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High-Frequency Ventilation in Premature Neonates

With great interest we read the review paper by Bollen and colleagues (1), which was submitted for publication before our paper "Development of airway function following high-frequency oscillation or conventional mechanical ventilation" (2) was published. Bollen and colleagues did not find evidence that optimized high-frequency oscillation treatment was superior compared with optimized conventional mechanical ventilation treatment with respect to the prevalence of chronic lung disease, but did not evaluate lung function. Our findings, however, might have modified their conclusions. We studied _maxFRC as a measure of airway function, expressed as Z score (3), and observed that, in infants born prematurely, mean airway function decreased longitudinally during the first year. Infants ventilated on high-frequency oscillation did not demonstrate worsening airway function, unlike those on conventional mechanical ventilation. Though ventilation strategy for the preterm infants in our study was not randomized according to a protocol, the mode of ventilation was largely determined by chance (2).

As sex-specific reference equations have become available and are now recommended (4), we reanalyzed the same data using the latter reference equations. In contrast to our initial analysis, mean (SEM) _maxFRC (Z score) between 6 and 12 months of age in 23 infants with chronic lung disease showed no decrease and remained at –1.8 (0.2). However, the high-frequency oscillation group showed a mean (95% CI) increase of 0.5 (0.1–0.9) in _maxFRC, whereas the conventional mechanical ventilation group showed a mean (95% CI) decrease of 0.4 (0.0–0.8) between 6 and 12 months of the first year. When individual mean paired _maxFRC values were interpolated or extrapolated linearly to values at exactly 6 and 12 months, mean (SEM) of these adjusted _maxFRC (Z score) values at 6 months were: –1.8 (0.2) for both groups, and at 12 months were –1.3 (0.2) in the high-frequency oscillation group (n = 12) and –2.3 (0.3) in the conventional mechanical ventilation group (n = 11). Hence, there was a mean (95% CI) difference of 1.0 (0.2–1.7) Z score, depending on ventilation strategy. Hence, worsening of lung function observed in preterm infants with and without chronic lung disease by others (4, 5) is not confirmed by our data, possibly due to a shorter period of follow-up in our study. These findings strongly suggest that the choice of reference equation significantly influences the results, and that the type of ventilation strategy may have a significant impact on development of airway function that is even more pronounced than previously thought.

W. Hofhuis, J. C. de Jongste and P. J. F. M. Merkus

University Medical Center Rotterdam/Sophia Children's Hospital Rotterdam, The Netherlands

FOOTNOTES

Conflict of Interest Statement: W.H., J.C.J., and P.J.F.M. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

REFERENCES

1. Bollen CW, Uiterwaal CS, van Vught AJ. Cumulative metaanalysis of high-frequency versus conventional ventilation in premature neonates. Am J Respir Crit Care Med 2003;168:1150–1155.[Free Full Text]
2. Hofhuis W, Huysman MW, van der Wiel EC, Holland WP, Hop WC, Brinkhorst G, de Jongste JC, Merkus PJ. Worsening of _maxFRC in infants with chronic lung disease in the first year of life: a more favorable outcome after high-frequency oscillation ventilation. Am J Respir Crit Care Med 2002;166:1539–1543.[Abstract/Free Full Text]
3. Sly PD, Tepper R, Henschen M, Gappa M, Stocks J. Tidal forced expirations. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. European Respiratory Society/American Thoracic Society. Eur Respir J 2000;16:741–748.[Abstract]
4. Hoo AF, Dezateux C, Hanrahan JP, Cole TJ, Tepper RS, Stocks J. Sex-specific prediction equations for Vmax(FRC) in infancy: a multicenter collaborative study. Am J Respir Crit Care Med 2002;165:1084–1092.[Abstract/Free Full Text]
5. Süßmuth S, Bahr A, Hoo A, Poets C, Gappa M. Longitudinal assessment of lung function in sick preterm infants with and without chronic lung disease (CHRONIC LUNG DISEASE). Eur Respir J 2001;18:359s.

From the Authors:

We thank Dr. Hofhuis and colleagues for their interesting comments on late respiratory follow-up using sophisticated techniques to evaluate pulmonary function. Hofhuis and colleagues conducted a follow-up study in neonates who developed chronic lung disease (CLD) after ventilation by either high-frequency oscillation ventilation (HFOV) or conventional mechanical ventilation (CMV) (1). At 6 and 12 months lung function tests were performed. Their objective was to relate maximal flow at functional residual capacity (_maxFRC) to perinatal patient characteristics. However, they did not state an a priori comparison between patients ventilated by initial HFOV and CMV as an objective of their study. Patient selection was limited to patients that already had developed CLD. Furthermore, confounding by indication and information bias could not be excluded, as their study was not randomized and assessment of lung function was not explicitly blinded. These facts pose serious limitations to the validity of their conclusion that the initial HFOV in premature neonates has a significant benefit on development of airway function over CMV.

However, we agree that the definition of CLD is a crude measure of respiratory outcome. Lung function measurements at later age have been done after randomized trials comparing HFOV and CMV (2–4). Infants that participated in the HIFI trial did not differ in pulmonary function between those that were randomized to HFOV and those that were randomized to CMV (2). In the Provo respiratory follow-up study, children who had been initially ventilated by CMV had inferior pulmonary function compared with HFOV-ventilated children (3). Lung function tests at the age of one, in a subset of children from the most recent and largest trial, did not differ between patients ventilated by HFOV and patients ventilated by CMV (4).

In our cumulative meta-analysis we investigated sources of heterogeneity (5). It appeared that lung protective strategies in CMV moderated the relative benefit of HFOV in preventing CLD. We think this explains the difference between respiratory outcome at later age after the Provo trial compared with the UKOS trial.

In a thesis by W. Hofhuis entitled "Clinical Applications of Infant Lung Function Testing," one of his propositions was a quote from Jobe: "Differences in outcomes between HFOV and CMV may relate more to the way these techniques are used, and to patient selection, than to the intrinsic characteristics of the ventilator device" (6). In this we fully agree.

Casper W. Bollen, Cuno S. P. M. Uiterwaal and Adrianus J. van Vught

University Medical Centre Utrecht Utrecht, the Netherlands

FOOTNOTES

Conflict of Interest Statement: C.W.B., C.S.P.M.U, and A.J.V.V. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

REFERENCES

1. Hofhuis W, Huysman MW, van der Wiel EC, Holland WP, Hop WC, Brinkhorst G, de Jongste JC, Merkus PJFM. Worsening of _maxFRC in infants with chronic lung disease in the first year of life: a more favorable outcome after high-frequency oscillation ventilation. Am J Respir Crit Care Med 2002;166:1539–1543.
2. HiFi Study Group. High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants: assessment of pulmonary function at 9 months of corrected age. J Pediatr 1990;116:933–941.[CrossRef][Medline]
3. Gerstmann DR, Wood K, Miller A, Steffen M, Ogden B, Stoddard RA, Minton SD. Childhood outcome after early high-frequency oscillatory ventilation for neonatal respiratory distress syndrome. Pediatrics 2001;108:617–623.[Abstract/Free Full Text]
4. Thomas MR, Rafferty GF, Limb ES, Peacock JL, Calvert SA, Marlow N, Milner D, Greenough A. Pulmonary function at follow-up of very preterm infants from the UK oscillation study. Am J Respir Crit Care Med 2004;169:868–872.[Abstract/Free Full Text]
5. Bollen CW, Uiterwaal CS, van Vught AJ. Cumulative metaanalysis of high-frequency versus conventional ventilation in premature neonates. Am J Respir Crit Care Med 2003;168:1150–1155.
6. Jobe AH. An unknown: lung growth and development after very preterm birth. Am J Respir Crit Care Med 2002;166:1529–1530.[Free Full Text]

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