PEDIATRICS Vol. 100 No. 5 November 1997, p. e6 Copyright © by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Elective High-frequency Oscillatory Ventilation Versus
Conventional Ventilation in Preterm Infants With Pulmonary Dysfunction:
Systematic Review and Meta-analyses
From the NSW Center for Perinatal Health Services Research at the University of Sydney and Department of Neonatal Medicine Royal Prince Alfred Hospital, Sydney, NSW, Australia.
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 harmful in preterm infants requiring mechanical ventilation for pulmonary failure principally due to respiratory distress syndrome.
Methods. All randomized controlled trials of elective HFOV versus CV in preterm infants <36 weeks' gestation with respiratory failure mainly attributable to respiratory distress syndrome were identified from the literature through a search of MEDLINE, EMBASE, Oxford database of Perinatal trials, and previous reviews including cross-references and abstracts. Meta-analyses using event rate ratios (ERR), event rate difference, and if significant, number needed-to-treat were calculated (95% confidence limits were used for all analyses). Two prespecified subgroup analyses were performed.
Results. Four published trials9,18 were included. Meta-analyses revealed the following ERR (95% confidence 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 ventilation 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 the ERR for CLD was 0.53 (0.36, 0.78); mortality or CLD, 0.56 (0.40, 0.77); supplemental 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 surfactant.19,20 One 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,9 which was criticized for its methodology11 and 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 postneonatal survival, lung function, and neurodevelopment have not been reported from HVS trials; and 3) the benefits 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.
Key words: meta-analyses, high-frequency ventilation, high-frequency oscillatory ventilation, chronic lung disease, preterm, neonatal ventilation, neonatal morbidity.Although assisted ventilation has reduced mortality, morbidity with chronic pulmonary disease is a significant problem.1 Chronic lung disease (CLD) develops in 20% to 60% of preterm infants with respiratory distress syndrome (RDS) due in part to barotrauma from conventional ventilation (CV).1
Animal studies have suggested that the use of high-frequency ventilation is associated with effective 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 disease, high-frequency oscillatory ventilation (HFOV) results in more uniform lung inflation pattern, improves 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 Group9 failed to show any benefit in decreasing the frequency of CLD. On the contrary, it showed an increased incidence of intraventricular hemorrhage (IVH) and neurodevelopmental abnormalities at follow-up.10 There were criticisms of the trial methodology particularly regarding the large intercenter variability in outcomes and the failure to use measures to recruit and maintain lung volumes.11 Since the HIFI study,9 other 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 number of patients in the recent trials, it was felt appropriate to do a systematic review and a meta-analysis of the results of all these trials.
All randomized studies were sought with the use of the MEDLINE bibliographic retrieval system (National Library of Medicine) by means of the MeSH (medical subject heading thesaurus) terms "high frequency ventilation," and "high frequency oscillatory 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 obtained from experts in the field. Expert informant searches were carried out in the Japanese language by Professor Ogawa.
Eight randomized controlled trials were found in the search.9,18 Four met the inclusion criteria and were published in full.9,18 There were two recently presented abstracts23,24 that 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 because 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 conditions.18 The HIFI study9 did 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 outcomes.19 Characteristics of the trials included in the review are shown in Table 1. The important methodologies used in each trial are summarized in Table 2.
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Table 1. Characteristics of Trials Included in the Review |
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Table 2. Validity Assessment of Randomized Trials |
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).|
Table 3. The Effect of Elective High-frequency Oscillatory Ventilation on Mortality at 28 to 30 Days |
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Table 9. Analysis of Infants Treated With High Volume Strategy18 |
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Table 10. Analysis of Infants Treated With Surfactant19,20 |
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 analysis of trials in which surfactant was used there was a trend towards a reduced incidence of ALS in patients randomized to HFOV (see Table 10).|
Table 4. The Effect of Elective High-frequency Oscillatory Ventilation on Air Leak Syndromes |
CLD
In all but one trial9 and 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].|
Table 5. The Effect of Elective High-Frequency Oscillatory Ventilation on Chronic Lung Disease at 28 to 30 days |
Table 6.
The Effect of Elective High-Frequency Oscillatory Ventilation on Death
or Chronic Lung Disease
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 al20 reported 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 al18 reported 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), including pulmonary function tests (in 43% of survivors) were carried out at 9 months corrected age on infants who were in the HIFI trial.25 There were no significant differences in the rate of growth, incidence of respiratory tract infections, hospital readmission, 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 subgroups in which HVS or surfactant were used (Tables 9 and 10). The rates of more severe IVH (grades 3 or 4) are increased in the HIFI study9 and there is a similar effect in the overall analysis, which is statistically 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).|
Table 7. The Effect of Elective High-Frequency Oscillatory Ventilation on Intraventricular Hemorrhage (all grades) |
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Table 8. The Effect of Elective High-Frequency Oscillatory Ventilation on Intraventricular Hemorrhage (Grades 3 or 4) |
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 (
1.41, 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 HIFI study trial9 (HFOV, 185 and CV, 201) using Bayley's psychometric evaluations and central nervous system examinations.10 Cerebral palsy was diagnosed in 10% of HFOV-treated infants and 11% in CV infants. A significantly higher incidence of hydrocephalus (12% vs 6%) was present in the HFOV group. The overall proportion of children with abnormal 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.Total Hospital Costs
The total hospital costs from a subgroup of patients from one center in the trial by Gerstmann et al19 suggests that the median hospital costs were less in the group of patients randomized to HFOV. However, there was no reduction in the length of hospital stay.The methods used in this review were those recommended 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 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.
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 measures for CLD (oxygen dependency and an abnormal radiograph at 28 to 30 days); however, this result is dominated by the HIFI study,9 which 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.18,19 This 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 stability 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 different in the two groups. In the excluded abstract by Lambert et al24 there was no significant difference in the incidence of CLD.Neurodevelopmental Outcomes
A major concern, which first arose with the HIFI study,9 was the increased rates of acute and chronic neurologic injury that seemed to be associated with HFOV. This has been measured in the neonatal period by assessing rates of IVH and PVL and at neurodevelopment follow-up within the first 3 years of life.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 trial20 postneonatal 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 experienced 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 important. There is a need for more data on the optimum strategy for safely ventilating neonates with HFOV. The economic implications along with important long-term pulmonary and neurodevelopmental outcomes, are also important issues that need to be addressed.No reprints available.
Received for publication Jan 24, 1997; accepted Apr 11, 1997.
CLD, chronic lung disease. RDS, respiratory distress syndrome. CV, conventional ventilation. HFOV, high-frequency oscillatory ventilation. IVH, intraventricular hemorrhage. 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 leukomalacia.
- Saigal S, O'Brodovich H Long term outcome of infants with respiratory disease. Clin Perinatol. 1987; 14:635-650[Medline]
-
Sauve RS,
Siaghal N
Long term morbidity of infants with
bronchopulmonary dysplasia.
Pediatrics.
1985;
76:725-733
[Abstract/Free Full Text] - O'Brodovich H, Mellins BB Bronchopulmonary dysplasia: unresolved neonate acute lung injury. Am Rev Respir Dis. 1985; 132:694-709[Medline]
-
Nickerson BG
Bronchopulmonary dysplasia. Chronic pulmonary disease
following neonatal respiratory failure.
Chest
1985;
87:528-535
[Abstract/Free Full Text] - Truong WE, Standaert TA, Murphy JH, Woodrum DE, Hodson WA Effect of prolonged high frequency oscillatory ventilation in premature primates with experimental hyaline membrane disease. Am Dev Respir Dis. 1984; 130:76-80
- deLemos RA, Coalson JS, Gerstmann DR, Ventilatory management of infant baboons with hyaline membrane disease: the use of high frequency ventilation. Pediatr Res 1987; 21:594-602[Medline]
-
Meredith KS,
deLemos RA,
Coalson JJ,
Role of lung injury in
pathogenesis of hyaline membrane disease in premature baboons.
J Appl Physiol.
1989;
66:2150-2158
[Abstract/Free Full Text] - deLemos RA, Coalson JJ, deLemos JA, High frequency oscillation improves the non-uniform lung inflation of hyaline membrane disease. Am Rev Respir Dis. 1989; 139:A438
- The HIFI, Study Group High frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. N Engl J Med 1989; 320:88-93[Abstract]
- The HIFI, Study Group High frequency oscillatory ventilation compared with conventional intermittent mechanical ventilation in the treatment of respiratory failure in preterm infants: neurodevelopmental status at 16 to 24 months postterm age. J Pediatr. 1990; 117:939-46[CrossRef][Medline]
-
Froese AB,
Bryan AC
Reflections on the HIFI trial.
Pediatrics
1991;
87:565-567
[Abstract/Free Full Text] - Papazoglou K, Suzuki H, Bohn DJ, Bryan AC The effect of late intervention with high frequency oscillatory ventilation (HFOV) in a lavage model of acute lung injury. Am Rev Respir Dis 1990; 141:A685
- Papile L-A, Burstein J, Burstein R, Koffler H Incidence and evolution of subependymal and intraventricular haemorrhage: a study of infants with birthweights less than 1500 gm. J Pediatr 1978; 92:529-534[CrossRef][Medline]
- The Cochrane Library [database on disk and CD Rom]. The Cochrane Collaboration; Oxford Update Software; 1996 updated quarterly; available from BMJ Publisher
- Sinclair JC, Bracken MB. Effective Care of the Newborn Infant. New York, NY: Oxford University Press; 1992
- Bhuta T, Henderson-Smart DJ. Elective high frequency oscillatory ventilation vs conventional ventilation in preterm infants with acute pulmonary dysfunction. In: Sinclair J, Bracken M, Soll RF, Horbar JD, eds. Neonatal Module of The Cochrane Database of Systematic Reviews. Available in: The Cochrane Library [database on disk and CD Rom]. The Cochrane Collaboration; Issue 4. Oxford: Update Software; 1996
-
Schultz KF,
Chalmers F,
Haynes RJ,
Altman DG
Empirical evidence of
bias: dimensions of methodologic quality associated with estimates of
treatment effect in controlled clinical trials.
JAMA
1995;
273:408-412
[Abstract/Free Full Text] -
Clark RH,
Gerstmannn DR,
Null DM Jr,
deLemos RA
Prospective randomized
comparison of high frequency oscillatory and conventional ventilation
in respiratory distress syndrome.
Pediatrics
1992;
89:5-12
[Abstract/Free Full Text] -
Gerstmann DR,
Minton SD,
Stoddard RA,
Meredith KS,
Bertrand JM
The
Provo multicentre early high frequency oscillatory ventilation trial.
Improved pulmonary and clinical outcomes in respiratory distress
syndrome.
Pediatrics
1996;
98:1044-1057
[Abstract/Free Full Text] - Ogawa Y, Miyasaha K, Kawano T, A multicentre randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure. Early Hum Dev 1993; 32:1-10[CrossRef][Medline]
- The HIFO, Study Group Randomized study of high-frequency oscillatory ventilation infants with severe respiratory distress syndrome. J Pediatr. 1993; 122:609-619[Medline]
- Ramanathan R, Ruiz I, Tantivit P, Cavabvab R, deLemos R. High frequency oscillatory ventilation compared to conventional mechanical ventilation in preterm infants with respiratory distress syndrome. Abstract. San Diego, CA: Society for Pediatric Research; 1995
- Rettwitz-Volk W, Veldman A, Roth B, A prospective randomized multicentre trial of high frequency oscillatory ventilation compared to conventional ventilation in preterm infants with respiratory distress syndrome on surfactant treatment. Abstract. Z Geburtsh Neonatol 1995; 199:214
- Lambert J, Clarke O, Debnuche C, et al. High Frequency Oscillation Versus Conventional Mechanical Ventilation for Respiratory Distress Syndrome. Abstract. Lyon, France: European Society for Paediatric Research; 1996
- The HIFI, Study Group High frequency oscillatory ventilation compared with conventional ventilation in the treatment of respiratory failure in preterm infants: assessment of pulmonary function at 9 months of corrected age. J Pediatr 1990; 166:933-941
- Kinsella JP, Gerstmann DR, Clark RH, High frequency oscillatory ventilation versus intermittent mandatory ventilation: early hemodynamic effects in the premature baboon with hyaline membrane disease. Pediatr Res 1991; 29:160-166
- Laubscher B, van Melle G, Fawer C-L, Sekarski N, Calarne A Haemodynamic changes during high frequency oscillation for respiratory distress syndrome. Arch Dis Child 1996; 74:F172-F176
-
Wiswell TE,
Graziani LJ,
Kornhauser MS,
High-frequency jet
ventilation in the early management of respiratory distress syndrome is
associated with a greater risk of adverse outcomes.
Pediatrics
1996;
98:1035-1043
[Abstract/Free Full Text] -
Clark RH,
Dykes FD,
Bachman TE,
Ashurst JT
Intraventricular
haemorrhage and high frequency ventilation: a meta-analyses of
prospective clinical trials.
Pediatrics
1996;
98:1058-1061
[Abstract/Free Full Text]
Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
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