Leukomalacia

Mechanical ventilation can induce lung injury, particularly in premature and diseased lungs. There is increasing evidence that high peak inspiratory pressures and repetitive end-expiratory collapse are major determinants of lung injury (1). This injury may extend to other organ systems, leading to multiorgan failure (2-4). Ventilatory strategies that limit high inflation pressures and prevent end-expiratory collapse are designated as lung protective mechanical ventilation (5).

High-frequency ventilation is a method of ventilation in which alveolar gas exchange is maintained by pressure swings initiating small displacements of ventilatory gases, considerably smaller than conventional tidal volumes, at frequencies generally from 5-20 Hz superimposed on a continuous positive pressure. High-frequency ventilation allows higher end-expiratory pressures with lower peak inspiratory pressures and higher mean airway pressures and is therefore proposed as currently the most optimal form of lung protective ventilation (6, 7).

In animal experiments, high-frequency ventilation has been shown to prevent ventilator-induced lung injury (8-10). The majority of clinical trials so far have been performed in neonates, but results are equivocal. The two most recent large randomized controlled trials failed to demonstrate a significant advantage of high-frequency ventilation over conventional mechanical ventilation or showed only a small benefit (11, 12). The last metaanalysis of the pooled data in neonates showed no reduction in either mortality or oxygen dependency at Day 28-30 after birth but a small reduction in the risk of chronic lung disease at 36-to 37-week postgestational age in patients treated with high-frequency ventilation with optimized lung volume in comparison with conventional mechanical ventilation (13).

The conventional mechanical ventilation strategies for treating respiratory failure have evolved since the first published clinical trial in 1987 comparing high-frequency ventilation with conventional mechanical ventilation due to the introduction of surfactant replacement therapy and the concept of lung protective ventilation (14). Therefore, early results cannot be easily compared with later studies, a limitation that prior metaanalyses accounted for only partially or not at all (13, 15-17).

We reviewed the published comparative data on high-frequency ventilation and conventional mechanical ventilation in neonates and performed an updated metaanalysis, including the two most recent and largest randomized clinical trials (11, 12). We stratified trials by different high-frequency ventilators and by different ventilatory strategies. In addition, we performed a cumulative metaanalysis within relevant strata, which allowed us to examine the development of the available evidence over time and to assess the influence of the introduction of surfactant replacement therapy and of lung protective ventilation.

METHODS

Search Strategy and Data Collection

The Embase, Medline, and Current Contents databases were searched to identify all systematic reviews and randomized controlled trials of treatment with high-frequency ventilation compared with conventional mechanical ventilation. Clinical trials had to meet criteria that were previously adopted by Bhuta and Henderson-Smart (18). A more detailed description of the search strategy can be found in the online supplement.

Data on the following outcomes were extracted: mortality at 28 to 30 days of age; bronchopulmonary dysplasia, defined as oxygen dependency at the age of 28 to 30 days with radiologic evidence of bronchopulmonary dysplasia; chronic lung disease, defined as oxygen dependency at the postconceptional age of 36 weeks; intraventricular hemorrhage; and periventricular leukomalacia.

A high lung volume strategy with high-frequency ventilation was assumed if two or more of the following items were explicitly stated in the methods; initial use of a higher mean airway pressure than on conventional mechanical ventilation, initial lowering of inspired oxygen before reducing mean airway pressure, and use of alveolar recruitment maneuvers. A lung protective strategy in the conventional mechanical ventilation group was based on specifying the PCO2 goal, allowing permissive hypercapnia, and a high initial ventilatory rate, targeted at reducing tidal volume as previously suggested by Thome and Carlo (16).

Data Analysis and Statistical Methods

A number of hypotheses were proposed in advance to explain differences between study outcomes. First, differences could be attributed to the type of ventilator being used. We therefore stratified studies by the following subgroups: the SensorMedics ventilator (SensorMedics, Bilthoven, the Netherlands), other high-frequency oscillatory ventilators, high-frequency jet ventilators, and high-frequency flow interruption ventilators. Another possible explanation of different treatment effects could be the use of surfactant. Subgroups were made of studies with and studies without the concomitant use of surfactant. Finally, recent improvements in ventilation strategies could affect outcome. We therefore defined the following subgroups: no high lung volume strategy in high-frequency ventilation and no lung protective strategy in conventional mechanical ventilation, high lung volume strategy in high-frequency ventilation and no lung protective strategy in conventional mechanical ventilation, high lung volume strategy in high-frequency ventilation, and lung protective strategy in conventional mechanical ventilation.

A cumulative metaanalysis was performed by pooling data again each time a new study was published (19). To assess changes in relative treatment effects and to identify possible sources of heterogeneity, a graph was constructed using pooled estimates and corresponding 95% confidence intervals as a function of the cumulative number of patients included in the analysis in a chronologic order. The particular purpose of this graph was to show the ratio of the cumulative treatment effect to the previous cumulative treatment effect. This so-called recursive cumulative metaanalysis was created to identify graphically sources of heterogeneity emerging at specific points in time (20). Furthermore, heterogeneity was statistically evaluated using visual examination of the extent of overlapping confidence intervals and Cochrane's Q test (21, 22). Different treatment effects were assumed in case of graphical evidence for heterogeneity and a significant test for heterogeneity (p

RESULTS

We identified five systematic reviews (13, 15, 16, 18, 23). Using the reference lists of these systematic reviews, 14 original articles were selected. Our literature search yielded no additional references. Thus, 14 articles were available for our analyses that represented a total of 3,260 randomized patients (11,12, 24-35). The main features of these articles are summarized in the online supplement in Table E1.

There was significant heterogeneity between different studies for chronic lung disease (p = 0.05) and periventricular leukomalacia (p = 0.08) (Table E2 in the online supplement). This corresponded with significant differences between subgroups of surfactant (p = 0.02 for chronic lung disease and p = 0.07 for periventricular leukomalacia) and ventilatory strategy (p

Graphical presentation of the cumulative relative risk of chronic lung disease showed a distinctive shape (Figure 1). There was a convergence of the 95% confidence interval with a regression of the estimate to the line of no effect. The recursive cumulative metaanalysis is depicted by the dotted line in Figure 1. A ratio above one implied overestimation of the treatment (highfrequency ventilation) effect. The first peak thus visualized corresponded with the first trial in which surfactant was used to treat respiratory distress syndrome and chronic lung disease was reported as an outcome (27). The second peak coincided with the start of protective lung ventilation in conventional mechanical ventilation (29). Thus, the use of surfactant and lung protective strategy in conventional mechanical ventilation was graphically indicated to be two major sources of study heterogeneity.

Table 1 describes the metaanalyses stratified by ventilalory strategy and ventilator subgroups with the remaining heterogeneity. In none of the ventilatory strategy subgroups was there a difference in mortality when high-frequency ventilation was compared with conventional mechanical ventilation. Respiratory outcomes were better in the ventilation strategy subgroup in which high-frequency ventilation with high lung volume strategy was compared with conventional mechanical ventilation without lung protective strategy. However, high-frequency ventilation without high lung volume strategy lost the ability to prevent lung damage. Furthermore, high-frequency ventilation without high lung volume strategy resulted in an elevated risk of intraventricular hemorrhage, intraventricular hemorrhage grades 3 and 4, and periventricular leukomalacia. The beneficial effects on respiratory outcome also disappeared when high-frequency ventilation with high lung volume strategy was compared with conventional mechanical ventilation with lung protective strategy. Remaining significant heterogeneity existed only for intraventricular hemorrhage grades 3 and 4 in the subgroup of high-frequency ventilation with high lung volume strategy and conventional mechanical ventilation with lung protective strategy.

Stratification by the type of ventilator being used had less impact on treatment results and did not eliminate heterogeneity for chronic lung disease, intraventricular hemorrhage, and periventricular leukomalacia (Table 1). Significantly better respiratory outcomes were reported only in the SensorMedics subgroup. In this subgroup, the relative risk of chronic lung disease was 0.57 (95% confidence interval, 0.36-0.93). However, there was significant heterogeneity, and visual examination of the cumulative metaanalysis revealed a progressive trend of the estimate of the relative risk to the line of no effect. The relative risk of death or chronic lung disease was not statistically different when high-frequency ventilation with the SensorMedics was compared with conventional mechanical ventilation (relative risk = 0.67; 95% confidence interval, 0.43-1.04). There was still unexplained significant heterogeneity for intraventricular hemorrhage all grades and grades 3 and 4 in the high-frequency oscillatory ventilation subgroup (p = 0.06 and p = 0.02, respectively), and there was significant heterogeneity for periventricular leukomalacia in the high-frequency jet and high-frequency flow interruption ventilator subgroup (p = 0.02).

Figure 2 is a graphical presentation of our main cumulative analysis of chronic lung disease, which is in subgroups of ventilatory strategy. The cumulative estimate of the relative risk of chronic lung disease in high-frequency ventilation with high lung volume strategy compared with conventional mechanical ventilation without a lung protective strategy did not change any further during the last three trials of the total of four studies and remained significant. The cumulative metaanalyses of chronic lung disease in the subgroup with high-frequency ventilation without high lung volume strategy and the subgroup of high-frequency ventilation with high lung volume strategy but also lung protective strategy in conventional mechanical ventilation did not show any tendency to migrate from the line of no effect. Cumulative metaanalysis of the relative risk for intraventricular hemorrhage grades 3 and 4 in the subgroup of high-frequency ventilation without a high lung volume strategy showed a harmful effect compared with conventional mechanical ventilation (Figure 3). When a high lung volume strategy was being used, this effect disappeared. Thus, within comparisons of optimized high-frequency ventilation and optimized conventional mechanical ventilation, including the latest large trials, there was no beneficial effect of either treatment, nor was there an indication of significant remaining heterogeneity or change in treatment effect.

DISCUSSION

When optimized high-frequency ventilation with high lung volume strategy was compared with optimized conventional mechanical ventilation with lung protective strategy, there was no reduction in chronic lung disease. As in previous metaanalyses on highfrequency ventilation versus conventional mechanical ventilation in neonates, we also did not find differences in mortality (13, 15, 16, 18, 23). Cumulative metaanalysis of the data allowed us to analyze the development of the evidence and to investigate how consecutive trials contributed to the estimation of the treatment effects (19).

There is a growing understanding that clinical evidence is a dynamic process, not a static estimation of a single treatment effect at a single time point (36). In this respect, cumulative metaanalysis should be distinguished from an updating of an existing metaanalysis. In a cumulative metaanalysis, the accumulating results allow assessment of changes in patient and treatment characteristics over time. Although there was clearly significant heterogeneity, precluding pooling of estimates, a cumulative metaanalysis of chronic lung disease, including all studies, was performed exclusively to identify graphically such effects at specific points in time. As such, this analysis was not intended to calculate a single pooled treatment effect.

A first important source of heterogeneity might be small trial bias (publication bias), which results in systematic differences in effect size estimates derived from small versus large trials (37). The other possible explanation is the improvement of conventional ventilation over time. One of the major advances in neonatal respiratory care is the introduction of surfactant (38). Numerous clinical studies have confirmed the beneficial effect of surfactant administration on outcome of premature infants with respiratory distress syndrome (39). Our results indicate that introduction of surfactant therapy is reflected in a considerable change in relative treatment effects. Another advance in ventilatory care is the application of lower tidal volumes and higher positive end-expiratory pressure levels, designated as lung protective ventilation (40). A ventilatory strategy to maintain lung volume (higher mean airway pressures) with low tidal volumes has the potential for better alveolar recruitment compared with a low volume strategy with higher tidal volumes and thus would result in better outcome in terms of chronic lung disease. Although in adult respiratory care there is increasing evidence of the beneficial effect on mortality and morbidity of lung protective ventilation (40), a large body of controversy remains (41-44). In neonates, only few studies have addressed this topic (45, 46). We speculate that the introduction of lung protective ventilation also reflected an important change of relative treatment effects, albeit smaller than with the introduction of surfactant.

It is now generally believed that high-frequency ventilation is most beneficial if the lungs are optimally recruited (6, 10, 47, 48). However, the evidence for this comes mainly from animal experiments (10, 48). There are no clinical studies comparing high-frequency ventilation with high lung volume strategy and high-frequency ventilation without high lung volume strategy. We show that the best effects of high-frequency ventilation on chronic lung disease were reported in studies in which high lung volume strategy was part of the high-frequency ventilation protocol but in which the conventional mechanical ventilation protocol did not meet the criteria for lung protective ventilation (25, 27, 28, 31). Studies not mentioning high lung volume strategy and lung protective ventilation as part of their protocol failed to show differences in effect of high-frequency ventilation on chronic lung disease (32,34). Instead, these studies demonstrated an increased incidence of intraventricular hemorrhage. When lung protective conventional mechanical ventilation was compared with high-frequency ventilation with high lung volume strategy, there were no differences in either chronic lung disease or intraventricular hemorrhage (11, 12, 29, 33).

In previous reports, it has been suggested that particularly premature neonates with a higher baseline risk of chronic lung disease would benefit more from high-frequency ventilation (29, 33). It has also been suggested that using high-frequency ventilation as the primary mode of ventilation immediately after birth would increase its effectiveness (28, 49). In consecutive studies, patients had lower birth weights and were more premature. In consequence, this would imply a higher risk of chronic lung disease. Furthermore, institution of high-frequency ventilation after birth was earlier in the more recent trials. However, our cumulative analysis of chronic lung disease showed that this did not result in a larger benefit of high-frequency ventilation over conventional mechanical ventilation over time, as would have been expected.

A limitation of our analysis is the varying definitions of high lung volume strategy in the high-frequency ventilation group and of lung protective strategy for conventional mechanical ventilation used in the original studies. In the definition of high lung volume strategy, a higher mean airway pressure was limited to initial use, and use of recruitment maneuvers did not necessarily mean that an open lung strategy was used the entire study period. Furthermore, the definition of lung protective ventilatory strategy did not include tidal volumes standardized to body weight or levels of positive end-expiratory pressure being applied. The actual implementation of these strategies could not be accounted for either in our analysis.

In the most recent metaanalysis published by the Cochrane Library, the use of a high lung volume strategy and treatment with surfactant was taken into account as well (13). However, this did not eliminate existing heterogeneity between trials. It was concluded that high-frequency oscillatory ventilation caused a modest reduction in chronic lung disease. In our analyses, we did not only identify the use of surfactant as a source of heterogeneity but also the application of a lung protective strategy in the conventional mechanical ventilation group. The most significant differences between subgroups were found between trials using different ventilation strategies, not only in the high-frequency ventilation group but also in the conventional mechanical ventilation group. By stratifying trials by ventilation strategies, we were able to minimize heterogeneity. We therefore explain heterogeneity between trials mainly by changes in the conventional treatment of respiratory distress in premature neonates over time. Unlike the Cochrane metaanalysis, we did not find differences in chronic lung disease between optimized high-frequency ventilation and optimized conventional mechanical ventilation. We suggest that future investigations should be directed toward identifying the specific pulmonary conditions in which optimized high-frequency ventilation does have benefits compared with optimized conventional mechanical ventilation (50).

Cumulative metaanalysis and subsequent stratification are valuable methods to summarize and interpret the effects of changes in patient characteristics and treatments over time. These methods enabled us to show that use of surfactant and the emergence of lung protective ventilation strategies in conventional mechanical ventilation moderates the relative beneficial effect on chronic lung disease of high-frequency ventilation.

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

Pediatric Intensive Care Unit, Wilhelmina Children's Hospital, and Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands

(Received in original form June 2, 2003; accepted in final form August 29, 2003)

Correspondence and requests for reprints should be addressed to Adrianus J. van Vught, M.D., Ph.D., Pediatric Intensive Care Unit, Room KG 01.319.0, University Medical Centre, Utrecht, POB 85090, 3508 AB Utrecht, The Netherlands. E-mail: a.vanvught@wkz.azu.nl

Conflict of Interest Statement: C.W.B. has no declared conflict of interest; C.S.P.M.U. has no declared conflict of interest; A.J.v.V. has no declared conflict of interest.

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