Marks J. Inhaled nitric
oxide decreases BPD, death and IVH/PVL in premature infants with
respiratory distress syndrome. Pediatric Research 2003;53:31.
Thome 1998 {published and unpublished data}
Thome U, Kossel H, Lipowsky G, Porz F, Furste H, Genzel-
Boroviczeny O, Troger J, Oppermann H-C, Hogel J, Pohlandt F
and the HFOV Study Group. High frequency oscillatory ventila-
tion (HFOV) compared with high rate intermittent positive pressure
ventilation (IPPV) as first line therapy for premature infants with
respiratory insufficiency. A prospective randomized multicenter trial.
Pediatric Research 1998;43:300A.
Thome U, Kossel H, Lipowsky G, Porz F, Furste H, Genzel-
Boroviczeny O, Troger J, Oppermann H-C, Hogel J, Pohlandt F und
das Team der HFOV-Studie. [Hochfrequenzoszillationsbeatmung
(HFOV) im Vergleich mit hochfrequenter intermittierender posi-
tiver Druckbeatmung (IPPV) als Ersttherapie bei Fruhgeborenen
(FG) mit Atemnotsyndrom. Eine propektive randomisierte multi-
zentrische Studie]. Proc. German-Austrian Society for Neonatology
and Pediatric Critical Care, Munster. October 1997.
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
∗
Thome U, Kossel H, Lipowsky G, Porz F, Furste HO, Genzel-
Boroviczeny O, Troger J, Oppermann HC, Hogel J, Pohlandt F.
Randomized comparison of high-frequency ventilation with high-
rate intermittent positive pressure ventilation in preterm infants with
respiratory failure. Journal of Pediatrics 1999;135:39–46.
Van Reempts 2003 {published data only}
∗
Van Reempts P, Borstlap C, Laroche S, Van der Auwer J-C. Early
use of high frequency ventilation in the premature neonate. Eurpean
Journal of Pediatrics 2003;162:219–226.
Van Reempts P, Borstlap K, Laroche S. Randomised controlled trial
comparing high frequency ventilation versus conventional ventila-
tion in preterm infants. Pediatric Research 2000;47:379A.
Vento 2005 {published data only}
Vento G, Matassa PG, Ameglio F, Capoluongo E, Zecca E, Martelli
M, Tortorolo L, Romagnoli C. HFOV improves lung mechanics and
late pulmonary outcome in extremely low gestational age infants (<30
wks) with resoiratory distress syndrome. Pediatric Research 2002;51:
393A.
∗
Vento G, Matassa PG, Ameglio F, Capoluongo E, Zecca E, Tor-
torolo L, Martelli M, Romagnoli C. HFOV in premature neonates:
effects on pulmonary mechanics and epithelial lining fluid cytokines.
A randomized controlled trial. Intensive Care Medicine 2005;31:463–
70.
References to studies excluded from this review
Cambonie 2003
Cambonie G. Guillaumont S. Luc F. Vergnes C. Milesi C. Voisin M.
Haemodynamic features during high-frequency oscillatory ventila-
tion in preterms. Acta Paediatrica 2003;92:1068–1073.
Froese 1987
Froese AB, Butler PO, Fletcher WA, Byford LJ. High-frequency os-
cillatory ventilation in premature infants with respiratory failure: a
preliminary report. Anesthesia and Analgesia 1987;66:814–24.
HiFO 1993
HiFO study group. Randomised study of high-frequency oscillatory
ventilation in infants with severe respiratory distress syndrome. Jour-
nal of Pediatrics 1993;122:609–19.
Lombert 1996
Lombert J, Claris O, Debauche C, Putet G, Rigo J, Verellen G, Salle
B. High frequency oscillation (HFO) versus conventional mechani-
cal ventilation (CMV) for respiratory distress syndrome (RDS). Pro-
ceedings of the European Society for Pediatric Research 1996:Abstract
110.
Pardou 1993
Pardou A, Vermeylen D, Muller MF, Detemmerman D. High-fre-
quency ventilation and conventional mechanical ventilation in new-
born babies with respiratory distress syndrome: a prospective, ran-
domized trial. Critical Care Medicine 1993;19:406–10.
Ramanathan 1995
Ramanathan R, Ruiz I, Tantivit P, Cayabyab R, deLemos R. High
frequency oscillatory ventilation compared to conventional mechan-
ical ventilation in preterm infants with respiratory distress syndrome.
Pediatric Research 1995;37:347A.
13
References to studies awaiting assessment
Dani 2006
Dani C, Bertini G, Pezzati M, Filippi L, Pratesi S, Caviglioli C, Rubal-
telli F. Effects of pressure support ventilation plus volume guarantee
vs. high-frequency ventilation on lung inflammation in preterm in-
fants. Pediatric Pulmonology 2006;41:242–249.
References to ongoing studies
Texas Infant Star
Eligible infants include < 1250 gms birth weight or < 29 weeks
gestation. Randomization to 3 modes of ventilation: conventional,
high frequency oscillation, and combination (HFOV + 2 - 5 bpm
CV). Study commenced in late 1996. Contact: Dr Anthony L Tal-
bert, Texas Tech University School of Medicine, Odessa, Texas, USA
Phone +1 915 335 5270.
Additional references
Bancalari 1992
Bancalari E, Sinclair JC. Mechanical ventilation. In: SinclairJC,
BrackenMB editor(s). Effective Care of the Newborn Infant. Oxford:
Oxford University Press, 1992:200–220.
Bhuta 2003
Bhuta T, Henderson-Smart DJ. Elective high frequency jet ventila-
tion versus conventional ventilation in preterm infants mechanically
ventilated for RDS (Cochrane Review). Cochrane Database of System-
atic Reviews 2003, Issue 1.
Bhuta 2005
Bhuta T, Henderson-Smart DJ. Rescue high frequency oscillatory
ventilation vs conventional ventilation in preterm infants with acute
pulmonary dysfunction (Cochrane Review). Cochrane Database of
Systematic Reviews 2005, Issue 1.
Bollen 2003
Bollen CW, Uiterwaal CS, van Vught AJ. Cumulative meta-analy-
sis of high-frequency versus conventional ventilation in premature
neonates. American Journal of Respiratory Critical Care Medicine 2003;
168:1150–5.
Clark 2000
Clark RH, Slutsky AS, Gerstmann DR. Lung protective strategies
of ventilation in the neonate: what are they?. Pediatrics 2000;105:
112–4.
de Lemos 1987
de Lemos RA, Coalson JS, Gerstmann DR, et al. Ventilatory man-
agement of infant baboons with hyaline membrane disease; the use
of high frequency ventilation. Pediatric Research 1987;21:594–602.
Ehrenkrantz 1992
Ehrenkranz RA, Mercurio MR. Bronchopulmonary dysplasia. In:
SinclairJC, BrackenMB editor(s). Effective Care of theNewborn Infant.
Oxford: Oxford University Press, 1992:399–424.
Froese 1991
Froese AB, Bryan AC. Reflections on the HIFI trial. Pediatrics 1991;
87:565–567.
Greenough 2003
Greenough A, Milner AD, Dimitriou G. Synchronised mechanical
ventilation in neonates (Cochrane Review). Cochrane Database of
Systematic Reviews 2004, Issue 3.
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Halliday 2003
Halliday H, Ehrenkranz R. Moderately early (7-14 days) postnatal
corticosteroids for preventing chronic lung disease in preterm infants
(Cochrane Review). Cochrane Database of Systematic Reviews 2003,
Issue 1. Art. No.: CD001144. DOI:10.1002/14651858.CD001144.
Jobe 2000
Jobe AH, Ikegami M. Lung development and function in preterm in-
fants in the surfactant treatment era. Annual Review Physiology 2000;
62:825–46.
Jouvet 1997
Jouvet P, Hubert P, Isabey D, Oinquier D, Dahan E, Cloup M, Harf
A. Assessment of high-frequency neonatal ventilator performances.
Intensive Care Medicine 1997;23:208–213.
Kinsella 1991
Kinsella JP, Gerstmann DR, Clark RH, Null DM Jr, Morrow WR,
Taylor AF, deLemos RA. High frequency oscillatory ventilation versus
intermittent mandatory ventilation: early hemodynamic effects in the
premature baboon with hyaline membrane disease. Pediatric Research
1991;29:160–166.
Laubscher 1996
Laubscher B, van Melle G, Fawer C-L, Sekarski N, Calame A.
Haemodynamic changes during high frequency oscillation for respi-
ratory distress syndrome. Archives of Diseases in Childhood 1996;74:
F172–F176.
McCulloch 1988
McCulloch PR, Forkert PG, Froese AB. Lung volume maintenance
prevents lung injury during high-frequency oscillatory ventilation in
surfactant-deficient rabbits. American Review of Respiratory Disease
1988;137:1185–92.
Meredith 1989
Meredith KS, deLemos RA, Coalson JJ, King RJ, Gerstmann DR,
Kumar R, et al. Role of lung injury in the pathogenesis of hyaline
membrane disease in premature baboons. Journal of Applied Pysiology
1989;66:2150–8.
Northway 1992
Northway WH. An introduction to bronchopulmonary dysplasia.
Clinics in Perinatology 1992;19:489–495.
Petrucci 2006
Petrucci N, Iacovelli W. Ventilation with lower tidal volumes versus
traditional tidal volumes in adults for acute lung injury and acute res-
piratory distress syndrome. Cochrane Database of Systematic Reviews
2006, Issue 3.
Pillow 1999
Pillow, Neil, et al. Effect of I/E ratio on mean alveolar pressure during
high-frequency oscillatory ventilation. Journal of Applied Physiology
1999;87:407–414.
Roberts 2006
Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fe-
tal lung maturation for women at risk of preterm birth. Cochrane
Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454.
DOI:10.1002/14651858.CD004454.pub2.
Thome 2005
Thome UH, Carlo WA, Pohlandt F. Ventilation strategies and out-
come in randomized trials of high frequency ventilation. Archives of
Disease in Childhood Fetal and Neonatal Edition 2005;90:F466–73.
14
Truog 1984
Truog WE, Standaert TA, Murphy JH, Woodrum DE, Hodson WA.
Effect of prolonged high frequency oscillatory ventilation in prema-
ture primates with experimental hyaline membrane disease. Ameri-
can Review of Respiratory Disease 1984;130:76–80.
Woodgate 2006
Woodgate PG, Davies WW. Permissive hypercapnia for the preven-
tion of morbidity and mortality in mechanically ventilated newborn
infants. Cochrane Database of Systematic Reviews 2006, Issue 3. Art.
No.: CD002061. DOI:10.1002/14651858.CD002061.

References to other published versions of this review

Henderson-Smart 1999
Henderson-Smart DJ, Bhuta T, Cools F, Offringa M. Elective
high frequency oscillatory ventilation vs conventional ventilation for
acute pulmonary dysfunction in preterm infants (Cochrane Review).
Cochrane Database of Systematic Reviews 1999, Issue 2.
Henderson-Smart 2001
Henderson-Smart DJ, Bhuta T, Cools F, Offringa M. Elective high
frequency oscillatory ventilation versus conventional ventilation for
acute pulmonary dysfunction in preterm infants (Cochrane Review).
Cochrane Database of Systematic Reviews 2001, Issue 4.
Henderson-Smart 2003
Henderson-Smart DJ, Bhuta T, Cools F, Offringa M. Elective high
frequency oscillatory ventilation versus conventional ventilation for
acute pulmonary dysfunction in preterm infants (Cochrane Review).
Cochrane Database of Systematic Reviews 2003, Issue 4.

∗
Indicates the major publication for the study

TABLES

Characteristics of included studies

Study Clark 1992

Methods Concealment of randomisation - yes (blind draw of cards); Blinding of treatment - no; Complete follow up
- yes (after additional data from author); blinding of outcome assessment - unknown
Participants Single centre; RDS & gestational age <36 weeks & birth weight <1751 gms & age <24 hrs; stratified by birth
weight <1001 / 1001 vs 1750 gms and by age 0 - 12 vs 12 - 24 hrs, in blocks of 5 per category. 152 eligible, 98
(63%) enrolled: 78% inborn; RDS chest Xray score at entry HFOV > CV; 15 post randomisation exclusions
in publication - data retrieved from author.
Interventions HFOV [Sensormedics 3100, 10 HZ, IT 0.33 (1:2), MAP 1-2 cms > CV]. HVS used (higher MAP, wean
FiO2 first)
CV [IT 0.3 - 0.6 sec, 25 - 40/min, PEEP 4-6 cms H2O, PIP 20 - 27 cms H2O]. CO2 target 35 - 55 mmHg.
Mean age at randomisation, HFOV 7 vs CV 9 hrs.
Outcomes Chronic lung disease (CLD) = oxygen therapy at 30 days + abnormal chest Xray; oxygen therapy at 36 weeks
postmenstrual age; failure of assigned treatment to maintain PaO2 >50 mm Hg or PaCO2 < 60 mm Hg or
in CV group development of pulmonary air leak; Pulmonary air leak (+/- pneumothorax); All IVH; grades
3 or 4 IVH; mortality at 30 days

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 15
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Notes No surfactant; prenatal corticosteroids in 12% of HFOV and 13% of CV: additional arm to the trial consisted
of HFOV for 72 hrs then switch to CV (not analysed here).
Allocation concealment A – Adequate

Study Courtney 2002

Methods Concealment of randomisation - yes (central randomization); blinding of treatment - no; complete follow
up - yes for early outcomes, 4% loss in HFOV and 2% loss in CV by 36 wks PMA;
blinding of outcome assessment - yes for head ultrasounds, not specified for other outcomes.
Participants Multicentre (26); 494 preterm infants with birth weights of 601 to 1200 gms which were appropriate for
gestational age, less than four hrs of age, had received one dose of surfactant, required IPPV, FiO2 0.25 or
more, MAP 6 cms H2O or more.
Exclusions - Apgar score at 5 min of less than 4 or base deficit more than 14, congenital abnormality.
HFOV group - 245 randomized, 1 excluded due to cong. heart disease, 10 late exclusions due to parental
request (data used for early outcomes).
CV group - 255 randomised, 1 excluded due to cong. heart disease, 4 exclusions due to parental request
(data used for early outcomes).
Interventions HFOV [SensorMedics 3100A, 10-15 HZ, IT 0.33, initial MAP 2 cm H20 > than CV.
CV - synchronized intermittent mandatory ventilation with VIP Bird or Draeger Babylog 800 or Bear Cub
with volume monitor or Bear Cub 750vs; VT 4 - 7 ml/kg, IT 0.25 - 0.40 sec, rates <60/min. PaCO2 target
45 - 60 mm Hg.
Randomised at mean age of 2.7 hrs in each group.
Outcomes Death by 36 weeks PMA, chronic lung disease at 36 weeks PMA (oxygen therapy or other assisted ventilation),
IVH, PVL, pneumothorax, ROP grade 2 or more, NEC, duration of IPPV.
Notes Surfactant and prophylactic indomethacin used in all; prenatal corticosteroids given in 74% of HFOV cases
and 71% of CV cases
Allocation concealment A – Adequate

Study Craft 2003

Methods Concealment of randomisation - yes.
Blinding of treatment - no
Completeness of followup - yes
Blinding of outcome assessment - no for CLD, unknown for IVH
Participants 46 preterm infants 23 - 34 weeks & <1000gms birth wt.
Two centres
Interventions HFO - Infant Star 10-12 HZ, high volume strategy.
CV - Infant Star, ’open lung strategy (PEEP 4-6, PIP 16-24, SIMV. PaCo2 target 50 - 60 mm Hg.
Age at randomisation not reported.
Outcomes CLD at 36 weeks PMA - oxygen required to maintain SaO2 >92%, death, IVH grades 3 or 4, Airleak,
Retinopathy of prematurity,
failure leading to cross-over of ventilation type
Notes Jan. 1999 - may 2000. trial stopped because of lack of effect.
Full course of antenatal corticosteroids given to 50% in each group
Allocation concealment A – Adequate

Study Durand 2001

Methods Randomised but concealment of randomization - unknown
Blinding of intervention - no.
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 16
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
completeness of followup - 2 infants withdraw from HFOV arm at parent request.
Blinding of outcome assessment - no
Participants 48 preterm infants with birth weights 501 - 1200 gms, < 4 hrs of age, had one dose of surfactant, on
mechanical ventilation, MAP =or> 6 cms H2O, ongoing ventilation for >24 hrs anticipated.
7 nurseries involved
Interventions HFOV - Sensormedics 3100A, 15 HZ, I/T 0.33, high volume strategy.
CV - SIMV using Drager Babylog, Bearcub, VIP Bird - lung protective strategy - Rate <60, PEEP 4-6, Ti
0.25-0.35, CO2 target 40 55 or higher.
Outcomes Death by 36 weeks, CLD at 36 weeks in survivors, IVH grades 3 or 4, PVL, mean no. of doses of surfactant.
Notes Pilot study for Courtney 2003 - subjects not include in later study.
Allocation concealment B – Unclear

Study Gerstmann 1996

Methods Concealment of randomisation - yes (sealed opaque envelopes) in 2 tiered balanced blocks; blinding of
treatment - no; complete follow up - yes; blinding of outcome assessment - no.
Participants Multicentre (3); <35 weeks gestation and respiratory distress with abnormal chest Xray consistent with poor
inflation and use of IPPV and < 12 hrs of age; 125 ( approx. 63 % of eligible) subjects enrolled; stratified by
birth weight more or less than 1 kg and by age more or less than 4 hrs;
Interventions HFOV (Sensormedics 3100, insp/exp 0.33, 10 - 15 Hz, airway pressure > CV). HVS used (higher MAP,
wean FiO2 first)
CV (IT 0.35 - 0.55 sec, rates <60/min, PEEP 3 - 7 cms H2O, PIP up to 30 cms H2O if <1 kg and up to 35
cms H2O if > 1 kg); crossed over to other treatment if met set failure criteria. Mean age at randomisation
2.9 vs 2 hrs.
Outcomes Chronic lung disease (CLD) = oxygen therapy at 30 days & abnormal chest Xray; oxygen at discharge (mean
age 37 weeks PMA); mortality at 30 days; failure of assigned treatment (PaO2 <50 or PaCO2 >60 mmHg
for > 2 hrs, or excessive pressures of IPPV); pulmonary air leak; all IVH; grade 3 or 4 IVH; PVL; mechanical
ventilation at 28 days; NEC; use of vasopressors; PDA (treated); ROP; BAER; hospital cost
Notes Bovine surfactant used in about 70%; prenatal steroid use 29.7% in HFOV and 18% in CV; original design
had 3 arms, including a HFOV without surfactant arm; interim analysis after 50 subjects
Allocation concealment A – Adequate

Study HIFI 1989

Methods Concealment of randomisation - yes; blinding of treatment - no; complete follow up - yes for primary
outcome (CLD, 98.3%), lower for late outcomes (see below); blinding of outcome assessment - yes
Participants Multicentre (10); RDS & birth weight 750 - 2000 gms (those at 1250 - 2000 gms only eligible if severe
RDS) & < 24 hrs of age & IPPV for < 12hrs; stratified by centre and in 250 gms weight groups in those at
500 - 1500 gms; 823 eligible, 673 randomised, 12 withdrawals (died or consent withdrawn before treated);
exclusions - meconium aspiration, neuromuscular conditions, hydrops, congenital heart disease, congenital
abnormalities, multiple births of 3 or more.
Interventions HFOV [Hummingbird, 15 HZ, MAP same or below CV] vs CV [20 - 40 /min, IT 0.3 - 1.0 sec, PIP 20 -
25 cms H2O, PEEP 2 - 5 cms H2O]. Mean age at randomisation 5.8 vs 6.1 hrs in HFOV and CV groups.
Outcomes Chronic lung disease (CLD) = oxygen therapy at 28 days & abnormal chest Xray; mortality at 28 days;
pulmonary air leak (+ / - pneumothorax); all IVH; grade 3 & 4 IVH; PVL; mechanical ventilation at 28
days; failure of assigned treatment (PaO2 < 45 mmHg or PaCO2 > 65 mm Hg; NEC; use of vasopressors;
pulmonary function at 9 months (432, 82% of survivors); neurodevelopmental outcome at 16 - 24 months
(386, 74% of survivors).
Notes Surfactant not used; rate of prenatal corticosteroid usage not reported.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 17
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Allocation concealment A – Adequate

Study Johnson 2002

Methods Concealment of randomisation - unclear; blinding of treatment - no; complete follow up - yes; blinding of
outcome assessment - no for primary outcomes, yes for head ultrasounds.
Participants Multicentre (25); 870 infants 23 to 28 weeks inclusive. Randomised immediately before the birth. 33 infants
in each group subsequently did not meet eligibility criteria and were not continued in the trial. Eligibility
criteria included - intubated from birth for respiratory support, < 1 hr of age.
Exclusions - congenital abnormality or needing transfer out.
Of 804 eligible infants 7 withdrawn (?groups) leaving 400 in HFOV group and 397 in CV group.
Interventions HFOV [SLE 2000 HFO - 187 infants, Drager Babylog 8000 - 165 infants, SensorMedics 3100A - 38
infants]; 10 HZ, MAP 6-8 cms H20; I:E 1:1 or 1:2, FiO2 weaned before MAP (high volume strategy)
CV [SLE 2000 - 193 infants, Drager Babylog 8000 - 192 infants, other ventilators - 12 infants]; IT 0.4 sec,
initial rate 60/min, target PaCO2 34-53 mm Hg, Au: most on synchronised ventilation.
Outcomes Death by 36 weeks PMA, chronic lung disease at 36 weeks PMA (oxygen therapy or other assisted ventilation),
failure of assigned treatment, IVH, PVL, pulmonary airleak (not defined), ROP grade 2 or more, NEC,
length of hospital stay.
Notes Surfactant given to 97% of HFOV group and 99% of CV group.
Prenatal corticosteroids given in 91% of HFOV cases and 92% of CV cases.
Allocation concealment B – Unclear

Study Moriette 2001

Methods Concealment of randomisation - yes (central randomization); blinding of treatment - no; complete follow
up - yes (7% loss); blinding of outcome assessment - yes for head ultrasound and chest xrays, no for other
outcomes.
Participants Multicentre (10); 292 infants 24 - 29 weeks with clinical and radiological RDS and PaO2/Fio2 < 200 mm
Hg randomized, 273 analysed (139 HFOV and 134 CV).
Exclusions: congenital abnormalities, PPROM >24 hrs, hydrops, grade 3/ 4 IVH or pulmonary air leak
before entry.
Age < 6hrs (median 142 mins in HFOV and 145 mins in CV).
Interventions HFOV with piston oscillator (OHFI, Dufour, France), 1:1 I:E ratio, 15 hz, high volume strategy (higher
mean airway pressure, sighs); vs CV with Drager babylog 8000, TI < 0.45 sec, PEEP 4-5 cms H2O, SIMV,
77%.
Use of alternative mode in 1st 10 days if MAP > 14 cms H2O in HFOV gp or after surfactant FiO2 > 0.5
&/or PIP >25 in CV gp
Outcomes Death (neonatal and before discharge);
Use of > 1 dose of surfactant;
Pulmonary airleak (PIE and pneumothorax);
ROP (? grade)
CLD (oxygen at 28 days and oxygen at 36 weeks;
Duration of IPPV, O2 therapy, hospitalisation
Grade 3/4 IVH (7-10 day U/S);
PVL (28 day U/S);
Notes All received 1 dose of surfactant; maternal antenatal corticosteroids in 52% HFOV and 55% CV 21
Allocation concealment A – Adequate

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 18
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Study Ogawa 1993
Methods Concealment of randomisation - yes (opaque sealed envelops); blinding of treatment - no; complete follow
up - yes; blinding of outcome assessment - yes
Participants Multicentre (9); Presumed RDS; 750 - 2000 gms; <1 hr of age for inborn and <6 hrs for outborn (mean 2
+/- 1.6 vs 1.7 +/- 1.5 hrs); stratified by birth weight 750 - 1249 vs 1250 - 2000 gms; 118 admissions, 16 met
exclusion criteria (as for HIFI 1989); 46 allocated to each treatment.
Interventions HFOV (Hummingbird, 15 Hz). HVS used (higher MAP, sighs).
CV (pressure limited time cycled, method not stated). PaCO2 target 35-50 mm Hg.
Mean age at randomization HFOV 2 vs CV 1.7 hrs.
Outcomes Primary outcome all IVH and grade 3 or 4 IVH; Chronic lung disease (CLD) = oxygen therapy at 28 days
& abnormal chest Xray; mortality at 28 days; failure of assigned treatment (as for HIFI 1989); pulmonary
air leak; PVL; mechanical ventilation at 28 days; duration of mechanical ventilation; neurodevelopmental
outcome at 12 months (all survivors).
Notes Bovine surfactant given for RDS as rescue
Allocation concealment A – Adequate

Study Plavka 1999

Methods Concealment of randomisation - yes (sealed envelopes); blinding of treatment - no; completeness of followup
- 2 excluded (1 CNS abnormality in HFOV gp. and 1 congenital heart disease in CV); blinding of outcome
assessment - not stated for most outcomes, chest xrays reviewed by blinded observers.
Participants Single centre; 43 preterm infants <31 weeks and 500 - 1499 gms birth weight. Exclusions - small for gestational
age, major congenital abnormality, neuromuscular condition or ventilated for CNS disorder or circulatory
reason.
Interventions HFOV (Sensormedics 3100A) at 15 HZ, high volume strategy (high MAP and FiO2 weaned before pressure)
vs CV (Bearcub 2100 or Infant Star) time cycled, pressure limited, + or - patient triggered, rate 30 - 60, IT
0.3 - 0.5, PEEP 3-5.
Outcomes Mortality at 30 days and at 36 weeks PMA, any airleak, pneumothorax, CLD 30 days and 36 weeks PMA,
any IVH and severe grade 3 or 4 IVH, periventricular leucomalacia, retinopathy > gd 2
Notes Selective intubation at birth, chest xray and surfactant treatment < 3 hrs, randomised < 3hrs
Author provided additional data on rates of IVH and pulmonary air leaks in excluded early deaths
Allocation concealment A – Adequate

Study Rettwitz-Volk 1998

Methods Concealment of randomisation - yes (central computer); blinding of treatment - no; complete follow up -
yes; blinding of outcome assessment - no
Participants Multicentre (3); preterm infants birth weight 750 - 1500 gms (stratified > or < 1000gms) and < 2 hrs old
and RDS with FiO2 > 0.6; exclusions - Congenital abnormalities, hydrops. 46 in HFOV gp and 50 in CV
gp.
Interventions HFOV Stephan SHF 3000 piston oscillator, 15-20 Hz, not HVS.
CV using time cycled pressure limited ventilators, IT 0.25 - 0.45, I:E = 1:2, PEEP 3-4.
Mean age at randomisation 70 vs 40 mins.
Outcomes Mortality before discharge, CLD (O2 at 37 weeks PMA), failure of assigned treatment (PaO2 <45 mmHg
or PaCO2 > 60 mm Hg), pulmonary ALS +/- pneumothorax, IVH, PVL
Notes Bovine surfactant used as rescue in all; antenatal corticosteroids in 71%, 92% inborn; all patients still on
oxygen therapy at 7 days of age received a 21 day course of Dexamethasone (HFOV 43% vs CV 60%). Cross
over from CV to HFOV also allowed if PIE developed.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 19
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Allocation concealment A – Adequate

Study Schreiber 2003

Methods Randomised but concealment unclear.
Blinding of treatment - no.
Completeness of follow up - yes for primary analysis, 82% for developmental follow up.
Blinding of outcome assessment - yes for chest xray, head ultrasound, ROP, neurodevelopment.
Participants 207 preterm infants <34 weeks gestation and birthweight <200gms, <72 hrs of age, with RDS and IPPV to
be given.
Interventions Trial randomised infants to Nitric oxide vs placebo and to HFOV vs CV.
HFOV 102 infants - Sensormedics 3100A, 10-15 hz.
CV - 105 infants, Ventilator type ?, rate 40/min, PEEP 4-6cms H2O. PaCO2 target 35 - 55 mm Hg.
Outcomes Death, CLD at 28 days and 36 week PMA, pulmonary air leak, severe IVH grds 3 or 4, PVL, ROP
Notes Antenatal steroid rate 55%, all recieve surfactant
Allocation concealment B – Unclear

Study Thome 1998

Methods Concealment at randomisation - yes (consecutively numbered, sealed opaque envelopes); blinding of treat-
ment - no; complete follow up - yes (98.3%); blinding of outcome assessment - yes for chest xrays, no for
head ultrasound.
Participants Multicentre (6); preterm < 30 weeks gestational age (stratified 24-25, 26-27, 28-29 wks) and intubated for
IPPV < 6 hrs; exclusions - outborn or cong. abnormality. 140 in HFOV gp and 144 in CV gp.
Interventions HFOV with Infant Star ventilator (software version 83) at 10 Hz. HVS used (higher MAP, wean FiO2 first,
sighs).
CV with various time cycled pressure limited ventilators, initial rates 60 - 80/min, aimed at lower PIP and
PEEP 3 cms H2O or more.
Age at randomisation < 1 hr in all but 2 infants.
Outcomes Failure (ALS < 10 days, oxygenation index > 35 , 40 or 45 in the 3 gestation strata, CLD at 36 weeks or
death before discharge), CLD = oxygen or vent. support at 36 weeks, ALS = PIE or gross air leaks; IVH;
PVL; ROP
Notes Bovine or porcine surfactant given to 68% of HFOV and 71% of CV; prenatal corticosteroids in 86% of
HFOV and 81% of CV. Postnatal corticosteroids given to 39% of HFOV vs 41% of CV.
Allocation concealment A – Adequate

Study Van Reempts 2003

Methods Concealment at randomisation - yes (sealed folded papers); blinding of treatment - no; complete follow up
- yes; blinding of outcome assessment - yes for grading of chronic lung disease, intracranial hemorrhage,
periventricular leukomalacia and retinopathy of prematurity.
Participants 300 infants (147 HFOV and 153 controls) born at <32 weeks gestation, less than 6 hours of age, FiO2 >0.40
or MAPXFiO2 >3.8, clinical and radiological diagnosis of RDS.
Exclusions - major congenital abnormality, active infection.
Interventions HFOV using a high volume strategy (higher mean airway pressure than CV, wean O2 before pressure) using
Sensormedics 3100A (122 infants) or Infant Star (25 infants) - MAP 8 cms H2O if <29 weeks & 10 cms
H2O if 29-31 weeks. Rate 10 hz.
CV - Drager Babylog (73 infants), Infant Star (80 infants) - PIP=20 cmsH2O (aim low), PEEP 4 cms H2O
start, IT <.35 start, rate 80/min, PaCO2 target 35 - 70 mmHg. I:E=1:1.1

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 20
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Outcomes Chronic lung disease (CLD - on O2 or assisted ventilation) at 36 weeks, death before discharge, failure of
assigned treatment, CLD at 28 days, pulmonary interstitial air, pneumothorax, intraventricular haemorrhage,
periventricular leukomalacia, retinopathy of prematurity, days of IPPV/CPAP/O2, developmental outcome
in early childhood for infants <30 weeks or with an abnormal head ultrasound.
Notes All infants given surfactant; prenatal corticosteroids given to 63% in HFOV group and 66% of CV group
Author provided additional information on grades of ROP, prenatal steroids and neonatal mortality.
Allocation concealment A – Adequate

Study Vento 2005

Methods Concealment of randomization - yes.
Blinding of intervention - no.
Completeness of follow up - two infants (one from each group) excluded after randomisation due to diagnosis
of congenital pneumonia.
Blinding of outcome assessment - unknown
Participants 42 infants with birthweights 501 - 1500gms and gestational age 24 - 29 weeks.
All required intubation at birth and required ongoing ventilation.
Exclusions - congenital abnormalities, congenital pneumonia.
Interventions HFOV - via flow interrupter (Drager Babylog 8000+), high volume strategy, 10HZ.
CV - Draeger Babylog, SIMV, PEEP 4-6 cm, TI 0.30 - 0.40, Max. rate 60/min, PIP weaned first,.
In both CO2 target 45 - 55 mmHg.
Interventions commenced after randomization at 30mins of age.
Outcomes death before discharge, CLD (O2 therapy at 36 weeks PMA), pneumothorax, PIE, IVH grades 3 or 4, PVL,
ROP >stage 2.
Notes Antenatal corticosteroids - any 100% HFOV & 95% CV, completed course 55% HFOV & 60% CV.
Allocation concealment A – Adequate
IT = inspiratory time; PIP = positive inspiratory pressure; PEEP = positive end-expiratory pressure; MAP = mean airway pressure; CLD = chronic lung
disease; ALS = air-leak syndrome; IVH = intraventicular haemorrahge; PVL = periventricular leukomalacia; PMA = post-mentrual age

Characteristics of excluded studies

Study Reason for exclusion

Cambonie 2003
Froese 1987 After randomization of infants (unknown gestation range), 5 of 11 in the HFOV group and an unknown number
from the CV group were excluded from the comparisons between treatments.
HiFO 1993 Rescue treatment with primary aim of preventing pulmonary air leak.
Lombert 1996 22% excluded after randomization, mixed population of preterm and term infants.
Pardou 1993 Results reported for only 13 (54%) of the 24 subjects randomised to high frequency flow interrupter or CV.
Ramanathan 1995 Mandatory crossover of treatments at 96 hrs.

Characteristics of ongoing studies

Study Texas Infant Star

Trial name or title Texas infant Star
Participants Eligible infants include < 1250 gms birth weight or < 29 weeks gestation.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 21
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of ongoing studies (Continued )
Interventions Randomization to 3 modes of ventilation: conventional, high frequency oscillation, and combination (HFOV
+ 2 - 5 bpm CV).
Outcomes
Starting date Study commenced in late 1996 - has been completed but not yet published.
Contact information Contact: Dr Anthony L Talbert, Texas Tech University School of Medicine, Odessa, Texas, USA. Phone +1 915
335 5270.
Notes

ANALYSES

Comparison 01. HFOV vs CV (all trials)

No. of No. of
Outcome title studies participants Statistical method Effect size
01 Death by 28-30 days 9 2060 Relative Risk (Fixed) 95% CI 1.09 [0.88, 1.35]
02 Mechanical ventilation at 28 - 3 767 Relative Risk (Fixed) 95% CI 1.08 [0.86, 1.35]
30 days in survivors
03 Oxygen at 28-30 days in 6 1043 Relative Risk (Fixed) 95% CI 0.98 [0.88, 1.10]
survivors
04 CLD at 28-30 days (O2 + xray) 4 820 Relative Risk (Fixed) 95% CI 0.86 [0.74, 1.01]
in survivors
05 Death or CLD at 28-30 days 5 1160 Relative Risk (Fixed) 95% CI 0.94 [0.85, 1.04]
06 Death by 36-37 weeks or 13 2820 Relative Risk (Fixed) 95% CI 0.98 [0.83, 1.14]
discharge
07 CLD at 36-37 weeks PMA or 13 2310 Relative Risk (Fixed) 95% CI 0.89 [0.81, 0.99]
discharge in survivors
08 Death or CLD at 36-37 weeks 13 2820 Relative Risk (Fixed) 95% CI 0.93 [0.86, 1.00]
PMA or discharge
09 Any pulmonary air leak 11 2726 Relative Risk (Fixed) 95% CI 1.19 [1.05, 1.34]
10 Gross pulmonary air leak 9 1804 Relative Risk (Fixed) 95% CI 1.32 [1.00, 1.72]
11 Intraventricular hemorrhage - 10 2971 Relative Risk (Fixed) 95% CI 1.05 [0.96, 1.15]
all grades
12 Intraventricular hemorrhage - 15 3585 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.30]
grd 3 or 4
13 Periventricular leukomalacia 13 3474 Relative Risk (Fixed) 95% CI 1.10 [0.85, 1.43]
14 Retinopathy of prematurity 10 2367 Relative Risk (Fixed) 95% CI 0.85 [0.74, 0.99]
(grd 2 or more) in survivors

Comparison 02. HFOV vs CV subgrouped by volume strategy on HFOV

No. of No. of
Outcome title studies participants Statistical method Effect size
01 Death by 36-37 weeks or 13 2820 Relative Risk (Fixed) 95% CI 0.98 [0.83, 1.14]
discharge
02 CLD at 36-37 weeks PMA or 13 2310 Relative Risk (Fixed) 95% CI 0.89 [0.81, 0.99]
discharge in survivors
03 Death or CLD at 36-37 weeks 13 2820 Relative Risk (Fixed) 95% CI 0.93 [0.86, 1.00]
PMA or discharge
04 Gross pulmonary air leak 9 1804 Relative Risk (Fixed) 95% CI 1.32 [1.00, 1.72]
05 Intraventricular hemorrhage - 15 3585 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.30]
grd 3 or 4
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 22
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
06 Periventricular leukomalacia 13 3474 Relative Risk (Fixed) 95% CI 1.10 [0.85, 1.43]

Comparison 03. HFOV vs CV subgouped by use of surfactant

No. of No. of
Outcome title studies participants Statistical method Effect size

01 Death by 36-37 weeks or 13 2820 Relative Risk (Fixed) 95% CI 0.98 [0.83, 1.14]
discharge
02 CLD at 36-37 weeks PMA or 13 2310 Relative Risk (Fixed) 95% CI 0.89 [0.81, 0.99]
discharge in survivors
03 Death or CLD at 36-37 weeks 13 2820 Relative Risk (Fixed) 95% CI 0.93 [0.86, 1.00]
PMA or discharge
04 Gross pulmonary air leak 9 1804 Relative Risk (Fixed) 95% CI 1.32 [1.00, 1.72]
05 Intraventricular hemorrhage - 15 3585 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.30]
grd 3 or 4
06 Periventricular leukomalacia 13 3474 Relative Risk (Fixed) 95% CI 1.10 [0.85, 1.43]

Comparison 04. HFOV vs CV subgrouped by type of HFO ventilator

No. of No. of
Outcome title studies participants Statistical method Effect size

01 Death by 36-37 weeks or 13 2820 Relative Risk (Fixed) 95% CI 0.98 [0.83, 1.14]
discharge
02 CLD at 36-37 weeks PMA or 13 2310 Relative Risk (Fixed) 95% CI 0.89 [0.81, 0.99]
discharge in survivors
03 Death or CLD at 36-37 weeks 13 2820 Relative Risk (Fixed) 95% CI 0.93 [0.86, 1.00]
PMA or discharge
04 Gross pulmonary air leak 9 1804 Relative Risk (Fixed) 95% CI 1.32 [1.00, 1.72]
05 Intraventricular hemorrhage - 15 3585 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.30]
grd 3 or 4
06 Periventricular leukomalacia 14 3476 Relative Risk (Fixed) 95% CI 1.10 [0.85, 1.43]

Comparison 05. HFOV vs CV subgrouped by lung protective (LPS) CV strategy

No. of No. of
Outcome title studies participants Statistical method Effect size

01 Death by 36-37 weeks or 13 2820 Relative Risk (Fixed) 95% CI 0.98 [0.83, 1.14]
discharge
02 CLD at 36-37 weeks PMA or 13 2310 Relative Risk (Fixed) 95% CI 0.89 [0.81, 0.99]
discharge in survivors
03 Death or CLD at 36-37 weeks 13 2822 Relative Risk (Fixed) 95% CI 0.93 [0.86, 1.00]
PMA or discharge
04 Gross pulmonary air leak 9 1804 Relative Risk (Fixed) 95% CI 1.32 [1.00, 1.72]
05 Intraventricular hemorrhage - 15 3585 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.30]
grd 3 or 4
06 Periventricular leukomalacia 13 3474 Relative Risk (Fixed) 95% CI 1.10 [0.78, 1.55]
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 23
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Comparison 06. HFOV vs CV subgrouped by age at randomisation

No. of No. of
Outcome title studies participants Statistical method Effect size
01 Death by 36-37 weeks or 11 2474 Relative Risk (Fixed) 95% CI 0.95 [0.80, 1.12]
discharge
02 CLD at 36-37 weeks PMA or 11 2015 Relative Risk (Fixed) 95% CI 0.86 [0.78, 0.96]
discharge in survivors
03 Death or CLD at 36-37 weeks 11 2474 Relative Risk (Fixed) 95% CI 0.90 [0.83, 0.97]
PMA or discharge
04 Gross pulmonary air leak 8 1504 Relative Risk (Fixed) 95% CI 1.29 [0.97, 1.70]
05 Intraventricular hemorrhage - 13 3239 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.31]
grd 3 or 4
06 Periventricular leukomalacia 13 3176 Relative Risk (Fixed) 95% CI 1.08 [0.82, 1.41]

Comparison 07. HFOV vs CV subgrouped by I:E ratio on HFOV

No. of No. of
Outcome title studies participants Statistical method Effect size
01 Death by 36-37 weeks or 13 2820 Relative Risk (Fixed) 95% CI 0.98 [0.83, 1.14]
discharge
02 CLD at 36-37 weeks PMA or 13 2310 Relative Risk (Fixed) 95% CI 0.89 [0.78, 1.02]
discharge in survivors
03 Death or CLD at 36-37 weeks 13 2820 Relative Risk (Fixed) 95% CI 0.93 [0.86, 1.00]
PMA or discharge
04 Gross pulmonary air leak 9 1804 Relative Risk (Fixed) 95% CI 1.32 [1.00, 1.72]
05 Intraventricular hemorrhage - 14 3544 Relative Risk (Fixed) 95% CI 1.11 [0.95, 1.30]
grd 3 or 4
06 Periventricular leukomalacia 13 3474 Relative Risk (Fixed) 95% CI 1.10 [0.85, 1.43]

INDEX TERMS
Medical Subject Headings (MeSH)
Chronic Disease; ∗ High-Frequency Ventilation; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases [∗ prevention &
control]; ∗ Intermittent Positive-Pressure Ventilation; Lung Diseases [∗ prevention & control]; Randomized Controlled Trials; Respiratory
Distress Syndrome, Newborn [therapy]
MeSH check words
Humans

COVER SHEET
Title Elective high frequency oscillatory ventilation versus conventional ventilation for acute
pulmonary dysfunction in preterm infants
Authors Henderson-Smart DJ, Cools F, Bhuta T, Offringa M
Contribution of author(s) An earlier version of this review was developed by Bhuta and Henderson-Smart and pub-
lished in 1996. Both authors were involved at all stages in the review. In 1999 the review
was reformatted by Henderson-Smart with inclusion of two new reviewers, Cools and Of-
fringa. Each author evaluated the trials and extracted data independently. Henderson-Smart
entered the data and wrote the text while all the co-reviewers contributed to data checking
Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 24
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 and editing. The current update included a search by Henderson-Smart and Cools who
both evaluated and extracted the data from 4 new trials. Henderson-Smart entered the data
and edited the review. The review was evaluated by all authors.

Issue protocol first published /

Review first published 1997/1

Date of most recent amendment 23 May 2007

Date of most recent 14 May 2007

SUBSTANTIVE amendment

What’s New This updates the review ’Elective high frequency oscillatory ventilation versus conventional
ventilation for acute pulmonary dysfunction in preterm infants’ published in The Cochrane
Library, Issue 1, 2003 (Henderson-Smart 2003).
As a result of a search update to Novemer 2006, data from four trials have been added. One
new trial is still awaiting assessment and another is yet to be published.
Additional subgroup analyses have been added to explore heterogeneity.

Date new studies sought but 24 April 2007

none found

Date new studies found but not 28 October 2006

yet included/excluded

Date new studies found and 28 October 2006

included/excluded

Date authors’ conclusions 28 October 2006

section amended

Contact address Prof David Henderson-Smart

Director
NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW
2006
AUSTRALIA
E-mail: dhs@mail.usyd.edu.au
Tel: +61 2 93517318
Fax: +61 2 93517742

DOI 10.1002/14651858.CD000104.pub2

Cochrane Library number CD000104

Editorial group Cochrane Neonatal Group

Editorial group code HM-NEONATAL

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 25
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 GRAPHS AND OTHER TABLES
Analysis 01.01. Comparison 01 HFOV vs CV (all trials), Outcome 01 Death by 28-30 days
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 01 Death by 28-30 days

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Clark 1992 7/37 5/28 4.1 1.06 [ 0.38, 2.99 ]

Gerstmann 1996 0/64 2/61 1.9 0.19 [ 0.01, 3.89 ]

HIFI 1989 60/327 60/346 42.3 1.06 [ 0.77, 1.46 ]

Moriette 2001 28/139 24/134 17.7 1.12 [ 0.69, 1.84 ]

Ogawa 1993 0/46 1/46 1.1 0.33 [ 0.01, 7.98 ]

Plavka 1999 2/21 2/20 1.5 0.95 [ 0.15, 6.13 ]

Schreiber 2003 17/102 15/105 10.7 1.17 [ 0.62, 2.21 ]

Thome 1998 10/140 11/144 7.9 0.94 [ 0.41, 2.13 ]

Van Reempts 2003 24/147 18/153 12.8 1.39 [ 0.79, 2.45 ]

Total (95% CI) 1023 1037 100.0 1.09 [ 0.88, 1.35 ]

Total events: 148 (HFOV), 138 (CV)
Test for heterogeneity chi-square=2.76 df=8 p=0.95 I² =0.0%
Test for overall effect z=0.79 p=0.4

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Analysis 01.02. Comparison 01 HFOV vs CV (all trials), Outcome 02 Mechanical ventilation at 28 - 30 days in
survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 02 Mechanical ventilation at 28 - 30 days in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Gerstmann 1996 9/64 12/59 12.0 0.69 [ 0.31, 1.52 ]

HIFI 1989 87/267 85/286 79.2 1.10 [ 0.86, 1.41 ]

Ogawa 1993 13/46 9/45 8.8 1.41 [ 0.67, 2.97 ]

Total (95% CI) 377 390 100.0 1.08 [ 0.86, 1.35 ]

Total events: 109 (HFOV), 106 (CV)
Test for heterogeneity chi-square=1.75 df=2 p=0.42 I² =0.0%
Test for overall effect z=0.63 p=0.5

0.2 0.5 1 2 5
Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 26
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 01.03. Comparison 01 HFOV vs CV (all trials), Outcome 03 Oxygen at 28-30 days in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 03 Oxygen at 28-30 days in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Moriette 2001 51/111 50/110 18.3 1.01 [ 0.76, 1.35 ]

Ogawa 1993 17/46 19/45 7.0 0.88 [ 0.53, 1.46 ]

Plavka 1999 11/19 13/18 4.9 0.80 [ 0.50, 1.29 ]

Schreiber 2003 65/85 61/88 21.8 1.10 [ 0.92, 1.32 ]

Thome 1998 74/130 80/133 28.7 0.95 [ 0.77, 1.16 ]

Van Reempts 2003 49/123 56/135 19.4 0.96 [ 0.71, 1.29 ]

Total (95% CI) 514 529 100.0 0.98 [ 0.88, 1.10 ]

Total events: 267 (HFOV), 279 (CV)
Test for heterogeneity chi-square=2.63 df=5 p=0.76 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.2 0.5 1 2 5
Favours HFOV Favours CV

Analysis 01.04. Comparison 01 HFOV vs CV (all trials), Outcome 04 CLD at 28-30 days (O2 + xray) in
survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 04 CLD at 28-30 days (O2 + xray) in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Clark 1992 10/30 17/23 10.3 0.45 [ 0.26, 0.79 ]

Gerstmann 1996 15/64 25/59 13.9 0.55 [ 0.32, 0.94 ]

HIFI 1989 130/267 141/286 72.6 0.99 [ 0.83, 1.17 ]

Ogawa 1993 4/46 6/45 3.2 0.65 [ 0.20, 2.16 ]

Total (95% CI) 407 413 100.0 0.86 [ 0.74, 1.01 ]

Total events: 159 (HFOV), 189 (CV)
Test for heterogeneity chi-square=10.44 df=3 p=0.02 I² =71.3%
Test for overall effect z=1.89 p=0.06

0.1 0.2 0.5 1 2 5 10

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 27
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 01.05. Comparison 01 HFOV vs CV (all trials), Outcome 05 Death or CLD at 28-30 days
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 05 Death or CLD at 28-30 days

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Clark 1992 17/37 22/28 7.6 0.58 [ 0.39, 0.87 ]

Gerstmann 1996 15/64 27/61 8.4 0.53 [ 0.31, 0.89 ]

HIFI 1989 190/327 201/346 59.1 1.00 [ 0.88, 1.14 ]

Ogawa 1993 4/46 7/46 2.1 0.57 [ 0.18, 1.82 ]

Schreiber 2003 82/102 76/103 22.9 1.09 [ 0.94, 1.27 ]

Total (95% CI) 576 584 100.0 0.94 [ 0.85, 1.04 ]

Total events: 308 (HFOV), 333 (CV)
Test for heterogeneity chi-square=15.33 df=4 p=0.004 I² =73.9%
Test for overall effect z=1.23 p=0.2

0.1 0.2 0.5 1 2 5 10

Favours HFOV Favours CV

Analysis 01.06. Comparison 01 HFOV vs CV (all trials), Outcome 06 Death by 36-37 weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 06 Death by 36-37 weeks or discharge
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

Clark 1992 8/37 6/28 2.7 1.01 [ 0.40, 2.58 ]

Courtney 2002 33/244 40/254 15.6 0.86 [ 0.56, 1.32 ]

Craft 2003 3/22 3/24 1.1 1.09 [ 0.25, 4.85 ]

Durand 2001 5/24 4/24 1.6 1.25 [ 0.38, 4.10 ]

Gerstmann 1996 0/64 2/61 1.0 0.19 [ 0.01, 3.89 ]

Johnson 2002 100/400 105/397 41.9 0.95 [ 0.75, 1.20 ]

Moriette 2001 31/139 27/134 10.9 1.11 [ 0.70, 1.75 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 4/50 1.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 18/102 21/105 8.2 0.88 [ 0.50, 1.56 ]

Thome 1998 14/140 15/144 5.9 0.96 [ 0.48, 1.91 ]

0.001 0.01 0.1 1 10 100 1000

Favours CV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 28
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Van Reempts 2003 25/147 20/153 7.8 1.30 [ 0.76, 2.24 ]

Vento 2005 1/20 2/20 0.8 0.50 [ 0.05, 5.08 ]

Total (95% CI) 1406 1414 100.0 0.98 [ 0.83, 1.14 ]

Total events: 245 (HFOV), 251 (CV)
Test for heterogeneity chi-square=3.81 df=12 p=0.99 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.001 0.01 0.1 1 10 100 1000

Favours CV Favours CV

Analysis 01.07. Comparison 01 HFOV vs CV (all trials), Outcome 07 CLD at 36-37 weeks PMA or discharge
in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 07 CLD at 36-37 weeks PMA or discharge in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Clark 1992 3/29 10/22 2.5 0.23 [ 0.07, 0.73 ]

Courtney 2002 70/201 93/210 20.2 0.79 [ 0.62, 1.00 ]

Craft 2003 13/19 13/21 2.7 1.11 [ 0.70, 1.74 ]

Durand 2001 5/19 14/20 3.0 0.38 [ 0.17, 0.84 ]

Gerstmann 1996 17/64 27/59 6.2 0.58 [ 0.35, 0.95 ]

Johnson 2002 165/300 163/292 36.7 0.99 [ 0.85, 1.14 ]

Moriette 2001 24/108 30/107 6.7 0.79 [ 0.50, 1.26 ]

Plavka 1999 3/19 8/18 1.8 0.36 [ 0.11, 1.13 ]

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Schreiber 2003 43/84 34/84 7.6 1.26 [ 0.91, 1.76 ]

Thome 1998 32/126 30/129 6.6 1.09 [ 0.71, 1.68 ]

Van Reempts 2003 24/122 19/133 4.0 1.38 [ 0.79, 2.39 ]

Vento 2005 2/19 8/18 1.8 0.24 [ 0.06, 0.97 ]

Total (95% CI) 1151 1159 100.0 0.89 [ 0.81, 0.99 ]

Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

0.01 0.1 1 10 100

Favours treatment Favours control

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 29
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 01.08. Comparison 01 HFOV vs CV (all trials), Outcome 08 Death or CLD at 36-37 weeks PMA or
discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 08 Death or CLD at 36-37 weeks PMA or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Clark 1992 11/37 16/28 2.6 0.52 [ 0.29, 0.94 ]

Courtney 2002 103/244 133/254 18.7 0.81 [ 0.67, 0.97 ]

Craft 2003 16/22 16/24 2.2 1.09 [ 0.74, 1.60 ]

Durand 2001 10/24 18/24 2.6 0.56 [ 0.33, 0.94 ]

Gerstmann 1996 17/64 28/61 4.1 0.58 [ 0.35, 0.94 ]

Johnson 2002 265/400 268/397 38.5 0.98 [ 0.89, 1.08 ]

Moriette 2001 55/139 57/134 8.3 0.93 [ 0.70, 1.24 ]

Plavka 1999 5/21 10/20 1.5 0.48 [ 0.20, 1.15 ]

Rettwitz-Volk 1998 5/46 4/50 0.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 61/102 55/105 7.8 1.14 [ 0.90, 1.45 ]

Thome 1998 46/140 45/144 6.4 1.05 [ 0.75, 1.48 ]

Van Reempts 2003 49/147 39/153 5.5 1.31 [ 0.92, 1.86 ]

Vento 2005 3/20 10/20 1.4 0.30 [ 0.10, 0.93 ]

Total (95% CI) 1406 1414 100.0 0.93 [ 0.86, 1.00 ]

Total events: 646 (HFOV), 699 (CV)
Test for heterogeneity chi-square=28.36 df=12 p=0.005 I² =57.7%
Test for overall effect z=2.02 p=0.04

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 30
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 01.09. Comparison 01 HFOV vs CV (all trials), Outcome 09 Any pulmonary air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 09 Any pulmonary air leak
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

Clark 1992 18/37 10/28 3.4 1.36 [ 0.75, 2.47 ]

Craft 2003 8/22 6/24 1.7 1.45 [ 0.60, 3.53 ]

Gerstmann 1996 8/64 11/61 3.4 0.69 [ 0.30, 1.61 ]

HIFI 1989 148/327 131/346 38.4 1.20 [ 1.00, 1.43 ]

Johnson 2002 64/400 72/397 21.8 0.88 [ 0.65, 1.20 ]

Ogawa 1993 4/46 6/46 1.8 0.67 [ 0.20, 2.21 ]

Plavka 1999 3/21 3/20 0.9 0.95 [ 0.22, 4.18 ]

Rettwitz-Volk 1998 7/46 7/50 2.0 1.09 [ 0.41, 2.86 ]

Schreiber 2003 47/102 29/105 8.6 1.67 [ 1.15, 2.43 ]

Thome 1998 59/140 44/144 13.1 1.38 [ 1.01, 1.89 ]

Van Reempts 2003 24/147 16/153 4.7 1.56 [ 0.86, 2.82 ]

Total (95% CI) 1352 1374 100.0 1.19 [ 1.05, 1.34 ]

Total events: 390 (HFOV), 335 (CV)
Test for heterogeneity chi-square=11.47 df=10 p=0.32 I² =12.8%
Test for overall effect z=2.80 p=0.005

0.1 0.2 0.5 1 2 5 10

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 31
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 01.10. Comparison 01 HFOV vs CV (all trials), Outcome 10 Gross pulmonary air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 10 Gross pulmonary air leak
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

Clark 1992 14/37 8/28 11.3 1.32 [ 0.65, 2.71 ]

Courtney 2002 32/244 33/254 40.0 1.01 [ 0.64, 1.59 ]

Moriette 2001 7/139 4/134 5.0 1.69 [ 0.51, 5.63 ]

Plavka 1999 1/21 2/20 2.5 0.48 [ 0.05, 4.85 ]

Rettwitz-Volk 1998 3/46 5/50 5.9 0.65 [ 0.17, 2.58 ]

Schreiber 2003 17/102 10/105 12.2 1.75 [ 0.84, 3.64 ]

Thome 1998 20/140 11/144 13.4 1.87 [ 0.93, 3.76 ]

Van Reempts 2003 11/147 7/153 8.5 1.64 [ 0.65, 4.10 ]

Vento 2005 2/20 1/20 1.2 2.00 [ 0.20, 20.33 ]

Total (95% CI) 896 908 100.0 1.32 [ 1.00, 1.72 ]

Total events: 107 (HFOV), 81 (CV)
Test for heterogeneity chi-square=5.11 df=8 p=0.75 I² =0.0%
Test for overall effect z=1.99 p=0.05

0.01 0.1 1 10 100

Favours HFOV Favours CV

Analysis 01.11. Comparison 01 HFOV vs CV (all trials), Outcome 11 Intraventricular hemorrhage - all grades
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 11 Intraventricular hemorrhage - all grades
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

Clark 1992 18/37 13/28 2.7 1.05 [ 0.62, 1.76 ]

Courtney 2002 113/244 124/254 22.1 0.95 [ 0.79, 1.14 ]

Gerstmann 1996 11/64 16/61 3.0 0.66 [ 0.33, 1.30 ]

HIFI 1989 160/327 146/346 25.8 1.16 [ 0.98, 1.37 ]

Johnson 2002 158/400 150/397 27.3 1.05 [ 0.88, 1.25 ]

Ogawa 1993 7/46 6/46 1.1 1.17 [ 0.42, 3.21 ]

Plavka 1999 15/21 15/20 2.8 0.95 [ 0.66, 1.38 ]

0.2 0.5 1 2 5
Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 32
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Rettwitz-Volk 1998 9/46 8/50 1.4 1.22 [ 0.52, 2.90 ]

Thome 1998 46/140 50/144 8.9 0.95 [ 0.68, 1.31 ]

Van Reempts 2003 39/147 28/153 5.0 1.45 [ 0.94, 2.23 ]

Total (95% CI) 1472 1499 100.0 1.05 [ 0.96, 1.15 ]

Total events: 576 (HFOV), 556 (CV)
Test for heterogeneity chi-square=7.37 df=9 p=0.60 I² =0.0%
Test for overall effect z=1.16 p=0.2

0.2 0.5 1 2 5
Favours HFOV Favours CV

Analysis 01.12. Comparison 01 HFOV vs CV (all trials), Outcome 12 Intraventricular hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 12 Intraventricular hemorrhage - grd 3 or 4
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

Clark 1992 7/37 6/28 2.7 0.88 [ 0.33, 2.34 ]

Courtney 2002 45/244 45/254 17.4 1.04 [ 0.72, 1.51 ]

Craft 2003 4/22 5/24 1.9 0.87 [ 0.27, 2.84 ]

Durand 2001 1/24 4/24 1.6 0.25 [ 0.03, 2.08 ]

Gerstmann 1996 2/64 6/61 2.4 0.32 [ 0.07, 1.51 ]

HIFI 1989 84/327 63/346 24.2 1.41 [ 1.06, 1.88 ]

Johnson 2002 38/400 55/397 21.8 0.69 [ 0.46, 1.01 ]

Moriette 2001 34/139 19/134 7.7 1.73 [ 1.04, 2.87 ]

Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Schreiber 2003 18/102 14/105 5.5 1.32 [ 0.70, 2.52 ]

Thome 1998 19/140 18/144 7.0 1.09 [ 0.60, 1.98 ]

Van Reempts 2003 14/147 13/153 5.0 1.12 [ 0.55, 2.30 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

0.01 0.1 1 10 100

Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 33
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Total (95% CI) 1779 1806 100.0 1.11 [ 0.95, 1.30 ]
Total events: 278 (HFOV), 255 (CV)
Test for heterogeneity chi-square=18.15 df=14 p=0.20 I² =22.9%
Test for overall effect z=1.31 p=0.2

0.01 0.1 1 10 100

Favours HFOV Favours CV

Analysis 01.13. Comparison 01 HFOV vs CV (all trials), Outcome 13 Periventricular leukomalacia

Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 13 Periventricular leukomalacia

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Courtney 2002 18/244 26/254 25.5 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.0 1.50 [ 0.27, 8.19 ]

Gerstmann 1996 4/64 3/61 3.1 1.27 [ 0.30, 5.45 ]

HIFI 1989 38/327 25/346 24.3 1.61 [ 0.99, 2.60 ]

Johnson 2002 8/400 8/397 8.0 0.99 [ 0.38, 2.62 ]

Moriette 2001 14/139 18/134 18.3 0.75 [ 0.39, 1.45 ]

Ogawa 1993 1/46 4/46 4.0 0.25 [ 0.03, 2.15 ]

Plavka 1999 2/21 1/20 1.0 1.90 [ 0.19, 19.40 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Schreiber 2003 4/102 4/105 3.9 1.03 [ 0.26, 4.01 ]

Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Van Reempts 2003 11/147 8/153 7.8 1.43 [ 0.59, 3.46 ]

Vento 2005 1/20 1/20 1.0 1.00 [ 0.07, 14.90 ]

Total (95% CI) 1720 1754 100.0 1.10 [ 0.85, 1.43 ]

Total events: 108 (HFOV), 100 (CV)
Test for heterogeneity chi-square=10.38 df=12 p=0.58 I² =0.0%
Test for overall effect z=0.75 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 34
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 01.14. Comparison 01 HFOV vs CV (all trials), Outcome 14 Retinopathy of prematurity (grd 2 or
more) in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 01 HFOV vs CV (all trials)
Outcome: 14 Retinopathy of prematurity (grd 2 or more) in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Courtney 2002 86/211 105/214 38.4 0.83 [ 0.67, 1.03 ]

Craft 2003 3/22 6/24 2.1 0.55 [ 0.15, 1.92 ]

Gerstmann 1996 3/64 7/59 2.7 0.40 [ 0.11, 1.46 ]

HIFI 1989 69/267 75/286 26.6 0.99 [ 0.74, 1.31 ]

Johnson 2002 43/300 42/292 15.7 1.00 [ 0.67, 1.48 ]

Moriette 2001 6/20 8/21 2.9 0.79 [ 0.33, 1.87 ]

Plavka 1999 2/19 4/18 1.5 0.47 [ 0.10, 2.28 ]

Thome 1998 8/126 15/129 5.5 0.55 [ 0.24, 1.24 ]

Van Reempts 2003 3/122 5/133 1.8 0.65 [ 0.16, 2.68 ]

Vento 2005 6/20 8/20 2.9 0.75 [ 0.32, 1.77 ]

Total (95% CI) 1171 1196 100.0 0.85 [ 0.74, 0.99 ]

Total events: 229 (HFOV), 275 (CV)
Test for heterogeneity chi-square=5.42 df=9 p=0.80 I² =0.0%
Test for overall effect z=2.13 p=0.03

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 35
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.01. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 01 Death by
36-37 weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 02 HFOV vs CV subgrouped by volume strategy on HFOV
Outcome: 01 Death by 36-37 weeks or discharge
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 High volume strategy

Clark 1992 8/37 6/28 2.7 1.01 [ 0.40, 2.58 ]

Courtney 2002 33/244 40/254 15.6 0.86 [ 0.56, 1.32 ]

Craft 2003 3/22 3/24 1.1 1.09 [ 0.25, 4.85 ]

Durand 2001 5/24 4/24 1.6 1.25 [ 0.38, 4.10 ]

Gerstmann 1996 0/64 2/61 1.0 0.19 [ 0.01, 3.89 ]

Johnson 2002 100/400 105/397 41.9 0.95 [ 0.75, 1.20 ]

Moriette 2001 31/139 27/134 10.9 1.11 [ 0.70, 1.75 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Schreiber 2003 18/102 21/105 8.2 0.88 [ 0.50, 1.56 ]

Thome 1998 14/140 15/144 5.9 0.96 [ 0.48, 1.91 ]

Van Reempts 2003 25/147 20/153 7.8 1.30 [ 0.76, 2.24 ]

Vento 2005 1/20 2/20 0.8 0.50 [ 0.05, 5.08 ]

Subtotal (95% CI) 1360 1364 98.5 0.97 [ 0.83, 1.14 ]

Total events: 240 (HFOV), 247 (CV)
Test for heterogeneity chi-square=3.55 df=11 p=0.98 I² =0.0%
Test for overall effect z=0.37 p=0.7

02 No high volume strategy

Rettwitz-Volk 1998 5/46 4/50 1.5 1.36 [ 0.39, 4.75 ]

Subtotal (95% CI) 46 50 1.5 1.36 [ 0.39, 4.75 ]

Total events: 5 (HFOV), 4 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.48 p=0.6
Total (95% CI) 1406 1414 100.0 0.98 [ 0.83, 1.14 ]
Total events: 245 (HFOV), 251 (CV)
Test for heterogeneity chi-square=3.81 df=12 p=0.99 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 36
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.02. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 02 CLD at
36-37 weeks PMA or discharge in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 02 HFOV vs CV subgrouped by volume strategy on HFOV
Outcome: 02 CLD at 36-37 weeks PMA or discharge in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 High volume strategy

Clark 1992 3/29 10/22 2.5 0.23 [ 0.07, 0.73 ]

Courtney 2002 70/201 93/210 20.2 0.79 [ 0.62, 1.00 ]

Craft 2003 13/19 13/21 2.7 1.11 [ 0.70, 1.74 ]

Durand 2001 5/19 14/20 3.0 0.38 [ 0.17, 0.84 ]

Gerstmann 1996 17/64 27/59 6.2 0.58 [ 0.35, 0.95 ]

Johnson 2002 165/300 163/292 36.7 0.99 [ 0.85, 1.14 ]

Moriette 2001 24/108 30/107 6.7 0.79 [ 0.50, 1.26 ]

Plavka 1999 3/19 8/18 1.8 0.36 [ 0.11, 1.13 ]

Schreiber 2003 43/84 34/84 7.6 1.26 [ 0.91, 1.76 ]

Thome 1998 32/126 30/129 6.6 1.09 [ 0.71, 1.68 ]

Van Reempts 2003 24/122 19/133 4.0 1.38 [ 0.79, 2.39 ]

Vento 2005 2/19 8/18 1.8 0.24 [ 0.06, 0.97 ]

Subtotal (95% CI) 1110 1113 100.0 0.89 [ 0.81, 0.99 ]

Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

02 No high volume strategy of HFOV

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Subtotal (95% CI) 41 46 0.0 Not estimable

Total events: 0 (HFOV), 0 (CV)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 1151 1159 100.0 0.89 [ 0.81, 0.99 ]
Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 37
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.03. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 03 Death or
CLD at 36-37 weeks PMA or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 02 HFOV vs CV subgrouped by volume strategy on HFOV
Outcome: 03 Death or CLD at 36-37 weeks PMA or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 High volume strategy on HFOV

Clark 1992 11/37 16/28 2.6 0.52 [ 0.29, 0.94 ]

Courtney 2002 103/244 133/254 18.7 0.81 [ 0.67, 0.97 ]

Craft 2003 16/22 16/24 2.2 1.09 [ 0.74, 1.60 ]

Durand 2001 10/24 18/24 2.6 0.56 [ 0.33, 0.94 ]

Gerstmann 1996 17/64 28/61 4.1 0.58 [ 0.35, 0.94 ]

Johnson 2002 265/400 268/397 38.5 0.98 [ 0.89, 1.08 ]

Moriette 2001 55/139 57/134 8.3 0.93 [ 0.70, 1.24 ]

Plavka 1999 5/21 10/20 1.5 0.48 [ 0.20, 1.15 ]

Schreiber 2003 61/102 55/105 7.8 1.14 [ 0.90, 1.45 ]

Thome 1998 46/140 45/144 6.4 1.05 [ 0.75, 1.48 ]

Van Reempts 2003 49/147 39/153 5.5 1.31 [ 0.92, 1.86 ]

Vento 2005 3/20 10/20 1.4 0.30 [ 0.10, 0.93 ]

Subtotal (95% CI) 1360 1364 99.5 0.92 [ 0.86, 1.00 ]

Total events: 641 (HFOV), 695 (CV)
Test for heterogeneity chi-square=28.07 df=11 p=0.003 I² =60.8%
Test for overall effect z=2.08 p=0.04

02 No high volume strategy on HFOV

Rettwitz-Volk 1998 5/46 4/50 0.5 1.36 [ 0.39, 4.75 ]

Subtotal (95% CI) 46 50 0.5 1.36 [ 0.39, 4.75 ]

Total events: 5 (HFOV), 4 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.48 p=0.6
Total (95% CI) 1406 1414 100.0 0.93 [ 0.86, 1.00 ]
Total events: 646 (HFOV), 699 (CV)
Test for heterogeneity chi-square=28.36 df=12 p=0.005 I² =57.7%
Test for overall effect z=2.02 p=0.04

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 38
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 02.04. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 04 Gross
pulmonary air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 02 HFOV vs CV subgrouped by volume strategy on HFOV
Outcome: 04 Gross pulmonary air leak

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 High volume strategy HFOV

Clark 1992 14/37 8/28 11.3 1.32 [ 0.65, 2.71 ]

Courtney 2002 32/244 33/254 40.0 1.01 [ 0.64, 1.59 ]

Moriette 2001 7/139 4/134 5.0 1.69 [ 0.51, 5.63 ]

Plavka 1999 1/21 2/20 2.5 0.48 [ 0.05, 4.85 ]

Schreiber 2003 17/102 10/105 12.2 1.75 [ 0.84, 3.64 ]

Thome 1998 20/140 11/144 13.4 1.87 [ 0.93, 3.76 ]

Van Reempts 2003 11/147 7/153 8.5 1.64 [ 0.65, 4.10 ]

Vento 2005 2/20 1/20 1.2 2.00 [ 0.20, 20.33 ]

Subtotal (95% CI) 850 858 94.1 1.36 [ 1.03, 1.79 ]

Total events: 104 (HFOV), 76 (CV)
Test for heterogeneity chi-square=4.09 df=7 p=0.77 I² =0.0%
Test for overall effect z=2.17 p=0.03

02 No high volume strategy on HFOV

Rettwitz-Volk 1998 3/46 5/50 5.9 0.65 [ 0.17, 2.58 ]

Subtotal (95% CI) 46 50 5.9 0.65 [ 0.17, 2.58 ]

Total events: 3 (HFOV), 5 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.61 p=0.5
Total (95% CI) 896 908 100.0 1.32 [ 1.00, 1.72 ]
Total events: 107 (HFOV), 81 (CV)
Test for heterogeneity chi-square=5.11 df=8 p=0.75 I² =0.0%
Test for overall effect z=1.99 p=0.05

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 39
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 02.05. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 05
Intraventricular hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 02 HFOV vs CV subgrouped by volume strategy on HFOV
Outcome: 05 Intraventricular hemorrhage - grd 3 or 4

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 High volume strategy on HFOV

Clark 1992 7/37 6/28 2.7 0.88 [ 0.33, 2.34 ]

Courtney 2002 45/244 45/254 17.4 1.04 [ 0.72, 1.51 ]

Craft 2003 4/22 5/24 1.9 0.87 [ 0.27, 2.84 ]

Durand 2001 1/24 4/24 1.6 0.25 [ 0.03, 2.08 ]

Gerstmann 1996 2/64 6/61 2.4 0.32 [ 0.07, 1.51 ]

Johnson 2002 38/400 55/397 21.8 0.69 [ 0.46, 1.01 ]

Moriette 2001 34/139 19/134 7.7 1.73 [ 1.04, 2.87 ]

Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Schreiber 2003 18/102 14/105 5.5 1.32 [ 0.70, 2.52 ]

Thome 1998 19/140 18/144 7.0 1.09 [ 0.60, 1.98 ]

Van Reempts 2003 14/147 13/153 5.0 1.12 [ 0.55, 2.30 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

Subtotal (95% CI) 1406 1410 75.0 1.00 [ 0.83, 1.20 ]

Total events: 189 (HFOV), 190 (CV)
Test for heterogeneity chi-square=13.36 df=12 p=0.34 I² =10.2%
Test for overall effect z=0.04 p=1

02 No high volume strategy on HFOV

HIFI 1989 84/327 63/346 24.2 1.41 [ 1.06, 1.88 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Subtotal (95% CI) 373 396 25.0 1.45 [ 1.09, 1.93 ]

Total events: 89 (HFOV), 65 (CV)
Test for heterogeneity chi-square=0.63 df=1 p=0.43 I² =0.0%
Test for overall effect z=2.56 p=0.01
Total (95% CI) 1779 1806 100.0 1.11 [ 0.95, 1.30 ]
Total events: 278 (HFOV), 255 (CV)
Test for heterogeneity chi-square=18.15 df=14 p=0.20 I² =22.9%
Test for overall effect z=1.31 p=0.2

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 40
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 02.06. Comparison 02 HFOV vs CV subgrouped by volume strategy on HFOV, Outcome 06
Periventricular leukomalacia
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 02 HFOV vs CV subgrouped by volume strategy on HFOV
Outcome: 06 Periventricular leukomalacia

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 High volume strategy on HFOV

Courtney 2002 18/244 26/254 25.5 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.0 1.50 [ 0.27, 8.19 ]

Gerstmann 1996 4/64 3/61 3.1 1.27 [ 0.30, 5.45 ]

Johnson 2002 8/400 8/397 8.0 0.99 [ 0.38, 2.62 ]

Moriette 2001 14/139 18/134 18.3 0.75 [ 0.39, 1.45 ]

Ogawa 1993 1/46 4/46 4.0 0.25 [ 0.03, 2.15 ]

Plavka 1999 2/21 1/20 1.0 1.90 [ 0.19, 19.40 ]

Schreiber 2003 4/102 4/105 3.9 1.03 [ 0.26, 4.01 ]

Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Van Reempts 2003 11/147 8/153 7.8 1.43 [ 0.59, 3.46 ]

Vento 2005 1/20 1/20 1.0 1.00 [ 0.07, 14.90 ]

Subtotal (95% CI) 1347 1358 75.2 0.93 [ 0.68, 1.27 ]

Total events: 69 (HFOV), 75 (CV)
Test for heterogeneity chi-square=6.25 df=10 p=0.79 I² =0.0%
Test for overall effect z=0.47 p=0.6

02 No high volume strategy on HFOV

HIFI 1989 38/327 25/346 24.3 1.61 [ 0.99, 2.60 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Subtotal (95% CI) 373 396 24.8 1.64 [ 1.02, 2.64 ]

Total events: 39 (HFOV), 25 (CV)
Test for heterogeneity chi-square=0.19 df=1 p=0.67 I² =0.0%
Test for overall effect z=2.04 p=0.04
Total (95% CI) 1720 1754 100.0 1.10 [ 0.85, 1.43 ]
Total events: 108 (HFOV), 100 (CV)
Test for heterogeneity chi-square=10.38 df=12 p=0.58 I² =0.0%
Test for overall effect z=0.75 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 41
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 03.01. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 01 Death by 36-37
weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 03 HFOV vs CV subgouped by use of surfactant
Outcome: 01 Death by 36-37 weeks or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Routine surfactant
Courtney 2002 33/244 40/254 15.6 0.86 [ 0.56, 1.32 ]

Craft 2003 3/22 3/24 1.1 1.09 [ 0.25, 4.85 ]

Durand 2001 5/24 4/24 1.6 1.25 [ 0.38, 4.10 ]

Gerstmann 1996 0/64 2/61 1.0 0.19 [ 0.01, 3.89 ]

Johnson 2002 100/400 105/397 41.9 0.95 [ 0.75, 1.20 ]

Moriette 2001 31/139 27/134 10.9 1.11 [ 0.70, 1.75 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 4/50 1.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 18/102 21/105 8.2 0.88 [ 0.50, 1.56 ]

Thome 1998 14/140 15/144 5.9 0.96 [ 0.48, 1.91 ]

Van Reempts 2003 25/147 20/153 7.8 1.30 [ 0.76, 2.24 ]

Vento 2005 1/20 2/20 0.8 0.50 [ 0.05, 5.08 ]

Subtotal (95% CI) 1369 1386 97.3 0.98 [ 0.83, 1.14 ]

Total events: 237 (HFOV), 245 (CV)
Test for heterogeneity chi-square=3.81 df=11 p=0.98 I² =0.0%
Test for overall effect z=0.31 p=0.8

02 No routine surfactant
Clark 1992 8/37 6/28 2.7 1.01 [ 0.40, 2.58 ]

Subtotal (95% CI) 37 28 2.7 1.01 [ 0.40, 2.58 ]

Total events: 8 (HFOV), 6 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.02 p=1
Total (95% CI) 1406 1414 100.0 0.98 [ 0.83, 1.14 ]
Total events: 245 (HFOV), 251 (CV)
Test for heterogeneity chi-square=3.81 df=12 p=0.99 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 42
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 03.02. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 02 CLD at 36-37
weeks PMA or discharge in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 03 HFOV vs CV subgouped by use of surfactant
Outcome: 02 CLD at 36-37 weeks PMA or discharge in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Routine surfactant
Courtney 2002 70/201 93/210 20.2 0.79 [ 0.62, 1.00 ]

Craft 2003 13/19 13/21 2.7 1.11 [ 0.70, 1.74 ]

Durand 2001 5/19 14/20 3.0 0.38 [ 0.17, 0.84 ]

Gerstmann 1996 17/64 27/59 6.2 0.58 [ 0.35, 0.95 ]

Johnson 2002 165/300 163/292 36.7 0.99 [ 0.85, 1.14 ]

Moriette 2001 24/108 30/107 6.7 0.79 [ 0.50, 1.26 ]

Plavka 1999 3/19 8/18 1.8 0.36 [ 0.11, 1.13 ]

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Schreiber 2003 43/84 34/84 7.6 1.26 [ 0.91, 1.76 ]

Thome 1998 32/126 30/129 6.6 1.09 [ 0.71, 1.68 ]

Van Reempts 2003 24/122 19/133 4.0 1.38 [ 0.79, 2.39 ]

Vento 2005 2/19 8/18 1.8 0.24 [ 0.06, 0.97 ]

Subtotal (95% CI) 1122 1137 97.5 0.91 [ 0.82, 1.01 ]

Total events: 398 (HFOV), 439 (CV)
Test for heterogeneity chi-square=24.10 df=10 p=0.007 I² =58.5%
Test for overall effect z=1.83 p=0.07

02 No routine surfactant
Clark 1992 3/29 10/22 2.5 0.23 [ 0.07, 0.73 ]

Subtotal (95% CI) 29 22 2.5 0.23 [ 0.07, 0.73 ]

Total events: 3 (HFOV), 10 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=2.49 p=0.01
Total (95% CI) 1151 1159 100.0 0.89 [ 0.81, 0.99 ]
Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 43
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 03.03. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 03 Death or CLD at
36-37 weeks PMA or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 03 HFOV vs CV subgouped by use of surfactant
Outcome: 03 Death or CLD at 36-37 weeks PMA or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Routine surfactant
Courtney 2002 103/244 133/254 18.7 0.81 [ 0.67, 0.97 ]

Craft 2003 16/22 16/24 2.2 1.09 [ 0.74, 1.60 ]

Durand 2001 10/24 18/24 2.6 0.56 [ 0.33, 0.94 ]

Gerstmann 1996 17/64 28/61 4.1 0.58 [ 0.35, 0.94 ]

Johnson 2002 265/400 268/397 38.5 0.98 [ 0.89, 1.08 ]

Moriette 2001 55/139 57/134 8.3 0.93 [ 0.70, 1.24 ]

Plavka 1999 5/21 10/20 1.5 0.48 [ 0.20, 1.15 ]

Rettwitz-Volk 1998 5/46 4/50 0.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 61/102 55/105 7.8 1.14 [ 0.90, 1.45 ]

Thome 1998 46/140 45/144 6.4 1.05 [ 0.75, 1.48 ]

Van Reempts 2003 49/147 39/153 5.5 1.31 [ 0.92, 1.86 ]

Vento 2005 3/20 10/20 1.4 0.30 [ 0.10, 0.93 ]

Subtotal (95% CI) 1369 1386 97.4 0.94 [ 0.87, 1.01 ]

Total events: 635 (HFOV), 683 (CV)
Test for heterogeneity chi-square=24.31 df=11 p=0.01 I² =54.7%
Test for overall effect z=1.69 p=0.09

02 No routine surfactant
Clark 1992 11/37 16/28 2.6 0.52 [ 0.29, 0.94 ]

Subtotal (95% CI) 37 28 2.6 0.52 [ 0.29, 0.94 ]

Total events: 11 (HFOV), 16 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=2.17 p=0.03
Total (95% CI) 1406 1414 100.0 0.93 [ 0.86, 1.00 ]
Total events: 646 (HFOV), 699 (CV)
Test for heterogeneity chi-square=28.36 df=12 p=0.005 I² =57.7%
Test for overall effect z=2.02 p=0.04

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 44
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 03.04. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 04 Gross pulmonary
air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 03 HFOV vs CV subgouped by use of surfactant
Outcome: 04 Gross pulmonary air leak

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Routine surfactant
Courtney 2002 32/244 33/254 40.0 1.01 [ 0.64, 1.59 ]

Moriette 2001 7/139 4/134 5.0 1.69 [ 0.51, 5.63 ]

Plavka 1999 1/21 2/20 2.5 0.48 [ 0.05, 4.85 ]

Rettwitz-Volk 1998 3/46 5/50 5.9 0.65 [ 0.17, 2.58 ]

Schreiber 2003 17/102 10/105 12.2 1.75 [ 0.84, 3.64 ]

Thome 1998 20/140 11/144 13.4 1.87 [ 0.93, 3.76 ]

Van Reempts 2003 11/147 7/153 8.5 1.64 [ 0.65, 4.10 ]

Vento 2005 2/20 1/20 1.2 2.00 [ 0.20, 20.33 ]

Subtotal (95% CI) 859 880 88.7 1.31 [ 0.98, 1.76 ]

Total events: 93 (HFOV), 73 (CV)
Test for heterogeneity chi-square=5.11 df=7 p=0.65 I² =0.0%
Test for overall effect z=1.84 p=0.07

02 No routine surfactant
Clark 1992 14/37 8/28 11.3 1.32 [ 0.65, 2.71 ]

Subtotal (95% CI) 37 28 11.3 1.32 [ 0.65, 2.71 ]

Total events: 14 (HFOV), 8 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.77 p=0.4
Total (95% CI) 896 908 100.0 1.32 [ 1.00, 1.72 ]
Total events: 107 (HFOV), 81 (CV)
Test for heterogeneity chi-square=5.11 df=8 p=0.75 I² =0.0%
Test for overall effect z=1.99 p=0.05

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 45
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 03.05. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 05 Intraventricular
hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 03 HFOV vs CV subgouped by use of surfactant
Outcome: 05 Intraventricular hemorrhage - grd 3 or 4

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Routine surfactant
Courtney 2002 45/244 45/254 17.4 1.04 [ 0.72, 1.51 ]

Craft 2003 4/22 5/24 1.9 0.87 [ 0.27, 2.84 ]

Durand 2001 1/24 4/24 1.6 0.25 [ 0.03, 2.08 ]

Gerstmann 1996 2/64 6/61 2.4 0.32 [ 0.07, 1.51 ]

Johnson 2002 38/400 55/397 21.8 0.69 [ 0.46, 1.01 ]

Moriette 2001 34/139 19/134 7.7 1.73 [ 1.04, 2.87 ]

Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Schreiber 2003 18/102 14/105 5.5 1.32 [ 0.70, 2.52 ]

Thome 1998 19/140 18/144 7.0 1.09 [ 0.60, 1.98 ]

Van Reempts 2003 14/147 13/153 5.0 1.12 [ 0.55, 2.30 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

Subtotal (95% CI) 1415 1432 73.1 1.02 [ 0.84, 1.23 ]

Total events: 187 (HFOV), 186 (CV)
Test for heterogeneity chi-square=14.73 df=12 p=0.26 I² =18.5%
Test for overall effect z=0.19 p=0.8

02 No routine surfactant
Clark 1992 7/37 6/28 2.7 0.88 [ 0.33, 2.34 ]

HIFI 1989 84/327 63/346 24.2 1.41 [ 1.06, 1.88 ]

Subtotal (95% CI) 364 374 26.9 1.36 [ 1.03, 1.79 ]

Total events: 91 (HFOV), 69 (CV)
Test for heterogeneity chi-square=0.82 df=1 p=0.37 I² =0.0%
Test for overall effect z=2.16 p=0.03
Total (95% CI) 1779 1806 100.0 1.11 [ 0.95, 1.30 ]
Total events: 278 (HFOV), 255 (CV)
Test for heterogeneity chi-square=18.15 df=14 p=0.20 I² =22.9%
Test for overall effect z=1.31 p=0.2

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 46
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 03.06. Comparison 03 HFOV vs CV subgouped by use of surfactant, Outcome 06 Periventricular
leukomalacia
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 03 HFOV vs CV subgouped by use of surfactant
Outcome: 06 Periventricular leukomalacia

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Rouitine surfactant
Courtney 2002 18/244 26/254 25.5 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.0 1.50 [ 0.27, 8.19 ]

Gerstmann 1996 4/64 3/61 3.1 1.27 [ 0.30, 5.45 ]

Johnson 2002 8/400 8/397 8.0 0.99 [ 0.38, 2.62 ]

Moriette 2001 14/139 18/134 18.3 0.75 [ 0.39, 1.45 ]

Ogawa 1993 1/46 4/46 4.0 0.25 [ 0.03, 2.15 ]

Plavka 1999 2/21 1/20 1.0 1.90 [ 0.19, 19.40 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Schreiber 2003 4/102 4/105 3.9 1.03 [ 0.26, 4.01 ]

Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Van Reempts 2003 11/147 8/153 7.8 1.43 [ 0.59, 3.46 ]

Vento 2005 1/20 1/20 1.0 1.00 [ 0.07, 14.90 ]

Subtotal (95% CI) 1393 1408 75.7 0.94 [ 0.69, 1.29 ]

Total events: 70 (HFOV), 75 (CV)
Test for heterogeneity chi-square=6.86 df=11 p=0.81 I² =0.0%
Test for overall effect z=0.37 p=0.7

02 No routine surfactant
HIFI 1989 38/327 25/346 24.3 1.61 [ 0.99, 2.60 ]

Subtotal (95% CI) 327 346 24.3 1.61 [ 0.99, 2.60 ]

Total events: 38 (HFOV), 25 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=1.93 p=0.05
Total (95% CI) 1720 1754 100.0 1.10 [ 0.85, 1.43 ]
Total events: 108 (HFOV), 100 (CV)
Test for heterogeneity chi-square=10.38 df=12 p=0.58 I² =0.0%
Test for overall effect z=0.75 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 47
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 04.01. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 01 Death by
36-37 weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 04 HFOV vs CV subgrouped by type of HFO ventilator
Outcome: 01 Death by 36-37 weeks or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Flow interrupter
Craft 2003 3/22 3/24 1.1 1.09 [ 0.25, 4.85 ]

Thome 1998 14/140 15/144 5.9 0.96 [ 0.48, 1.91 ]

Vento 2005 1/20 2/20 0.8 0.50 [ 0.05, 5.08 ]

Subtotal (95% CI) 182 188 7.8 0.93 [ 0.51, 1.70 ]

Total events: 18 (HFOV), 20 (CV)
Test for heterogeneity chi-square=0.33 df=2 p=0.85 I² =0.0%
Test for overall effect z=0.23 p=0.8

02 HF oscillator
Clark 1992 8/37 6/28 2.7 1.01 [ 0.40, 2.58 ]

Courtney 2002 33/244 40/254 15.6 0.86 [ 0.56, 1.32 ]

Durand 2001 5/24 4/24 1.6 1.25 [ 0.38, 4.10 ]

Gerstmann 1996 0/64 2/61 1.0 0.19 [ 0.01, 3.89 ]

Moriette 2001 31/139 27/134 10.9 1.11 [ 0.70, 1.75 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 4/50 1.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 18/102 21/105 8.2 0.88 [ 0.50, 1.56 ]

Subtotal (95% CI) 677 676 42.4 0.96 [ 0.75, 1.22 ]

Total events: 102 (HFOV), 106 (CV)
Test for heterogeneity chi-square=2.32 df=7 p=0.94 I² =0.0%
Test for overall effect z=0.36 p=0.7

03 Both HF oscillation and flow interruptors

Johnson 2002 100/400 105/397 41.9 0.95 [ 0.75, 1.20 ]

Van Reempts 2003 25/147 20/153 7.8 1.30 [ 0.76, 2.24 ]

Subtotal (95% CI) 547 550 49.7 1.00 [ 0.81, 1.24 ]

Total events: 125 (HFOV), 125 (CV)
Test for heterogeneity chi-square=1.12 df=1 p=0.29 I² =11.0%
Test for overall effect z=0.01 p=1
Total (95% CI) 1406 1414 100.0 0.98 [ 0.83, 1.14 ]
Total events: 245 (HFOV), 251 (CV)
Test for heterogeneity chi-square=3.81 df=12 p=0.99 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 48
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 04.02. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 02 CLD at 36-
37 weeks PMA or discharge in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 04 HFOV vs CV subgrouped by type of HFO ventilator
Outcome: 02 CLD at 36-37 weeks PMA or discharge in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Flow interrupter
Craft 2003 13/19 13/21 2.7 1.11 [ 0.70, 1.74 ]

Thome 1998 32/126 30/129 6.6 1.09 [ 0.71, 1.68 ]

Vento 2005 2/19 8/18 1.8 0.24 [ 0.06, 0.97 ]

Subtotal (95% CI) 164 168 11.2 0.96 [ 0.69, 1.32 ]

Total events: 47 (HFOV), 51 (CV)
Test for heterogeneity chi-square=4.53 df=2 p=0.10 I² =55.8%
Test for overall effect z=0.28 p=0.8

02 HF oscillator
Clark 1992 3/29 10/22 2.5 0.23 [ 0.07, 0.73 ]

Courtney 2002 70/201 93/210 20.2 0.79 [ 0.62, 1.00 ]

Durand 2001 5/19 14/20 3.0 0.38 [ 0.17, 0.84 ]

Gerstmann 1996 17/64 27/59 6.2 0.58 [ 0.35, 0.95 ]

Moriette 2001 24/108 30/107 6.7 0.79 [ 0.50, 1.26 ]

Plavka 1999 3/19 8/18 1.8 0.36 [ 0.11, 1.13 ]

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Schreiber 2003 43/84 34/84 7.6 1.26 [ 0.91, 1.76 ]

Subtotal (95% CI) 565 566 48.1 0.76 [ 0.65, 0.90 ]

Total events: 165 (HFOV), 216 (CV)
Test for heterogeneity chi-square=18.88 df=6 p=0.004 I² =68.2%
Test for overall effect z=3.27 p=0.001

03 Both HF oscillators and flow interrupters

Johnson 2002 165/300 163/292 36.7 0.99 [ 0.85, 1.14 ]

Van Reempts 2003 24/122 19/133 4.0 1.38 [ 0.79, 2.39 ]

Subtotal (95% CI) 422 425 40.7 1.02 [ 0.89, 1.18 ]

Total events: 189 (HFOV), 182 (CV)
Test for heterogeneity chi-square=1.39 df=1 p=0.24 I² =28.1%
Test for overall effect z=0.33 p=0.7
Total (95% CI) 1151 1159 100.0 0.89 [ 0.81, 0.99 ]
Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 49
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 04.03. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 03 Death or
CLD at 36-37 weeks PMA or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 04 HFOV vs CV subgrouped by type of HFO ventilator
Outcome: 03 Death or CLD at 36-37 weeks PMA or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 HF flow interrupter
Craft 2003 16/22 16/24 2.2 1.09 [ 0.74, 1.60 ]

Thome 1998 46/140 45/144 6.4 1.05 [ 0.75, 1.48 ]

Vento 2005 3/20 10/20 1.4 0.30 [ 0.10, 0.93 ]

Subtotal (95% CI) 182 188 10.0 0.95 [ 0.73, 1.24 ]

Total events: 65 (HFOV), 71 (CV)
Test for heterogeneity chi-square=4.82 df=2 p=0.09 I² =58.5%
Test for overall effect z=0.37 p=0.7

02 HF oscillation
Clark 1992 11/37 16/28 2.6 0.52 [ 0.29, 0.94 ]

Courtney 2002 103/244 133/254 18.7 0.81 [ 0.67, 0.97 ]

Durand 2001 10/24 18/24 2.6 0.56 [ 0.33, 0.94 ]

Gerstmann 1996 17/64 28/61 4.1 0.58 [ 0.35, 0.94 ]

Moriette 2001 55/139 57/134 8.3 0.93 [ 0.70, 1.24 ]

Plavka 1999 5/21 10/20 1.5 0.48 [ 0.20, 1.15 ]

Rettwitz-Volk 1998 5/46 4/50 0.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 61/102 55/105 7.8 1.14 [ 0.90, 1.45 ]

Subtotal (95% CI) 677 676 46.0 0.83 [ 0.74, 0.94 ]

Total events: 267 (HFOV), 321 (CV)
Test for heterogeneity chi-square=16.21 df=7 p=0.02 I² =56.8%
Test for overall effect z=3.04 p=0.002

03 Both HF oscillators and HF flow interrupters

Johnson 2002 265/400 268/397 38.5 0.98 [ 0.89, 1.08 ]

Van Reempts 2003 49/147 39/153 5.5 1.31 [ 0.92, 1.86 ]

Subtotal (95% CI) 547 550 44.0 1.02 [ 0.93, 1.13 ]

Total events: 314 (HFOV), 307 (CV)
Test for heterogeneity chi-square=2.52 df=1 p=0.11 I² =60.3%
Test for overall effect z=0.44 p=0.7
Total (95% CI) 1406 1414 100.0 0.93 [ 0.86, 1.00 ]
Total events: 646 (HFOV), 699 (CV)
Test for heterogeneity chi-square=28.36 df=12 p=0.005 I² =57.7%
Test for overall effect z=2.02 p=0.04

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 50
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 04.04. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 04 Gross
pulmonary air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 04 HFOV vs CV subgrouped by type of HFO ventilator
Outcome: 04 Gross pulmonary air leak

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 HF flow interrupter
Thome 1998 20/140 11/144 13.4 1.87 [ 0.93, 3.76 ]

Vento 2005 2/20 1/20 1.2 2.00 [ 0.20, 20.33 ]

Subtotal (95% CI) 160 164 14.6 1.88 [ 0.96, 3.67 ]

Total events: 22 (HFOV), 12 (CV)
Test for heterogeneity chi-square=0.00 df=1 p=0.96 I² =0.0%
Test for overall effect z=1.85 p=0.06

02 HF oscillation
Clark 1992 14/37 8/28 11.3 1.32 [ 0.65, 2.71 ]

Courtney 2002 32/244 33/254 40.0 1.01 [ 0.64, 1.59 ]

Moriette 2001 7/139 4/134 5.0 1.69 [ 0.51, 5.63 ]

Plavka 1999 1/21 2/20 2.5 0.48 [ 0.05, 4.85 ]

Rettwitz-Volk 1998 3/46 5/50 5.9 0.65 [ 0.17, 2.58 ]

Schreiber 2003 17/102 10/105 12.2 1.75 [ 0.84, 3.64 ]

Subtotal (95% CI) 589 591 76.9 1.17 [ 0.86, 1.60 ]

Total events: 74 (HFOV), 62 (CV)
Test for heterogeneity chi-square=3.31 df=5 p=0.65 I² =0.0%
Test for overall effect z=0.99 p=0.3

03 Both HF oscillators and HF flow interrupters

Van Reempts 2003 11/147 7/153 8.5 1.64 [ 0.65, 4.10 ]

Subtotal (95% CI) 147 153 8.5 1.64 [ 0.65, 4.10 ]

Total events: 11 (HFOV), 7 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=1.05 p=0.3
Total (95% CI) 896 908 100.0 1.32 [ 1.00, 1.72 ]
Total events: 107 (HFOV), 81 (CV)
Test for heterogeneity chi-square=5.11 df=8 p=0.75 I² =0.0%
Test for overall effect z=1.99 p=0.05

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 51
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 04.05. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 05
Intraventricular hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 04 HFOV vs CV subgrouped by type of HFO ventilator
Outcome: 05 Intraventricular hemorrhage - grd 3 or 4
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 HF flow interrupter
Craft 2003 4/22 5/24 1.9 0.87 [ 0.27, 2.84 ]

Thome 1998 19/140 18/144 7.0 1.09 [ 0.60, 1.98 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

Subtotal (95% CI) 182 188 9.7 1.08 [ 0.65, 1.79 ]

Total events: 26 (HFOV), 25 (CV)
Test for heterogeneity chi-square=0.27 df=2 p=0.87 I² =0.0%
Test for overall effect z=0.29 p=0.8

02 HF oscillator
Clark 1992 7/37 6/28 2.7 0.88 [ 0.33, 2.34 ]

Courtney 2002 45/244 45/254 17.4 1.04 [ 0.72, 1.51 ]

Durand 2001 1/24 4/24 1.6 0.25 [ 0.03, 2.08 ]

Gerstmann 1996 2/64 6/61 2.4 0.32 [ 0.07, 1.51 ]

HIFI 1989 84/327 63/346 24.2 1.41 [ 1.06, 1.88 ]

Moriette 2001 34/139 19/134 7.7 1.73 [ 1.04, 2.87 ]

Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Schreiber 2003 18/102 14/105 5.5 1.32 [ 0.70, 2.52 ]

Subtotal (95% CI) 1050 1068 63.4 1.26 [ 1.04, 1.52 ]

Total events: 200 (HFOV), 162 (CV)
Test for heterogeneity chi-square=9.95 df=9 p=0.35 I² =9.6%
Test for overall effect z=2.42 p=0.02

03 Both HF oscillators and HF flow interrupters

Johnson 2002 38/400 55/397 21.8 0.69 [ 0.46, 1.01 ]

Van Reempts 2003 14/147 13/153 5.0 1.12 [ 0.55, 2.30 ]

Subtotal (95% CI) 547 550 26.9 0.77 [ 0.55, 1.08 ]

Total events: 52 (HFOV), 68 (CV)
Test for heterogeneity chi-square=1.38 df=1 p=0.24 I² =27.7%
Test for overall effect z=1.52 p=0.1

0.01 0.1 1 10 100

Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 52
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Total (95% CI) 1779 1806 100.0 1.11 [ 0.95, 1.30 ]
Total events: 278 (HFOV), 255 (CV)
Test for heterogeneity chi-square=18.15 df=14 p=0.20 I² =22.9%
Test for overall effect z=1.31 p=0.2

0.01 0.1 1 10 100

Favours HFOV Favours CV

Analysis 04.06. Comparison 04 HFOV vs CV subgrouped by type of HFO ventilator, Outcome 06

Periventricular leukomalacia
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 04 HFOV vs CV subgrouped by type of HFO ventilator
Outcome: 06 Periventricular leukomalacia
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 HF flow interrupter
Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Vento 2005 1/20 1/20 1.0 1.00 [ 0.07, 14.90 ]

Subtotal (95% CI) 160 164 1.5 3.05 [ 0.49, 18.86 ]

Total events: 4 (HFOV), 1 (CV)
Test for heterogeneity chi-square=0.98 df=1 p=0.32 I² =0.0%
Test for overall effect z=1.20 p=0.2

02 HF oscillator
x Clark 1992 0/1 0/1 0.0 Not estimable

Courtney 2002 18/244 26/254 25.5 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.0 1.50 [ 0.27, 8.19 ]

Gerstmann 1996 4/64 3/61 3.1 1.27 [ 0.30, 5.45 ]

HIFI 1989 38/327 25/346 24.3 1.61 [ 0.99, 2.60 ]

Moriette 2001 14/139 18/134 18.3 0.75 [ 0.39, 1.45 ]

Ogawa 1993 1/46 4/46 4.0 0.25 [ 0.03, 2.15 ]

Plavka 1999 2/21 1/20 1.0 1.90 [ 0.19, 19.40 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Schreiber 2003 4/102 4/105 3.9 1.03 [ 0.26, 4.01 ]

Subtotal (95% CI) 1014 1041 82.6 1.05 [ 0.79, 1.40 ]

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 53
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Total events: 85 (HFOV), 83 (CV)
Test for heterogeneity chi-square=8.35 df=8 p=0.40 I² =4.2%
Test for overall effect z=0.32 p=0.7

03 Both HF oscillators and HF flow interrupters

Johnson 2002 8/400 8/397 8.0 0.99 [ 0.38, 2.62 ]

Van Reempts 2003 11/147 8/153 7.8 1.43 [ 0.59, 3.46 ]

Subtotal (95% CI) 547 550 15.9 1.21 [ 0.63, 2.32 ]

Total events: 19 (HFOV), 16 (CV)
Test for heterogeneity chi-square=0.30 df=1 p=0.58 I² =0.0%
Test for overall effect z=0.57 p=0.6
Total (95% CI) 1721 1755 100.0 1.10 [ 0.85, 1.43 ]
Total events: 108 (HFOV), 100 (CV)
Test for heterogeneity chi-square=10.38 df=12 p=0.58 I² =0.0%
Test for overall effect z=0.75 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Analysis 05.01. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 01
Death by 36-37 weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy
Outcome: 01 Death by 36-37 weeks or discharge
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Definitive LPS on CV
Courtney 2002 33/244 40/254 15.6 0.86 [ 0.56, 1.32 ]

Durand 2001 5/24 4/24 1.6 1.25 [ 0.38, 4.10 ]

Thome 1998 14/140 15/144 5.9 0.96 [ 0.48, 1.91 ]

Van Reempts 2003 25/147 20/153 7.8 1.30 [ 0.76, 2.24 ]

Vento 2005 1/20 2/20 0.8 0.50 [ 0.05, 5.08 ]

Subtotal (95% CI) 575 595 31.7 1.00 [ 0.75, 1.33 ]

Total events: 78 (HFOV), 81 (CV)
Test for heterogeneity chi-square=1.89 df=4 p=0.76 I² =0.0%
Test for overall effect z=0.02 p=1

02 Probable LPS on CV

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 54
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Craft 2003 3/22 3/24 1.1 1.09 [ 0.25, 4.85 ]

Johnson 2002 100/400 105/397 41.9 0.95 [ 0.75, 1.20 ]

Moriette 2001 31/139 27/134 10.9 1.11 [ 0.70, 1.75 ]

Subtotal (95% CI) 561 555 54.0 0.98 [ 0.80, 1.21 ]

Total events: 134 (HFOV), 135 (CV)
Test for heterogeneity chi-square=0.38 df=2 p=0.83 I² =0.0%
Test for overall effect z=0.18 p=0.9

03 Probably no LPS on CV
Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 4/50 1.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 18/102 21/105 8.2 0.88 [ 0.50, 1.56 ]

Subtotal (95% CI) 169 175 10.6 0.96 [ 0.58, 1.57 ]

Total events: 25 (HFOV), 27 (CV)
Test for heterogeneity chi-square=0.38 df=2 p=0.83 I² =0.0%
Test for overall effect z=0.18 p=0.9

04 Definitively no LPS on CV
Clark 1992 8/37 6/28 2.7 1.01 [ 0.40, 2.58 ]

Gerstmann 1996 0/64 2/61 1.0 0.19 [ 0.01, 3.89 ]

Subtotal (95% CI) 101 89 3.7 0.79 [ 0.33, 1.88 ]

Total events: 8 (HFOV), 8 (CV)
Test for heterogeneity chi-square=1.12 df=1 p=0.29 I² =10.6%
Test for overall effect z=0.54 p=0.6
Total (95% CI) 1406 1414 100.0 0.98 [ 0.83, 1.14 ]
Total events: 245 (HFOV), 251 (CV)
Test for heterogeneity chi-square=3.81 df=12 p=0.99 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 55
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 05.02. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 02
CLD at 36-37 weeks PMA or discharge in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy
Outcome: 02 CLD at 36-37 weeks PMA or discharge in survivors
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Definitive LPS on CV
Courtney 2002 70/201 93/210 20.2 0.79 [ 0.62, 1.00 ]

Durand 2001 5/19 14/20 3.0 0.38 [ 0.17, 0.84 ]

Thome 1998 32/126 30/129 6.6 1.09 [ 0.71, 1.68 ]

Van Reempts 2003 24/122 19/133 4.0 1.38 [ 0.79, 2.39 ]

Vento 2005 2/19 8/18 1.8 0.24 [ 0.06, 0.97 ]

Subtotal (95% CI) 487 510 35.7 0.85 [ 0.70, 1.02 ]

Total events: 133 (HFOV), 164 (CV)
Test for heterogeneity chi-square=11.74 df=4 p=0.02 I² =65.9%
Test for overall effect z=1.73 p=0.08

02 Probable LPS on CV
Craft 2003 13/19 13/21 2.7 1.11 [ 0.70, 1.74 ]

Johnson 2002 165/300 163/292 36.7 0.99 [ 0.85, 1.14 ]

Moriette 2001 24/108 30/107 6.7 0.79 [ 0.50, 1.26 ]

Subtotal (95% CI) 427 420 46.2 0.96 [ 0.84, 1.10 ]

Total events: 202 (HFOV), 206 (CV)
Test for heterogeneity chi-square=1.11 df=2 p=0.57 I² =0.0%
Test for overall effect z=0.53 p=0.6

03 Probably no LPS on CV
Plavka 1999 3/19 8/18 1.8 0.36 [ 0.11, 1.13 ]

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Schreiber 2003 43/84 34/84 7.6 1.26 [ 0.91, 1.76 ]

Subtotal (95% CI) 144 148 9.4 1.09 [ 0.79, 1.49 ]

Total events: 46 (HFOV), 42 (CV)
Test for heterogeneity chi-square=4.36 df=1 p=0.04 I² =77.1%
Test for overall effect z=0.52 p=0.6

04 Definitively no LPS on CV
Clark 1992 3/29 10/22 2.5 0.23 [ 0.07, 0.73 ]

Gerstmann 1996 17/64 27/59 6.2 0.58 [ 0.35, 0.95 ]

Subtotal (95% CI) 93 81 8.8 0.48 [ 0.31, 0.75 ]

0.01 0.1 1 10 100

Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 56
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
Total events: 20 (HFOV), 37 (CV)
Test for heterogeneity chi-square=2.15 df=1 p=0.14 I² =53.5%
Test for overall effect z=3.20 p=0.001
Total (95% CI) 1151 1159 100.0 0.89 [ 0.81, 0.99 ]
Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

0.01 0.1 1 10 100

Favours HFOV Favours CV

Analysis 05.03. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 03
Death or CLD at 36-37 weeks PMA or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy
Outcome: 03 Death or CLD at 36-37 weeks PMA or discharge
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Definitive LPS on CV
Courtney 2002 103/244 133/254 18.6 0.81 [ 0.67, 0.97 ]

Durand 2001 10/24 18/24 2.6 0.56 [ 0.33, 0.94 ]

Thome 1998 46/140 45/144 6.3 1.05 [ 0.75, 1.48 ]

Van Reempts 2003 49/147 39/153 5.5 1.31 [ 0.92, 1.86 ]

Vento 2005 3/20 10/20 1.4 0.30 [ 0.10, 0.93 ]

Subtotal (95% CI) 575 595 34.5 0.89 [ 0.77, 1.03 ]

Total events: 211 (HFOV), 245 (CV)
Test for heterogeneity chi-square=13.15 df=4 p=0.01 I² =69.6%
Test for overall effect z=1.59 p=0.1

02 Probable LPS on CV
Craft 2003 16/24 16/24 2.3 1.00 [ 0.67, 1.49 ]

Johnson 2002 265/400 268/397 38.5 0.98 [ 0.89, 1.08 ]

Moriette 2001 55/139 57/134 8.3 0.93 [ 0.70, 1.24 ]

Subtotal (95% CI) 563 555 49.1 0.97 [ 0.89, 1.07 ]

Total events: 336 (HFOV), 341 (CV)
Test for heterogeneity chi-square=0.14 df=2 p=0.93 I² =0.0%
Test for overall effect z=0.57 p=0.6

0.01 0.1 1 10 100

Favours HFOV Favours CV (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 57
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI
03 Probably no LPS on CV
Plavka 1999 5/21 10/20 1.5 0.48 [ 0.20, 1.15 ]

Rettwitz-Volk 1998 5/46 4/50 0.5 1.36 [ 0.39, 4.75 ]

Schreiber 2003 61/102 55/105 7.8 1.14 [ 0.90, 1.45 ]

Subtotal (95% CI) 169 175 9.8 1.05 [ 0.84, 1.33 ]

Total events: 71 (HFOV), 69 (CV)
Test for heterogeneity chi-square=3.70 df=2 p=0.16 I² =45.9%
Test for overall effect z=0.44 p=0.7

04 Definitively no LPS on CV
Clark 1992 11/37 16/28 2.6 0.52 [ 0.29, 0.94 ]

Gerstmann 1996 17/64 28/61 4.1 0.58 [ 0.35, 0.94 ]

Subtotal (95% CI) 101 89 6.7 0.56 [ 0.38, 0.81 ]

Total events: 28 (HFOV), 44 (CV)
Test for heterogeneity chi-square=0.07 df=1 p=0.79 I² =0.0%
Test for overall effect z=3.05 p=0.002
Total (95% CI) 1408 1414 100.0 0.93 [ 0.86, 1.00 ]
Total events: 646 (HFOV), 699 (CV)
Test for heterogeneity chi-square=27.85 df=12 p=0.006 I² =56.9%
Test for overall effect z=2.07 p=0.04

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 58
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 05.04. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 04
Gross pulmonary air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy
Outcome: 04 Gross pulmonary air leak
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Definitive LPS on CV
Courtney 2002 32/244 33/254 40.0 1.01 [ 0.64, 1.59 ]

Thome 1998 20/140 11/144 13.4 1.87 [ 0.93, 3.76 ]

Van Reempts 2003 11/147 7/153 8.5 1.64 [ 0.65, 4.10 ]

Vento 2005 2/20 1/20 1.2 2.00 [ 0.20, 20.33 ]

Subtotal (95% CI) 551 571 63.1 1.30 [ 0.92, 1.83 ]

Total events: 65 (HFOV), 52 (CV)
Test for heterogeneity chi-square=2.61 df=3 p=0.46 I² =0.0%
Test for overall effect z=1.48 p=0.1

02 Probable LPS on CV
Moriette 2001 7/139 4/134 5.0 1.69 [ 0.51, 5.63 ]

Subtotal (95% CI) 139 134 5.0 1.69 [ 0.51, 5.63 ]

Total events: 7 (HFOV), 4 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.85 p=0.4

03 Probably no LPS on CV
Plavka 1999 1/21 2/20 2.5 0.48 [ 0.05, 4.85 ]

Rettwitz-Volk 1998 3/46 5/50 5.9 0.65 [ 0.17, 2.58 ]

Schreiber 2003 17/102 10/105 12.2 1.75 [ 0.84, 3.64 ]

Subtotal (95% CI) 169 175 20.6 1.28 [ 0.70, 2.34 ]

Total events: 21 (HFOV), 17 (CV)
Test for heterogeneity chi-square=2.32 df=2 p=0.31 I² =13.9%
Test for overall effect z=0.80 p=0.4

04 Definitively no LPS on CV
Clark 1992 14/37 8/28 11.3 1.32 [ 0.65, 2.71 ]

Subtotal (95% CI) 37 28 11.3 1.32 [ 0.65, 2.71 ]

Total events: 14 (HFOV), 8 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.77 p=0.4
Total (95% CI) 896 908 100.0 1.32 [ 1.00, 1.72 ]
Total events: 107 (HFOV), 81 (CV)
Test for heterogeneity chi-square=5.11 df=8 p=0.75 I² =0.0%
Test for overall effect z=1.99 p=0.05

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 59
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 05.05. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 05
Intraventricular hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy
Outcome: 05 Intraventricular hemorrhage - grd 3 or 4
Study Treatment Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Definitive LPS on CV
Courtney 2002 45/244 45/254 17.4 1.04 [ 0.72, 1.51 ]

Durand 2001 1/24 4/24 1.6 0.25 [ 0.03, 2.08 ]

Thome 1998 19/140 18/144 7.0 1.09 [ 0.60, 1.98 ]

Van Reempts 2003 14/147 13/153 5.0 1.12 [ 0.55, 2.30 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

Subtotal (95% CI) 575 595 31.9 1.04 [ 0.78, 1.37 ]

Total events: 82 (Treatment), 82 (Control)
Test for heterogeneity chi-square=1.99 df=4 p=0.74 I² =0.0%
Test for overall effect z=0.24 p=0.8

02 Probable LPS on CV
Craft 2003 4/22 5/24 1.9 0.87 [ 0.27, 2.84 ]

Johnson 2002 38/400 55/397 21.8 0.69 [ 0.46, 1.01 ]

Moriette 2001 34/139 19/134 7.7 1.73 [ 1.04, 2.87 ]

Subtotal (95% CI) 561 555 31.4 0.95 [ 0.71, 1.27 ]

Total events: 76 (Treatment), 79 (Control)
Test for heterogeneity chi-square=7.99 df=2 p=0.02 I² =75.0%
Test for overall effect z=0.34 p=0.7

03 Probably no LPS on CV
Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Schreiber 2003 18/102 14/105 5.5 1.32 [ 0.70, 2.52 ]

Subtotal (95% CI) 215 221 7.4 1.46 [ 0.84, 2.53 ]

Total events: 27 (Treatment), 19 (Control)
Test for heterogeneity chi-square=0.95 df=3 p=0.81 I² =0.0%
Test for overall effect z=1.36 p=0.2

04 Definitively no PLS on CV
Clark 1992 7/37 6/28 2.7 0.88 [ 0.33, 2.34 ]

Gerstmann 1996 2/64 6/61 2.4 0.32 [ 0.07, 1.51 ]

0.01 0.1 1 10 100

Favours treatment Favours control (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 60
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study Treatment Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
HIFI 1989 84/327 63/346 24.2 1.41 [ 1.06, 1.88 ]

Subtotal (95% CI) 428 435 29.3 1.27 [ 0.97, 1.67 ]

Total events: 93 (Treatment), 75 (Control)
Test for heterogeneity chi-square=4.06 df=2 p=0.13 I² =50.8%
Test for overall effect z=1.74 p=0.08
Total (95% CI) 1779 1806 100.0 1.11 [ 0.95, 1.30 ]
Total events: 278 (Treatment), 255 (Control)
Test for heterogeneity chi-square=18.15 df=14 p=0.20 I² =22.9%
Test for overall effect z=1.31 p=0.2

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 05.06. Comparison 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy, Outcome 06
Periventricular leukomalacia
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 05 HFOV vs CV subgrouped by lung protective (LPS) CV strategy
Outcome: 06 Periventricular leukomalacia
Study Treatment Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Definitive LPS on cv
Courtney 2002 18/244 26/254 25.5 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.0 1.50 [ 0.27, 8.19 ]

Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Van Reempts 2003 11/147 8/153 7.8 1.43 [ 0.59, 3.46 ]

Vento 2005 1/20 1/20 1.0 1.00 [ 0.07, 14.90 ]

Subtotal (99% CI) 575 595 36.8 1.01 [ 0.57, 1.79 ]

Total events: 36 (Treatment), 37 (Control)
Test for heterogeneity chi-square=3.83 df=4 p=0.43 I² =0.0%
Test for overall effect z=0.04 p=1

02 Probable LPS on CV
Johnson 2002 8/400 8/397 8.0 0.99 [ 0.38, 2.62 ]

Moriette 2001 14/139 18/134 18.3 0.75 [ 0.39, 1.45 ]

Subtotal (99% CI) 539 531 26.4 0.82 [ 0.40, 1.68 ]

Total events: 22 (Treatment), 26 (Control)
Test for heterogeneity chi-square=0.22 df=1 p=0.64 I² =0.0%

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control (Continued . . . )

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 61
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 (. . . Continued)

Study Treatment Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Test for overall effect z=0.70 p=0.5

03 Probably no LPS on CV
Ogawa 1993 1/46 4/46 4.0 0.25 [ 0.03, 2.15 ]

Plavka 1999 2/21 1/20 1.0 1.90 [ 0.19, 19.40 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Schreiber 2003 4/102 4/105 3.9 1.03 [ 0.26, 4.01 ]

Subtotal (99% CI) 215 221 9.4 0.91 [ 0.28, 2.98 ]

Total events: 8 (Treatment), 9 (Control)
Test for heterogeneity chi-square=2.42 df=3 p=0.49 I² =0.0%
Test for overall effect z=0.21 p=0.8

04 Definitively no LPS on CV
Gerstmann 1996 4/64 3/61 3.1 1.27 [ 0.30, 5.45 ]

HIFI 1989 38/327 25/346 24.3 1.61 [ 0.99, 2.60 ]

Subtotal (99% CI) 391 407 27.4 1.57 [ 0.86, 2.86 ]

Total events: 42 (Treatment), 28 (Control)
Test for heterogeneity chi-square=0.09 df=1 p=0.76 I² =0.0%
Test for overall effect z=1.94 p=0.05
Total (99% CI) 1720 1754 100.0 1.10 [ 0.78, 1.55 ]
Total events: 108 (Treatment), 100 (Control)
Test for heterogeneity chi-square=10.38 df=12 p=0.58 I² =0.0%
Test for overall effect z=0.75 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 62
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 06.01. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 01 Death by 36-
37 weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 06 HFOV vs CV subgrouped by age at randomisation
Outcome: 01 Death by 36-37 weeks or discharge
Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI

01 Less than 2 hours

Johnson 2002 100/400 105/397 46.1 0.95 [ 0.75, 1.20 ]

Plavka 1999 2/21 2/20 0.9 0.95 [ 0.15, 6.13 ]

Rettwitz-Volk 1998 5/46 4/50 1.7 1.36 [ 0.39, 4.75 ]

Thome 1998 14/140 15/144 6.5 0.96 [ 0.48, 1.91 ]

Vento 2005 1/20 2/20 0.9 0.50 [ 0.05, 5.08 ]

Subtotal (95% CI) 627 631 56.0 0.95 [ 0.77, 1.18 ]

Total events: 122 (HFOV), 128 (CV)
Test for heterogeneity chi-square=0.61 df=4 p=0.96 I² =0.0%
Test for overall effect z=0.44 p=0.7

02 2 to 6 hours
Courtney 2002 33/244 40/254 17.1 0.86 [ 0.56, 1.32 ]

Durand 2001 5/24 4/24 1.7 1.25 [ 0.38, 4.10 ]

Gerstmann 1996 0/64 2/61 1.1 0.19 [ 0.01, 3.89 ]

Moriette 2001 31/139 27/134 12.0 1.11 [ 0.70, 1.75 ]

Subtotal (95% CI) 471 473 32.0 0.95 [ 0.70, 1.28 ]

Total events: 69 (HFOV), 73 (CV)
Test for heterogeneity chi-square=1.94 df=3 p=0.59 I² =0.0%
Test for overall effect z=0.34 p=0.7

03 Greater than 6 hours

Clark 1992 8/37 6/28 3.0 1.01 [ 0.40, 2.58 ]

Schreiber 2003 18/102 21/105 9.0 0.88 [ 0.50, 1.56 ]

Subtotal (95% CI) 139 133 12.0 0.91 [ 0.56, 1.48 ]

Total events: 26 (HFOV), 27 (CV)
Test for heterogeneity chi-square=0.06 df=1 p=0.81 I² =0.0%
Test for overall effect z=0.36 p=0.7
Total (95% CI) 1237 1237 100.0 0.95 [ 0.80, 1.12 ]
Total events: 217 (HFOV), 228 (CV)
Test for heterogeneity chi-square=2.63 df=10 p=0.99 I² =0.0%
Test for overall effect z=0.64 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 63
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 06.02. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 02 CLD at 36-37
weeks PMA or discharge in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 06 HFOV vs CV subgrouped by age at randomisation
Outcome: 02 CLD at 36-37 weeks PMA or discharge in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Less than 2 hours

Johnson 2002 165/300 163/292 39.4 0.99 [ 0.85, 1.14 ]

Plavka 1999 3/19 8/18 2.0 0.36 [ 0.11, 1.13 ]

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Thome 1998 32/126 30/129 7.1 1.09 [ 0.71, 1.68 ]

Vento 2005 2/19 8/18 2.0 0.24 [ 0.06, 0.97 ]

Subtotal (95% CI) 505 503 50.4 0.95 [ 0.82, 1.09 ]

Total events: 202 (HFOV), 209 (CV)
Test for heterogeneity chi-square=7.17 df=3 p=0.07 I² =58.2%
Test for overall effect z=0.78 p=0.4

02 2 to 6 hours
Courtney 2002 70/201 93/210 21.7 0.79 [ 0.62, 1.00 ]

Durand 2001 5/19 14/20 3.3 0.38 [ 0.17, 0.84 ]

Gerstmann 1996 17/64 27/59 6.7 0.58 [ 0.35, 0.95 ]

Moriette 2001 24/108 30/107 7.2 0.79 [ 0.50, 1.26 ]

Subtotal (95% CI) 392 396 38.8 0.72 [ 0.59, 0.87 ]

Total events: 116 (HFOV), 164 (CV)
Test for heterogeneity chi-square=3.91 df=3 p=0.27 I² =23.3%
Test for overall effect z=3.40 p=0.0007

03 Greater than 6 hours

Clark 1992 3/29 10/22 2.7 0.23 [ 0.07, 0.73 ]

Schreiber 2003 43/84 34/84 8.1 1.26 [ 0.91, 1.76 ]

Subtotal (95% CI) 113 106 10.8 1.00 [ 0.74, 1.37 ]

Total events: 46 (HFOV), 44 (CV)
Test for heterogeneity chi-square=8.07 df=1 p=0.004 I² =87.6%
Test for overall effect z=0.03 p=1
Total (95% CI) 1010 1005 100.0 0.86 [ 0.78, 0.96 ]
Total events: 364 (HFOV), 417 (CV)
Test for heterogeneity chi-square=27.17 df=9 p=0.001 I² =66.9%
Test for overall effect z=2.71 p=0.007

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 64
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 06.03. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 03 Death or
CLD at 36-37 weeks PMA or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 06 HFOV vs CV subgrouped by age at randomisation
Outcome: 03 Death or CLD at 36-37 weeks PMA or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Less than 2 hours

Johnson 2002 265/400 268/397 41.7 0.98 [ 0.89, 1.08 ]

Plavka 1999 5/21 10/20 1.6 0.48 [ 0.20, 1.15 ]

Rettwitz-Volk 1998 5/46 4/50 0.6 1.36 [ 0.39, 4.75 ]

Thome 1998 46/140 45/144 6.9 1.05 [ 0.75, 1.48 ]

Vento 2005 3/20 10/20 1.6 0.30 [ 0.10, 0.93 ]

Subtotal (95% CI) 627 631 52.3 0.96 [ 0.87, 1.06 ]

Total events: 324 (HFOV), 337 (CV)
Test for heterogeneity chi-square=7.26 df=4 p=0.12 I² =44.9%
Test for overall effect z=0.84 p=0.4

02 2-6 hours
Courtney 2002 103/244 133/254 20.2 0.81 [ 0.67, 0.97 ]

Durand 2001 10/24 18/24 2.8 0.56 [ 0.33, 0.94 ]

Gerstmann 1996 17/64 28/61 4.4 0.58 [ 0.35, 0.94 ]

Moriette 2001 55/139 57/134 9.0 0.93 [ 0.70, 1.24 ]

Subtotal (95% CI) 471 473 36.4 0.79 [ 0.68, 0.91 ]

Total events: 185 (HFOV), 236 (CV)
Test for heterogeneity chi-square=4.58 df=3 p=0.21 I² =34.5%
Test for overall effect z=3.22 p=0.001

03 Greater than 6 hours

Clark 1992 11/37 16/28 2.8 0.52 [ 0.29, 0.94 ]

Schreiber 2003 61/102 55/105 8.4 1.14 [ 0.90, 1.45 ]

Subtotal (95% CI) 139 133 11.2 0.99 [ 0.79, 1.23 ]

Total events: 72 (HFOV), 71 (CV)
Test for heterogeneity chi-square=5.92 df=1 p=0.01 I² =83.1%
Test for overall effect z=0.13 p=0.9
Total (95% CI) 1237 1237 100.0 0.90 [ 0.83, 0.97 ]
Total events: 581 (HFOV), 644 (CV)
Test for heterogeneity chi-square=24.58 df=10 p=0.006 I² =59.3%
Test for overall effect z=2.69 p=0.007

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 65
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 06.04. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 04 Gross
pulmonary air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 06 HFOV vs CV subgrouped by age at randomisation
Outcome: 04 Gross pulmonary air leak

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Less than 2 hours

Plavka 1999 1/21 2/20 2.8 0.48 [ 0.05, 4.85 ]

Rettwitz-Volk 1998 3/46 5/50 6.5 0.65 [ 0.17, 2.58 ]

Thome 1998 20/140 11/144 14.6 1.87 [ 0.93, 3.76 ]

Vento 2005 2/20 1/20 1.4 2.00 [ 0.20, 20.33 ]

Subtotal (95% CI) 227 234 25.2 1.41 [ 0.80, 2.48 ]

Total events: 26 (HFOV), 19 (CV)
Test for heterogeneity chi-square=2.77 df=3 p=0.43 I² =0.0%
Test for overall effect z=1.20 p=0.2

02 2 - 6 hours
Courtney 2002 32/244 33/254 43.7 1.01 [ 0.64, 1.59 ]

Moriette 2001 7/139 4/134 5.5 1.69 [ 0.51, 5.63 ]

Subtotal (95% CI) 383 388 49.2 1.09 [ 0.71, 1.66 ]

Total events: 39 (HFOV), 37 (CV)
Test for heterogeneity chi-square=0.61 df=1 p=0.43 I² =0.0%
Test for overall effect z=0.38 p=0.7

03 Greater than 6 hours

Clark 1992 14/37 8/28 12.3 1.32 [ 0.65, 2.71 ]

Schreiber 2003 17/102 10/105 13.3 1.75 [ 0.84, 3.64 ]

Subtotal (95% CI) 139 133 25.6 1.55 [ 0.92, 2.59 ]

Total events: 31 (HFOV), 18 (CV)
Test for heterogeneity chi-square=0.29 df=1 p=0.59 I² =0.0%
Test for overall effect z=1.66 p=0.1
Total (95% CI) 749 755 100.0 1.29 [ 0.97, 1.70 ]
Total events: 96 (HFOV), 74 (CV)
Test for heterogeneity chi-square=4.86 df=7 p=0.68 I² =0.0%
Test for overall effect z=1.74 p=0.08

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 66
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 06.05. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 05
Intraventricular hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 06 HFOV vs CV subgrouped by age at randomisation
Outcome: 05 Intraventricular hemorrhage - grd 3 or 4

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 less than 2 hours

Johnson 2002 38/400 55/397 23.5 0.69 [ 0.46, 1.01 ]

Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Plavka 1999 2/21 2/20 0.9 0.95 [ 0.15, 6.13 ]

Thome 1998 19/140 18/144 7.5 1.09 [ 0.60, 1.98 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

Subtotal (95% CI) 627 627 33.1 0.82 [ 0.60, 1.12 ]

Total events: 64 (HFOV), 78 (CV)
Test for heterogeneity chi-square=2.72 df=4 p=0.61 I² =0.0%
Test for overall effect z=1.24 p=0.2

02 2 - 6 hours
Courtney 2002 45/244 45/254 18.7 1.04 [ 0.72, 1.51 ]

Durand 2001 1/24 4/24 1.7 0.25 [ 0.03, 2.08 ]

Gerstmann 1996 2/64 6/61 2.6 0.32 [ 0.07, 1.51 ]

HIFI 1989 84/327 63/346 26.0 1.41 [ 1.06, 1.88 ]

Moriette 2001 34/139 19/134 8.2 1.73 [ 1.04, 2.87 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Subtotal (95% CI) 844 869 58.1 1.27 [ 1.04, 1.56 ]

Total events: 171 (HFOV), 139 (CV)
Test for heterogeneity chi-square=9.15 df=5 p=0.10 I² =45.4%
Test for overall effect z=2.33 p=0.02

03 Greater than 6 hours

Clark 1992 7/37 6/28 2.9 0.88 [ 0.33, 2.34 ]

Schreiber 2003 18/102 14/105 5.9 1.32 [ 0.70, 2.52 ]

Subtotal (95% CI) 139 133 8.8 1.18 [ 0.69, 2.01 ]

Total events: 25 (HFOV), 20 (CV)
Test for heterogeneity chi-square=0.46 df=1 p=0.50 I² =0.0%
Test for overall effect z=0.60 p=0.5
Total (95% CI) 1610 1629 100.0 1.11 [ 0.95, 1.31 ]
Total events: 260 (HFOV), 237 (CV)
Test for heterogeneity chi-square=17.97 df=12 p=0.12 I² =33.2%
Test for overall effect z=1.32 p=0.2

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 67
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 06.06. Comparison 06 HFOV vs CV subgrouped by age at randomisation, Outcome 06
Periventricular leukomalacia
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 06 HFOV vs CV subgrouped by age at randomisation
Outcome: 06 Periventricular leukomalacia

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Less than 2 hours

Johnson 2002 8/400 8/397 8.7 0.99 [ 0.38, 2.62 ]

Ogawa 1993 1/46 4/46 4.3 0.25 [ 0.03, 2.15 ]

Plavka 1999 2/21 1/20 1.1 1.90 [ 0.19, 19.40 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Vento 2005 1/20 1/20 1.1 1.00 [ 0.07, 14.90 ]

Subtotal (95% CI) 673 677 16.3 1.13 [ 0.57, 2.25 ]

Total events: 16 (HFOV), 14 (CV)
Test for heterogeneity chi-square=4.09 df=5 p=0.54 I² =0.0%
Test for overall effect z=0.36 p=0.7

02 2 - 6 hours
Courtney 2002 18/244 26/254 27.7 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.2 1.50 [ 0.27, 8.19 ]

Gerstmann 1996 4/64 3/61 3.3 1.27 [ 0.30, 5.45 ]

HIFI 1989 38/327 25/346 26.4 1.61 [ 0.99, 2.60 ]

Moriette 2001 14/139 18/134 19.9 0.75 [ 0.39, 1.45 ]

Subtotal (95% CI) 798 819 79.4 1.07 [ 0.79, 1.45 ]

Total events: 77 (HFOV), 74 (CV)
Test for heterogeneity chi-square=5.90 df=4 p=0.21 I² =32.2%
Test for overall effect z=0.42 p=0.7

03 Greater than 6 hours

x Clark 1992 0/1 0/1 0.0 Not estimable

Schreiber 2003 4/102 4/105 4.3 1.03 [ 0.26, 4.01 ]

Subtotal (95% CI) 103 106 4.3 1.03 [ 0.26, 4.01 ]

Total events: 4 (HFOV), 4 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.04 p=1
Total (95% CI) 1574 1602 100.0 1.08 [ 0.82, 1.41 ]
Total events: 97 (HFOV), 92 (CV)
Test for heterogeneity chi-square=9.99 df=11 p=0.53 I² =0.0%
Test for overall effect z=0.53 p=0.6

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 68
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 07.01. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 01 Death by 36-37
weeks or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 07 HFOV vs CV subgrouped by I:E ratio on HFOV
Outcome: 01 Death by 36-37 weeks or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 1:1
Moriette 2001 31/139 27/134 10.9 1.11 [ 0.70, 1.75 ]

Rettwitz-Volk 1998 5/46 4/50 1.5 1.36 [ 0.39, 4.75 ]

Subtotal (95% CI) 185 184 12.5 1.14 [ 0.74, 1.75 ]

Total events: 36 (HFOV), 31 (CV)
Test for heterogeneity chi-square=0.09 df=1 p=0.76 I² =0.0%
Test for overall effect z=0.59 p=0.6

02 1:2
Clark 1992 8/37 6/28 2.7 1.01 [ 0.40, 2.58 ]

Courtney 2002 33/244 40/254 15.6 0.86 [ 0.56, 1.32 ]

Durand 2001 5/24 4/24 1.6 1.25 [ 0.38, 4.10 ]

Gerstmann 1996 0/64 2/61 1.0 0.19 [ 0.01, 3.89 ]

Plavka 1999 2/21 2/20 0.8 0.95 [ 0.15, 6.13 ]

Schreiber 2003 18/102 21/105 8.2 0.88 [ 0.50, 1.56 ]

Subtotal (95% CI) 492 492 30.0 0.88 [ 0.65, 1.19 ]

Total events: 66 (HFOV), 75 (CV)
Test for heterogeneity chi-square=1.42 df=5 p=0.92 I² =0.0%
Test for overall effect z=0.83 p=0.4

03 Range of I:Es or unknown

Craft 2003 3/22 3/24 1.1 1.09 [ 0.25, 4.85 ]

Johnson 2002 100/400 105/397 41.9 0.95 [ 0.75, 1.20 ]

Thome 1998 14/140 15/144 5.9 0.96 [ 0.48, 1.91 ]

Van Reempts 2003 25/147 20/153 7.8 1.30 [ 0.76, 2.24 ]

Vento 2005 1/20 2/20 0.8 0.50 [ 0.05, 5.08 ]

Subtotal (95% CI) 729 738 57.6 0.99 [ 0.81, 1.22 ]

Total events: 143 (HFOV), 145 (CV)
Test for heterogeneity chi-square=1.48 df=4 p=0.83 I² =0.0%
Test for overall effect z=0.08 p=0.9
Total (95% CI) 1406 1414 100.0 0.98 [ 0.83, 1.14 ]
Total events: 245 (HFOV), 251 (CV)
Test for heterogeneity chi-square=3.81 df=12 p=0.99 I² =0.0%
Test for overall effect z=0.30 p=0.8

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 69
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 07.02. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 02 CLD at 36-37
weeks PMA or discharge in survivors
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 07 HFOV vs CV subgrouped by I:E ratio on HFOV
Outcome: 02 CLD at 36-37 weeks PMA or discharge in survivors

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 1:1
Moriette 2001 24/108 30/107 6.7 0.79 [ 0.50, 1.26 ]

x Rettwitz-Volk 1998 0/41 0/46 0.0 Not estimable

Subtotal (99% CI) 149 153 6.7 0.79 [ 0.43, 1.46 ]

Total events: 24 (HFOV), 30 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.98 p=0.3

02 1:2
Clark 1992 3/29 10/22 2.5 0.23 [ 0.07, 0.73 ]

Courtney 2002 70/201 93/210 20.2 0.79 [ 0.62, 1.00 ]

Durand 2001 5/19 14/20 3.0 0.38 [ 0.17, 0.84 ]

Gerstmann 1996 17/64 27/59 6.2 0.58 [ 0.35, 0.95 ]

Plavka 1999 3/19 8/18 1.8 0.36 [ 0.11, 1.13 ]

Schreiber 2003 43/84 34/84 7.6 1.26 [ 0.91, 1.76 ]

Subtotal (99% CI) 416 413 41.4 0.76 [ 0.61, 0.95 ]

Total events: 141 (HFOV), 186 (CV)
Test for heterogeneity chi-square=18.92 df=5 p=0.002 I² =73.6%
Test for overall effect z=3.15 p=0.002

03 Range of I:Es or unknown

Craft 2003 13/19 13/21 2.7 1.11 [ 0.70, 1.74 ]

Johnson 2002 165/300 163/292 36.7 0.99 [ 0.85, 1.14 ]

Thome 1998 32/126 30/129 6.6 1.09 [ 0.71, 1.68 ]

Van Reempts 2003 24/122 19/133 4.0 1.38 [ 0.79, 2.39 ]

Vento 2005 2/19 8/18 1.8 0.24 [ 0.06, 0.97 ]

Subtotal (99% CI) 586 593 51.9 1.01 [ 0.85, 1.20 ]

Total events: 236 (HFOV), 233 (CV)
Test for heterogeneity chi-square=5.68 df=4 p=0.22 I² =29.6%
Test for overall effect z=0.14 p=0.9
Total (99% CI) 1151 1159 100.0 0.89 [ 0.78, 1.02 ]
Total events: 401 (HFOV), 449 (CV)
Test for heterogeneity chi-square=29.88 df=11 p=0.002 I² =63.2%
Test for overall effect z=2.21 p=0.03

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 70
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 07.03. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 03 Death or CLD at
36-37 weeks PMA or discharge
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 07 HFOV vs CV subgrouped by I:E ratio on HFOV
Outcome: 03 Death or CLD at 36-37 weeks PMA or discharge

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 1:1
Moriette 2001 55/139 57/134 8.3 0.93 [ 0.70, 1.24 ]

Rettwitz-Volk 1998 5/46 4/50 0.5 1.36 [ 0.39, 4.75 ]

Subtotal (95% CI) 185 184 8.9 0.96 [ 0.72, 1.26 ]

Total events: 60 (HFOV), 61 (CV)
Test for heterogeneity chi-square=0.34 df=1 p=0.56 I² =0.0%
Test for overall effect z=0.31 p=0.8

02 1:2
Clark 1992 11/37 16/28 2.6 0.52 [ 0.29, 0.94 ]

Courtney 2002 103/244 133/254 18.7 0.81 [ 0.67, 0.97 ]

Durand 2001 10/24 18/24 2.6 0.56 [ 0.33, 0.94 ]

Gerstmann 1996 17/64 28/61 4.1 0.58 [ 0.35, 0.94 ]

Plavka 1999 5/21 10/20 1.5 0.48 [ 0.20, 1.15 ]

Schreiber 2003 61/102 55/105 7.8 1.14 [ 0.90, 1.45 ]

Subtotal (95% CI) 492 492 37.2 0.80 [ 0.70, 0.91 ]

Total events: 207 (HFOV), 260 (CV)
Test for heterogeneity chi-square=15.18 df=5 p=0.010 I² =67.1%
Test for overall effect z=3.30 p=0.001

03 Range of I:Es or unknown

Craft 2003 16/22 16/24 2.2 1.09 [ 0.74, 1.60 ]

Johnson 2002 265/400 268/397 38.5 0.98 [ 0.89, 1.08 ]

Thome 1998 46/140 45/144 6.4 1.05 [ 0.75, 1.48 ]

Van Reempts 2003 49/147 39/153 5.5 1.31 [ 0.92, 1.86 ]

Vento 2005 3/20 10/20 1.4 0.30 [ 0.10, 0.93 ]

Subtotal (95% CI) 729 738 54.0 1.01 [ 0.92, 1.11 ]

Total events: 379 (HFOV), 378 (CV)
Test for heterogeneity chi-square=7.00 df=4 p=0.14 I² =42.8%
Test for overall effect z=0.19 p=0.8
Total (95% CI) 1406 1414 100.0 0.93 [ 0.86, 1.00 ]
Total events: 646 (HFOV), 699 (CV)
Test for heterogeneity chi-square=28.36 df=12 p=0.005 I² =57.7%
Test for overall effect z=2.02 p=0.04

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 71
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 07.04. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 04 Gross pulmonary
air leak
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 07 HFOV vs CV subgrouped by I:E ratio on HFOV
Outcome: 04 Gross pulmonary air leak

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 1:1
Moriette 2001 7/139 4/134 5.0 1.69 [ 0.51, 5.63 ]

Subtotal (95% CI) 139 134 5.0 1.69 [ 0.51, 5.63 ]

Total events: 7 (HFOV), 4 (CV)
Test for heterogeneity: not applicable
Test for overall effect z=0.85 p=0.4

02 1:2
Clark 1992 14/37 8/28 11.3 1.32 [ 0.65, 2.71 ]

Courtney 2002 32/244 33/254 40.0 1.01 [ 0.64, 1.59 ]

Plavka 1999 1/21 2/20 2.5 0.48 [ 0.05, 4.85 ]

Rettwitz-Volk 1998 3/46 5/50 5.9 0.65 [ 0.17, 2.58 ]

Schreiber 2003 17/102 10/105 12.2 1.75 [ 0.84, 3.64 ]

Subtotal (95% CI) 450 457 71.9 1.14 [ 0.82, 1.57 ]

Total events: 67 (HFOV), 58 (CV)
Test for heterogeneity chi-square=2.94 df=4 p=0.57 I² =0.0%
Test for overall effect z=0.77 p=0.4

03 Range of I:Es or unknown

Thome 1998 20/140 11/144 13.4 1.87 [ 0.93, 3.76 ]

Van Reempts 2003 11/147 7/153 8.5 1.64 [ 0.65, 4.10 ]

Vento 2005 2/20 1/20 1.2 2.00 [ 0.20, 20.33 ]

Subtotal (95% CI) 307 317 23.1 1.79 [ 1.04, 3.08 ]

Total events: 33 (HFOV), 19 (CV)
Test for heterogeneity chi-square=0.06 df=2 p=0.97 I² =0.0%
Test for overall effect z=2.11 p=0.03
Total (95% CI) 896 908 100.0 1.32 [ 1.00, 1.72 ]
Total events: 107 (HFOV), 81 (CV)
Test for heterogeneity chi-square=5.11 df=8 p=0.75 I² =0.0%
Test for overall effect z=1.99 p=0.05

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 72
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 07.05. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 05 Intraventricular
hemorrhage - grd 3 or 4
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 07 HFOV vs CV subgrouped by I:E ratio on HFOV
Outcome: 05 Intraventricular hemorrhage - grd 3 or 4

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 1:1
Moriette 2001 34/139 19/134 7.7 1.73 [ 1.04, 2.87 ]

Rettwitz-Volk 1998 5/46 2/50 0.8 2.72 [ 0.55, 13.33 ]

Subtotal (95% CI) 185 184 8.5 1.81 [ 1.12, 2.94 ]

Total events: 39 (HFOV), 21 (CV)
Test for heterogeneity chi-square=0.29 df=1 p=0.59 I² =0.0%
Test for overall effect z=2.41 p=0.02

02 1:2
Clark 1992 7/37 6/28 2.7 0.88 [ 0.33, 2.34 ]

Courtney 2002 45/244 45/254 17.6 1.04 [ 0.72, 1.51 ]

Durand 2001 1/24 4/24 1.6 0.25 [ 0.03, 2.08 ]

Gerstmann 1996 2/64 6/61 2.4 0.32 [ 0.07, 1.51 ]

Schreiber 2003 18/102 14/105 5.5 1.32 [ 0.70, 2.52 ]

Subtotal (95% CI) 471 472 29.8 0.98 [ 0.73, 1.31 ]

Total events: 73 (HFOV), 75 (CV)
Test for heterogeneity chi-square=4.59 df=4 p=0.33 I² =12.8%
Test for overall effect z=0.16 p=0.9

03 Range of I:Es or unknown

Craft 2003 4/22 5/24 1.9 0.87 [ 0.27, 2.84 ]

HIFI 1989 84/327 63/346 24.4 1.41 [ 1.06, 1.88 ]

Johnson 2002 38/400 55/397 22.0 0.69 [ 0.46, 1.01 ]

Ogawa 1993 2/46 1/46 0.4 2.00 [ 0.19, 21.30 ]

Thome 1998 19/140 18/144 7.1 1.09 [ 0.60, 1.98 ]

Van Reempts 2003 14/147 13/153 5.1 1.12 [ 0.55, 2.30 ]

Vento 2005 3/20 2/20 0.8 1.50 [ 0.28, 8.04 ]

Subtotal (95% CI) 1102 1130 61.7 1.08 [ 0.88, 1.32 ]

Total events: 164 (HFOV), 157 (CV)
Test for heterogeneity chi-square=9.04 df=6 p=0.17 I² =33.6%
Test for overall effect z=0.75 p=0.5
Total (95% CI) 1758 1786 100.0 1.11 [ 0.95, 1.30 ]
Total events: 276 (HFOV), 253 (CV)
Test for heterogeneity chi-square=18.12 df=13 p=0.15 I² =28.3%
Test for overall effect z=1.32 p=0.2

0.01 0.1 1 10 100

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 73
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
 Analysis 07.06. Comparison 07 HFOV vs CV subgrouped by I:E ratio on HFOV, Outcome 06 Periventricular
leukomalacia
Review: Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants
Comparison: 07 HFOV vs CV subgrouped by I:E ratio on HFOV
Outcome: 06 Periventricular leukomalacia

Study HFOV CV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 1:1
Moriette 2001 14/139 18/134 18.3 0.75 [ 0.39, 1.45 ]

Rettwitz-Volk 1998 1/46 0/50 0.5 3.26 [ 0.14, 77.97 ]

Subtotal (95% CI) 185 184 18.8 0.81 [ 0.43, 1.54 ]

Total events: 15 (HFOV), 18 (CV)
Test for heterogeneity chi-square=0.79 df=1 p=0.37 I² =0.0%
Test for overall effect z=0.64 p=0.5

02 1:2
Courtney 2002 18/244 26/254 25.5 0.72 [ 0.41, 1.28 ]

Durand 2001 3/24 2/24 2.0 1.50 [ 0.27, 8.19 ]

Gerstmann 1996 4/64 3/61 3.1 1.27 [ 0.30, 5.45 ]

Plavka 1999 2/21 1/20 1.0 1.90 [ 0.19, 19.40 ]

Schreiber 2003 4/102 4/105 3.9 1.03 [ 0.26, 4.01 ]

Subtotal (95% CI) 455 464 35.5 0.88 [ 0.55, 1.40 ]

Total events: 31 (HFOV), 36 (CV)
Test for heterogeneity chi-square=1.56 df=4 p=0.82 I² =0.0%
Test for overall effect z=0.54 p=0.6

03 Range of I:Es or unknown

HIFI 1989 38/327 25/346 24.3 1.61 [ 0.99, 2.60 ]

Johnson 2002 8/400 8/397 8.0 0.99 [ 0.38, 2.62 ]

Ogawa 1993 1/46 4/46 4.0 0.25 [ 0.03, 2.15 ]

Thome 1998 3/140 0/144 0.5 7.20 [ 0.38, 138.10 ]

Van Reempts 2003 11/147 8/153 7.8 1.43 [ 0.59, 3.46 ]

Vento 2005 1/20 1/20 1.0 1.00 [ 0.07, 14.90 ]

Subtotal (95% CI) 1080 1106 45.7 1.40 [ 0.97, 2.01 ]

Total events: 62 (HFOV), 46 (CV)
Test for heterogeneity chi-square=4.50 df=5 p=0.48 I² =0.0%
Test for overall effect z=1.79 p=0.07
Total (95% CI) 1720 1754 100.0 1.10 [ 0.85, 1.43 ]
Total events: 108 (HFOV), 100 (CV)
Test for heterogeneity chi-square=10.38 df=12 p=0.58 I² =0.0%
Test for overall effect z=0.75 p=0.5

0.001 0.01 0.1 1 10 100 1000

Favours HFOV Favours CV

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants 74
(Review)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd