Elective High-frequency Oscillatory Ventilation Versus Conventional
Ventilation in Preterm Infants With Pulmonary Dysfunction: Systematic
Review and Meta-analyses
Tushar Bhuta, FRACP and David J. Henderson-Smart, PhD FRACP
ABSTRACT. Objectives. To systematically review the evidence to determine whether the routine use of high-frequency oscillatory ventilation (HFOV) as compared with conventional ventilation (CV) is beneficial or harm-ful in preterm infants requiring mechanical ventilation for pulmonary failure principally due to respiratory dis-tress syndrome.
Methods. All randomized controlled trials of elective HFOV versus CV in preterm infants<36 weeks’ gesta-tion with respiratory failure mainly attributable to respi-ratory distress syndrome were identified from the liter-ature through a search of MEDLINE, EMBASE, Oxford database of Perinatal trials, and previous reviews includ-ing cross-references and abstracts. Meta-analyses usinclud-ing event rate ratios (ERR), event rate difference, and if sig-nificant, number needed-to-treat were calculated (95% confidence limits were used for all analyses). Two pre-specified subgroup analyses were performed.
Results. Four published trials9,18 –20 were included. Meta-analyses revealed the following ERR (95% confi-dence intervals) for HFOV versus CV: mortality at 28 to 30 days, 1.02 (0.76, 1.39); chronic lung disease (CLD) at 28 days, 0.86 (0.73, 1.01); mortality or CLD, 0.9 (0.80, 1.01); air-leak syndromes, 1.13 (0.97, 1.33); mechanical ventila-tion at 28 days, 1.06 (0.84, 1.33); supplemental oxygen at discharge, 0.59 (0.37, 0.92); intraventricular hemorrhage (IVH) all grades, 1.11 (0.95, 1.29); IVH (grades 3 or 4), 1.32 (1.01, 1.72); and periventricular leukomalacia, 1.39 (0.91, 2.13). In the subgroup of trials in which a high volume strategy (HVS) was used18 –20the ERR for CLD was 0.53 (0.36, 0.78); mortality or CLD, 0.56 (0.40, 0.77); supplemen-tal oxygen at discharge, 0.57 (0.36, 0.92); IVH (all grades), 0.90 (0.61, 1.33); and IVH (grades 3 or 4), 0.84 (0.39, 1.84). Results were similar to these for the trials using surfac-tant.19,20One recent trial suggests that HFOV may reduce the cost of in-hospital care.19
Conclusions. The overall meta-analysis is dominated by the HIFI study,9which was criticized for its method-ology11and surfactant was not used. Subsequent studies, most of which used HVS and/or surfactant, have shown benefits in measures of CLD without an increase in rates of IVH. Caution is warranted in interpreting these results because: 1) the treatment is not blinded and this could affect some outcomes; 2) except for one small trial20 post-neonatal survival, lung function, and neurodevelopment have not been reported from HVS trials; and 3) the ben-efits and disadvantages have not been reported in infants
born at different gestational ages or different birth weights. Importantly, results from groups experienced in the use of HFOV may not be readily generalizable.
Pediatrics 1997;100(5). URL: http://www.pediatrics.org/
cgi/content/full/100/5/e6; meta-analyses, high-frequency ventilation, high-frequency oscillatory ventilation, chronic lung disease, preterm, neonatal ventilation, neo-natal morbidity.
ABBREVIATIONS. CLD, chronic lung disease; RDS, respiratory distress syndrome; CV, conventional ventilation; HFOV, high-frequency oscillatory ventilation; IVH, intraventricular hemor-rhage; MV, mechanical ventilation; ALS, air-leak syndrome; ERR, event rate ratio; ERD, event rate difference; NNT, number needed-to-treat; HVS, high volume strategy; PVL, periventricular leuko-malacia.
A
lthough assisted ventilation has reduced mortality, morbidity with chronic pulmonary disease is a significant problem.1 Chroniclung disease (CLD) develops in 20% to 60% of pre-term infants with respiratory distress syndrome (RDS) due in part to barotrauma from conventional ventilation (CV).1– 4
Animal studies have suggested that the use of high-frequency ventilation is associated with effec-tive gas exchange, less barotrauma, and it may be life saving in situations in which CV has failed.5,6 In
premature baboon models of hyaline membrane dis-ease, high-frequency oscillatory ventilation (HFOV) results in more uniform lung inflation pattern, im-proves oxygenation, and reduces the severity of lung pathology produced by assisted ventilation.7,8
Surprisingly the first multicenter randomized trial of HFOV versus CV by the HIFI Study Group9failed
to show any benefit in decreasing the frequency of CLD. On the contrary, it showed an increased inci-dence of intraventricular hemorrhage (IVH) and neu-rodevelopmental abnormalities at follow-up.10There
were criticisms of the trial methodology particularly regarding the large intercenter variability in out-comes and the failure to use measures to recruit and maintain lung volumes.11Since the HIFI study,9other
randomized trials have been conducted in the face of changing perinatal practice such as introduction of surfactant replacement therapy and increasing use of antenatal corticosteroids. In view of the small num-ber of patients in the recent trials, it was felt appro-priate to do a systematic review and a meta-analysis of the results of all these trials.
From the NSW Center for Perinatal Health Services Research at the Uni-versity of Sydney and Department of Neonatal Medicine Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Received for publication Jan 24, 1997; accepted Apr 11, 1997. No reprints available.
METHODS
All randomized studies were sought with the use of the MED-LINE bibliographic retrieval system (National Library of Medi-cine) by means of the MeSH (medical subject heading thesaurus) terms “high frequency ventilation,” and “high frequency oscilla-tory ventilation” from the years 1980 to 1995. The initial search was performed in June 1995 and updated in October 1996. The EMBASE database was also searched under the same terms from the years 1989 to 1996. Further studies identified in reference lists of publications noted above and in a review article were also included. The Oxford database of perinatal trials was also searched and trials identified by the Neonatal Review Group of Cochrane Collaboration were available. Information was also ob-tained from experts in the field. Expert informant searches were carried out in the Japanese language by Professor Ogawa.
Because it has been shown in the laboratory that there is diffi-culty in achieving alveolar expansion after exposure to CV12it was
decided to include only studies that randomized patients to HFOV early and electively rather than as rescue therapy. To be included in the review trials had to meet each of the following additional six criteria: 1) published randomized controlled study; 2) study in-fants had to be,36 weeks’ gestational age, or with a birth weight
,2 kg; 3) ventilated for pulmonary dysfunction principally due to RDS; 4) electively randomized in the first 24 hours of life; 5) the intervention was HFOV; and 6) no mandatory crossover.
The outcomes examined included: mortality at 28 to 30 days, CLD, which was defined as oxygen dependency at 28 to 30 days with chest radiography changes, supplemental oxygen at dis-charge, oxygen at 36 or 37 weeks’ postconceptual age, mechanical ventilation (MV) at 28 to 30 days, air-leak syndrome (ALS) (pneu-mothorax, pulmonary interstitial emphysema, and so forth), all grades of IVH, IVH grades 3 or 4,13and periventricular
leukoma-lacia (PVL). Also reviewed were long-term pulmonary and neu-rodevelopmental follow-up outcomes.
This review used the guidelines of the Cochrane Collaboration as outlined in the Cochrane Library14and in the text Effective Care
of the Newborn Infant.15An earlier version has been published as a
Cochrane review.16The data were extracted separately by each
author and then compared. Meta-analyses using event rate ratios (ERR), event rate difference (ERD), and if significant, number needed-to-treat (NNT) were calculated (95% confidence limits were used for all analyses). The data were synthesized using Meta-Analyzer, version 1.2 (Update Software Ltd, Oxford, England).
For these analyses the authors chose to base validity assessment on four methodologic criteria that can be associated with signifi-cant bias in trials assessing treatment effect17 and these were
evaluated separately by each author. These included concealment at randomization, blinding of treatment, blinding of outcome as-sessment, and completeness of follow-up. No scoring system is incorporated in this particular method of evaluation. The final assessment of the validity of the studies included is therefore left to the individual reader.
Two subgroup analyses were determined a priori and indepen-dently confirmed as relevant by a group of four neonatologists. The first subgroup analysis was based on whether a high volume strategy (HVS) was used in the HFOV ventilated group. To be included in this subgroup, trials needed to fulfill two of the following three criteria with which patients in the HFOV group were ventilated after randomization. The three criteria were: ven-tilation with mean airway pressures more than those of CV after randomization, adequate alveolar recruitment maneuvers (sighs, bagging, or increasing mean arterial pressure briefly), and wean-ing of fractional inspired oxygen before mean airway pressures. The second subgroup analysis was based on whether surfactant replacement therapy was used in all patients with RDS.
Additional information was obtained from Clark et al18
regard-ing the outcome of infants excluded after randomization and this allowed intention-to-treat analyses. Gerstmann et al19provided
additional information regarding methodology in their trial.
RESULTS
Eight randomized controlled trials were found in the search.9,18 –24 Four met the inclusion criteria and
were published in full.9,18 –20There were two recently
presented abstracts23,24that were not included in the
meta-analyses because it was not possible to assess the methodology and the outcomes according to the a priori protocol. The HIFO study21 was excluded
from the analysis because HFOV was used for rescue rather than electively. The study by Ramanathan et al22 published as an abstract was also excluded
be-cause there was a mandatory crossover from HFOV to CV at 96 hours of age. Three trials were deemed as having used HVS based on predetermined condi-tions.18 –20The HIFI study9did not meet the criteria to
be included in the subgroup analysis of HVS. No subgroup analysis by gestational age or birth weight, except for some pulmonary outcomes, was possible because only one trial published stratified out-comes.19 Characteristics of the trials included in the
review are shown in Table 1. The important meth-odologies used in each trial are summarized in Table 2.
Neonatal Mortality
There was no significant difference in neonatal mortality in any individual trial or in the overall analysis (Table 3). Subgroup analysis also failed to show any difference in mortality (see Tables 9 and 10).
Pulmonary ALS
There were no significant differences in incidence of ALS in individual trials or the overall analysis (Table 4). In the subgroup analysis of trials using a HVS the incidence of ALS was similar in the two treatment groups (see Table 9). In the subgroup anal-ysis of trials in which surfactant was used there was a trend towards a reduced incidence of ALS in pa-tients randomized to HFOV (see Table 10).
CLD
In all but one trial9and in the overall analysis, the
trend is towards a reduced incidence of CLD at 28 to 30 days of age that was not significant (Table 5). In the subgroup in which HVS was used there was a significant reduction in risk of CLD at 28 to 30 days [ERR, 0.53 (0.36, 0.78), NNT, 7 (4, 24) (see Table 9)]. This result suggests that, on average, for every seven infants treated, one case of CLD at 28 to 30 days would be prevented. In the subgroup with surfactant replacement therapy there is a similar significant reduction in CLD at 28 to 30 days in the HFOV group [ERR, 0.60 (0.37, 0.96); see Table 10].
In the overall analysis there is a trend towards a reduced risk of death or CLD in the HFOV group (Table 6). In the subgroup analysis of trials using HVS for HFOV death or CLD is significantly reduced in the HFOV-treated infants [ERR, 0.56 (0.40, 0.77), NNT, 6 (4, 15); see Table 9] and there is a similar effect in the subgroup in which surfactant was used [ERR, 0.54 (0.33, 0.87); see Table 10].
Oxygen use at 36-weeks’ postconceptual age in survivors to discharge was a documented outcome in only one of the studies and was reduced in the HFOV group [3/24 vs 10/22; ERR, 0.38; (0.16, 0.86)].18Oxygen therapy at discharge is documented
in two studies.18,19In the study by Clark et al18none
group required supplemental oxygen at discharge [ERR, 0.23 (0.01, 5.06)]. In the trial by Gerstmann et al1917 of 63 in the HFOV group and 27 of 59 in the
CV group required supplemental oxygen at dis-charge. The ERR of the combined data18,19 is 0.58
(0.36, 0.92); NNT, 8 (4, 77). Use of MV
The use of MV at or beyond 28 days was reported in three studies.9,19,20 In the HIFI study9 there is no
difference in the rate of MV at 28 days [HFOV 87/327 vs CV 85/346 all infants; ERR, 1.08 (0.8, 1.46)]. Ogawa et al20reported that 13 out of 46 in the HFOV
group and 9 out of 45 in the CV group who survived to 28 days, were still on MV (ERR, 1.41; 0.6, 3.31). Gerstmann et al19 reported this outcome and found
that 9 out of 64 in the HFOV group and 12 out of 59 survivors in the CV group were on MV beyond 28
days (ERR, 0.69; 0.29, 1.64). The pooled ERR was 1.06 (0.85, 1.34). In the trial by Gerstmann et al19 the
median (95% confidence interval) days on MV in those with a birth weight less than 1 kg is 24.7 (3.7, 61.4) in the HFOV group and 53.7 (28.4, 103) in the CV group, which is not significantly different. In this trial there are also similar median durations of MV in infants with birth weights more than 1 kg [(HFOV group, 4.1 (1.7, 6) vs CV group, 4.5 (3, 6.1)]. Clark et al18reported median and wide ranges for the days on
MV for all infants entered in the study that was not significantly different between the HFOV group (16; 1.8, 67) and the CV group (30.3; 0.5, 222).
Long-term Pulmonary Outcomes
Follow-up assessments (in 82% of survivors), in-cluding pulmonary function tests (in 43% of survi-vors) were carried out at 9 months corrected age on TABLE 1. Characteristics of Trials Included in the Review
Author Year Ref. No.
Patient Characteristic
No in Analysis Age at Randomization
Experimental Method Control Method Surfactant Replacement Experimental Control
HIFI study 1989 9 RDS,,24 h 327 346 664 h Hummingbird, 15 Hz CV, 0.3–1.0 IT No mean GA
28 w
MAP same or below CV 40–60/min
750–2000 g Clark,
et al*
1992 18 RDS,,24 h 30 26 965 h Sensormedics 3100 CV, 0.3–0.6 IT No mean GA
28 w
MAP 1–2 cms.CV, 10 Hz
25–40/min
,36 w,
,1751 g
(HVS), IT 0.33 (1:2)
Ogawa, et al
1993 20 RDS,,24 h 46 46 261.6h Hummingbird, 15 Hz CV, 0.3–1.0 IT Yes mean GA
29 w
MAP 1–2 cms.CV (HVS)
40–60/min
750–2000 g Gerstmann,
et al
1996 19 RDS,,12 h mean GA 30 w
,35 w,
,1751 g
64 61 2.9 (2.4, 3.3) (hrs)
Sensormedics 3100A, 10–15 Hz
MAP 1–2 cms.CV, (HVS), IT 0.33
CV, 0.35–0.55 IT 60/min
Yes
Abbreviations: HVS, high volume strategy; RDS, respiratory distress syndrome; MAP, mean airway pressure; CV, conventional venti-lation; HFOV, high frequency oscilventi-lation; GA, gestational age; w, week; IT, inspiratory time; PEEP, positive end expiratory pressure, Hz, hertz, h, hours.
* The middle arm of the trial had a mandatory crossover after 72 hours from HFOV to CV and thus was excluded from the meta-analysis.
TABLE 2. Validity Assessment of Randomized Trials Author Year Blinding of
Randomization
Blinding of Intervention
All Subjects Analyzed
Blinding of Observer to Outcomes
Chest X-ray Head Ultrasound
HIFI group 1989 Random (envelopes) No Yes No Yes
Clark, et al 1992 Random (cards) No Yes Yes Yes
Ogawa, et al 1993 Random (cards) No Yes Yes Yes
Gerstmann, et al 1996 Random (envelopes) No Yes No No
TABLE 3. The Effect of Elective High-frequency Oscillatory Ventilation on Mortality at 28 to 30 Days
Trials Event Rate Ratios
Experiment Observed
Experiment Total
Control Observed
Control Total
Event Rate Ratio (95% CI)
infants who were in the HIFI trial.25 There were no
significant differences in the rate of growth, inci-dence of respiratory tract infections, hospital read-mission, retractions and episodes of wheezing, or in respiratory function tests. Twelve month follow-up of patients in the trial by Ogawa et al20 showed
persistence of abnormal fibrous or emphysematous shadows on chest radiography in 2 of the infants in the HFOV group and 4 in the CV group.
IVH
In the overall analysis there is a trend towards increased risk of IVH of all grades in those treated with HFOV, which was not statistically significant (Table 7). This trend was not evident in the sub-groups in which HVS or surfactant were used (Ta-bles 9 and 10). The rates of more severe IVH (grades 3 or 4) are increased in the HIFI study9and there is a
similar effect in the overall analysis, which is
statis-tically significant [ERR, 1.32 (1.01, 1.72), NNT, 35, (14, 84) Table 8]. In the subgroup analysis of infants treated with surfactant and those in which a HVS was used for HFOV, there is a nonsignificant trend towards lower rates of grades 3 or 4 IVH in the HFOV-treated infants (Table 9 and Table 10). PVL
PVL was reported in four of the five studies and there is a nonsignificant trend towards an increased rate in the HIFI study9 and in the overall analysis
[43/429 vs 32/447, ERR, 1.39 (0.91, 2.13), ERD, 2.32 (21.41, 5.87)]. There is no such trend in the subgroup analyses of patients in which the HVS strategy was used or in those with surfactant treatment.
Neurodevelopmental Outcomes at Follow-Up
Neurodevelopmental status was assessed at 16 to 24 months corrected age in 77% of survivors of the TABLE 4. The Effect of Elective High-frequency Oscillatory Ventilation on Air Leak Syndromes
Trials Event Rate Ratios
Experiment Observed
Experiment Total
Control Observed
Control Total
Event Rate Ratio (95% CI)
Event Rate Difference (95% CI) HIFI study 1989 148 327 131 346 1.20 (0.94, 1.51) 7.40 (20.03, 14.83) Clark, et al 1992 24 37 16 28 1.14 (0.60, 2.14) 7.72 (216.21, 31.65) Ogawa, et al 1993 4 46 6 46 0.67 (0.19, 2.36) 24.35 (217.04, 8.34) Gerstmann, et al 1996 8 64 11 61 0.24 (0.01, 5.28) 25.53 (218.13, 7.07) Pooled 184 474 164 481 1.13 (0.97, 1.33) 2.64 (22.91, 8.20)
TABLE 5. The Effect of Elective High-Frequency Oscillatory Ventilation on Chronic Lung Disease at 28 to 30 days
Trials Event Rate Ratios
Experiment Observed
Experiment Total
Control Observed
Control Total
Event Rate Ratio (95% CI)
Event Rate Difference (95% CI) HIFI study 1989 130 327 141 346 0.98 (0.77, 1.24) 21.00 (28.41, 6.42) Clark, et al 1992 10 37 17 28 0.50 (0.20, 0.97) 233.69 (256.75,210.62) Ogawa, et al 1993 4 46 6 46 0.67 (0.19, 2.36) 24.35 (217.04, 8.34) Gerstmann, et al 1996 15 64 25 61 0.57 (0.30, 1.08) 217.55 (233.47,21.42) Pooled 159 474 189 481 0.86 (0.73, 1.01) 25.84 (211.60, 0.08)
TABLE 6. The Effect of Elective High-Frequency Oscillatory Ventilation on Death or Chronic Lung Disease
Trials Event Rate Ratios
Experiment Observed
Experiment Total
Control Observed
Control Total
Event Rate Ratio (95% CI)
Event Rate Difference (95% CI)
HIFI study 1989 190 327 201 346 1.00 (0.82, 1.22) 0.01 (27.47, 7.47) Clark, et al 1992 17 37 22 28 0.58 (0.31, 1.10) 26.19 (212.01,20.38) Ogawa, et al 1993 4 46 7 46 0.57 (0.17, 1.95) 26.52 (219.71, 6.67) Gerstmann, et al 1996 15 64 27 61 0.53 (0.28, 1.00) 220.82 (237.04,24.61) Pooled 226 474 257 481 0.90 (0.80, 1.01) 26.19 (212.01,20.38)
TABLE 7. The Effect of Elective High-Frequency Oscillatory Ventilation on Intraventricular Hemorrhage (all grades)
Trials Event Rate Ratios
Experiment Observed
Experiment Total
Control Observed
Control Total
Event Rate Ratio (95% CI)
Event Rate Difference (95% CI)
HIFI study trial9 (HFOV, 185 and CV, 201) using
Bayley’s psychometric evaluations and central ner-vous system examinations.10 Cerebral palsy was
di-agnosed in 10% of HFOV-treated infants and 11% in CV infants. A significantly higher incidence of hy-drocephalus (12% vs 6%) was present in the HFOV group. The overall proportion of children with ab-normal neurodevelopmental status was significantly higher in the HFOV group (65% vs 54%). The authors concluded that there were more neurologic deficits related to higher proportion of survivors with major IVH in the HFOV group.
One year follow-up in the trial by Ogawa et al20
found 4 infants in each group (8.7% vs 9%) had delays in motor and/or mental development, al-though the method of neurologic assessment was not given. No follow-up results have been reported for the other trials.
Total Hospital Costs
The total hospital costs from a subgroup of pa-tients from one center in the trial by Gerstmann et al19suggests that the median hospital costs were less
in the group of patients randomized to HFOV. How-ever, there was no reduction in the length of hospital stay.
DISCUSSION
The methods used in this review were those rec-ommended by the Cochrane Collaboration.14 The
main strength of this approach is that it endeavors to minimize bias by the use of rigorous methodology. This includes a priori setting up a protocol for the review that explicitly states the objectives, the criteria for considering studies for inclusion and exclusion, the search strategy, which is as comprehensive as possible, and the standards for assessing trial quality TABLE 8. The Effect of Elective High-Frequency Oscillatory Ventilation on Intraventricular Hemorrhage (Grades 3 or 4)
Trials Event Rate Ratios
Experiment Observed
Experiment Total
Control Observed
Control Total
Event Rate Ratio (95% CI)
Event Rate Difference (95% CI)
Number Needed to Treat HIFI study 1989 84 327 63 346 1.41 (1.02, 1.96) 7.48 (1.24, 13.72)
Clark, et al 1992 7 37 6 28 0.88 (0.30, 2.63) 22.51 (222.26, 17.25) Ogawa, et al 1993 2 46 1 46 2.00 (0.18, 22.06) 2.17 (25.07, 9.42) Gerstmann, et al 1996 2 56 6 55 0.33 (0.07, 1.62) 23.70 (212.11, 4.71)
Pooled 95 466 82 475 1.32 (1.01, 1.72) 2.84 (21.19, 6.88) 35 (14, 84)
TABLE 9. Analysis of Infants Treated With High Volume Strategy18 –20
Outcomes No. of Patients Pooled Event Rate Ratio 95% CI
Pooled Event Rate Difference 95% CI
Number Needed to Treat 95%
CI Treated Control
Neonatal mortality 7/147 8/135 0.80 (0.32, 2.02) 21.72 (25.24, 1.80)
Chronic lung disease 29/147 48/135 0.53 (0.36, 0.78) 213.22 (222.37,24.07) 7 (4, 24) Mortality or chronic lung disease 36/147 56/135 0.56 (0.40, 0.77) 215.82 (225.11,26.53) 6 (4, 15) Air leak syndrome 36/147 32/135 0.92 (0.63, 1.32) 23.39 (211.77, 4.98)
Mechanical Ventilation at 28
days19,20 18/57 16/52 0.95 (0.58, 1.57) 28.14 (223.17, 6.90)
O2therapy at discharge18,19 17/86 29/80 0.57 (0.36, 0.92) 212.00 (222.70,21.29) 8 (4, 77)
Intraventricular hemorrhage (all grades)
36/139 35/129 0.90 (0.61, 1.33) 22.18 (214.96, 10.61)
Intraventricular hemorrhage (grades 3 or 4)
11/139 11/129 0.84 (0.39, 1.84) 20.49 (25.77, 4.80)
Periventricular leukomalacia19,20 5/102 7/101 0.73 (0.26, 2.04) 22.35 (28.79, 4.08)
TABLE 10. Analysis of Infants Treated With Surfactant19,20
Outcomes No. of Patients Pooled Event R ate Ratio 95% CI
Pooled Event Rate Difference 95% CI
Number Needed to
Treat Treated Control
Neonatal mortality 0/110 3/107 0.42 (0.08, 2.28) 21.82 (25.40, 1.76)
Chronic lung disease 19/110 31/107 0.60 (0.37, 0.96) 29.40 (219.37, 0.58) 10 (5, 172) Mortality or chronic lung disease 19/110 33/107 0.54 (0.33, 0.87) 212.22 (222.45,21.98) 8 (4, 50) Air leak syndrome 12/110 17/107 0.69 (0.36, 1.35) 24.94 (213.89, 4.00)
Mechanical ventilation at 28 to 30 days
18/57 16/52 0.95 (0.57, 1.59) 28.14 (223.17, 6.90)
O2therapy at discharge19 17/63 27/59 0.60 (0.37, 0.97) 218.78 (235.56,21.99) 5 (2, 50)
Intraventricular hemorrhage (all grades)
20/102 22/101 0.81 (0.47, 1.40) 23.00 (213.60, 7.60)
Intraventricular hemorrhage (grades 3 or 4)
4/102 7/101 0.59 (0.20, 1.77) 21.29 (27.07, 4.48)
and for data extraction and analysis. If subgroup analysis is planned, the criteria are established before the search or data analysis, in keeping with the initial objectives of the review. Reviewer bias is minimized by independent assessment of trials for quality and independent data extraction by at least two authors. In this review, the search revealed eight possible trials, four of which were published in full and the others were in various stages of publication. Addi-tional information was obtained from Clark et al18
and Gerstmann et al19 to complete missing
informa-tion about methodology or results. Wherever possi-ble raw data was reanalyzed on an intention-to-treat basis.18 It is possible that there are other trials that
had not been published or published in a language not covered by this systematic review.
Four of the trials were included for analysis be-cause they met the prespecified criteria. The range of gestational ages and birth weights of infants enrolled in the trials was large. Although some authors strat-ified by weight or gestation at randomization, little data has been published by these strata. The four trials excluded were the HIFO study,21 which was
mainly designed to detect the difference in the rate of ALS rather than mortality and morbidity. Further-more, this study randomized infants with more se-vere RDS and at a later age (mean 21 hours). This was considered to be primarily a rescue rather than an elective use of HFOV. The other three studies were by Ramanathan et al,22 Rettwitz-Volk et al,23
and Lambert et al.24 The study by Ramanathan was
excluded from the main analysis because there was a mandatory crossover from HFOV to CV at 96 hours of age. This was felt to impair the ability to evaluate respiratory outcomes in the same way as assessed by the other studies in which crossover was allowed but not mandatory. Nevertheless, because IVH is pri-marily a disorder occurring in the first few days of life, this outcome is still of interest and is discussed below. The results of trials by Rettwitz-Volk23and by
Lambert et al24were excluded from the meta-analysis
because they had not been peer reviewed and it was difficult to assess the methodology and outcomes from the abstracts.
Pulmonary Outcomes
In the overall analysis of studies in which HFOV was used electively, there is no evidence to suggest that this form of therapy affects the incidence of air-leak syndrome. In the overall analysis, there is also no evidence for a reduction in short-term mea-sures for CLD (oxygen dependency and an abnormal radiograph at 28 to 30 days); however, this result is dominated by the HIFI study,9which is the largest.
After the completion of this study, it was criticized because the methodology used to apply HFOV did not include methods to recruit lung volume.11 This
criticism is supported by the results of subsequent trials that used a HVS in which there is a significant reduction in this measure of CLD. Furthermore, two of the trials found reductions in longer term oxygen requirements at 36 weeks18 or at discharge.18,19This
was the main reason for introducing HFOV for the treatment of RDS and the finding is supported by
animal studies reporting the reduction in lung injury with this form of treatment. The number of patients receiving more than one dose of surfactant was also lower in the HFOV group in the study by Gerstmann et al.19 This trial was also the only trial to show a
reduction in the total costs in the HFOV group, the reasons were thought to be attributable to patients needing lower degrees of support, exhibiting stabil-ity earlier in the hospital course, and having fewer critical setbacks. This data however was only from one of the centers of this multicenter trial. The total number of hospital days was not significantly differ-ent in the two groups. In the excluded abstract by Lambert et al24there was no significant difference in
the incidence of CLD.
Neurodevelopmental Outcomes
A major concern, which first arose with the HIFI study,9was the increased rates of acute and chronic
neurologic injury that seemed to be associated with HFOV. This has been measured in the neonatal pe-riod by assessing rates of IVH and PVL and at neu-rodevelopment follow-up within the first 3 years of life.
Adverse neurologic outcomes have not appeared in all trials. The increased rates of all IVH in the large HIFI study9contributes to the nonsignificant trends
in these outcomes in the overall meta-analysis. In the excluded trial by the HIFO study group,2181 infants
randomized to initial HFOV treatment and 84 infants randomized to CV had preentry and postentry ultra-sounds. At study entry, 10 patients in each group had grade 1 or 2 IVH. After study entry, the inci-dence of all grades of IVH was greater in the HFOV group (29/81, 36%) than in the CV group (17/84, 20%; P5.037). The number of infants for each group with grade 3 or 4 IVH was also higher in the HFOV group (HFOV, 6 vs CV, 2; P5.041). This latter result was no longer significant when confounding factors such as birth weight were controlled for in the logis-tic regression. In the abstracts reporting the trials by Ramanathan et al,22Rettwitz-Volk,23and Lambert et
al24, no difference in the rates of grade 3 or 4 IVH was
found.
The authors of the HIFI study9suggested that the
nearly constant mean airway pressure during HFOV might restrict venous return, increase intracranial venous pressure, and decrease cerebral blood flow. However, animal studies,26 and a recent human
study,27failed to show these changes. Failure to use
lung volume recruitment and the consequent cardio-respiratory instability were thought to be other mechanisms implicated.11A recent publication of
an-other high-frequency mode, namely jet ventilation, found an increased incidence of cystic PVL with the ventilatory strategy used in that study.28 Another
recent meta-analysis of IVH and high-frequency ven-tilation in which two different modes of high-fre-quency ventilation (HFOV and high-frehigh-fre-quency jet ventilation) were combined showed a nonsignificant trend towards increase in IVH but a significant in-crease in PVL if the HIFI study9was included.29
the time, the HIFI study9demonstrated how narrow
the risk benefit can be with this technique. This ad-verse outcome is not apparent in the subgroup anal-ysis of trials in which HVS was used with or without surfactant. Other factors such as improved overall neonatal care, increased use of antenatal corticoste-roids (19% CV vs 30% HFOV in the trial by Gerst-mann et al19and 64% CV vs 78% HFOV in the trial by
Rettwitz-Volk et al23), and increased experience with
HFOV may also have contributed. Thus, it would be very important to have long-term outcome data from the trials that have used HVS to establish beyond doubt that it is safe to use HFOV electively in pre-term infants with RDS.
Implications for Clinical Practice
The results of this review and the meta-analyses of elective HFOV in preterm infants with RDS suggest that there is some evidence of benefit in terms of decreased incidence of CLD at 28 to 30 days (a short-term pulmonary outcome), supplemental oxygen at discharge and CLD or mortality in a subgroup of infants who were ventilated with the HVS with or without surfactant. However, caution is warranted interpreting this result because: 1) the treatment is not blinded and this could affect assessment of some outcomes; 2) except for one small trial20postneonatal
survival, lung function, and neurodevelopment have not been reported from HVS trials; 3) the benefits and disadvantages have not been reported in infants born at different gestational ages or of different birth weights. Importantly, results from groups experi-enced in the use of HFOV may not be generalizable. Implications for Research
Future studies need to target infants most at risk of developing CLD. Stratification by gestational age, birth weight, and severity of disease would be im-portant. There is a need for more data on the opti-mum strategy for safely ventilating neonates with HFOV. The economic implications along with impor-tant long-term pulmonary and neurodevelopmental outcomes, are also important issues that need to be addressed.
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DOI: 10.1542/peds.100.5.e6
1997;100;e6
Pediatrics
Tushar Bhuta and David J. Henderson-Smart
Meta-analyses
in Preterm Infants With Pulmonary Dysfunction: Systematic Review and
Elective High-frequency Oscillatory Ventilation Versus Conventional Ventilation
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DOI: 10.1542/peds.100.5.e6
1997;100;e6
Pediatrics
Tushar Bhuta and David J. Henderson-Smart
Meta-analyses
in Preterm Infants With Pulmonary Dysfunction: Systematic Review and
Elective High-frequency Oscillatory Ventilation Versus Conventional Ventilation
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