High-frequency ventilation versus conventional ventilation: No winner—but no loser

Abstract

See related article, p. 39Two phenomena, one clinical and one experimental, emerged and converged in the early 1980s. The clinical phenomenon was the increasingly successful application of time-cycled, pressure-limited ventilators to the treatment of premature infants with respiratory failure. The experimental phenomenon was the successful application of subphysiologic tidal volume delivered in an oscillating pattern at supraphysiologic rates to sustain pulmonary gas exchange in experimental animals.The clinical success of a decreased neonatal mortality rate was purchased at the price of an increased number of surviving infants demonstrating airway and lung parenchymal injury, then called bronchopulmonary dysplasia and now called chronic lung disease of prematurity . Extending the observations in the 1970s by Jonzon et al,1Jonzon A Öberg PO Sedin G Sjöstrand U. High frequency positive-pressure ventilation by endotracheal insufflation.Acta Anaesthesiol Scand Suppl. 1971; 43: 1-43Crossref Scopus (10) Google Scholar Bohn et al2Bohn DJ Miyasaka K Marchak BE Thompson WK Froese AB Bryan AC. Ventilation by high-frequency oscillation.J Appl Physiol. 1980; 48: 710-716PubMed Google Scholar showed that one form of high-frequency ventilation, namely high-frequency oscillatory ventilation with its active exhalation pattern, could sustain apneic dogs at low positive airway pressures. Bohn et al2Bohn DJ Miyasaka K Marchak BE Thompson WK Froese AB Bryan AC. Ventilation by high-frequency oscillation.J Appl Physiol. 1980; 48: 710-716PubMed Google Scholar raised the possibility that oscillatory ventilation might be useful for the treatment of infants with pulmonary disorders. The science and art of applying ventilatory strategies to immature lungs of premature infants were now changed fundamentally. Maintaining pulmonary gas exchange without inducing lung injury became neonatology’s Holy Grail, long sought but never quite achieved.To help approach that goal, additional types of HFV, as well as a multitude of more sophisticated forms of conventional rate positive-pressure ventilation, continue to become available—often before clinical trials defining the utility of these systems are conducted. The fertile field of comparison of HFOV with conventional ventilation has nurtured 6 studies published over the last 10 years, beginning with the HIFI study.3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar After this came studies by Clark et al,4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar Ogawa et al,5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar Gerstmann et al,6Gerstmann DR Minton SD Stoddard RA Meredith KS Monaco F Bertrand JM et al.The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.Pediatrics. 1996; 98: 1044-1057PubMed Google Scholar and more recently Rettwitz-Volk et al.7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Each study attempted to investigate the early application of HFOV in low birth weight infants to reduce chronic lung disease. Now comes the study by Thome et al,8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar published in this issue of The Journal.Some additional history is useful here. The HIFI study,3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar which enrolled 673 infants with birth weights between 750 and 2000 g under a complicated enrollment scheme, mandated immediate crossover in the event of failure of one form of ventilation and did not mandate a “high volume maintenance” strategy to the HFOV group. Because infants were enrolled at a mean age of 6 hours, those randomly assigned to receive HFOV underwent significant exposure to conventional treatment first. The HIFI study did not produce evidence of reduced CLD and/or death in the patients assigned to HFOV. The next 4 studies produced variable results. Clark et al4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar did show a reduction in incidence of CLD; Ogawa et al5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar did not show and could not have shown a reduction in deaths or CLD with HFOV because of the low incidence of these outcomes in the conventional group; Gerstmann et al6Gerstmann DR Minton SD Stoddard RA Meredith KS Monaco F Bertrand JM et al.The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.Pediatrics. 1996; 98: 1044-1057PubMed Google Scholar found improved outcome with HFOV, but the study was conducted in significantly larger infants than the other studies; and Rettwitz-Volk et al7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar failed to show improvement with HFV.Thome et al8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar have conducted a study in an attempt to eliminate the limitations perceived to be present in the earlier studies. Those limitations included the following: under-powered studies (Clark et al,4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar Ogawa et al,5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar and Rettwitz-Volk et al7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar); failure to use high volume strategy with HFOV (HIFI3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar and Ogawa et al5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar); failure to provide the most modern treatments as adjunctive therapy, for example, exogenous surfactant and antenatal corticosteroids (Clark et al4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar and HIFI3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar); failure to enroll very small infants who are most at risk for death and CLD (Gerstmann et al6Gerstmann DR Minton SD Stoddard RA Meredith KS Monaco F Bertrand JM et al.The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.Pediatrics. 1996; 98: 1044-1057PubMed Google Scholar and Rettwitz-Volk et al7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar).Thome et al8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar enrolled a large number of patients (284). Almost 80% received antenatal steroids to help induce lung maturation, and more than 70% received exogenous surfactant. Randomization occurred in the first hour after initiation of assisted ventilation so that there was minimal time for pulmonary injury to occur before institution of HFV. The study was multi-centered. It was adequately powered to demonstrate a small but still potentially clinically significant improvement in the HFV-treated infants and to provide additional data about adverse outcomes. Patients were treated according to a clearly specified protocol for assisted ventilation. The study was appropriately conducted with multiple interim evaluations. Thus any advantage to either treatment would be detected quickly, or as actually occurred, the study could be terminated when it became apparent that there would be no obvious advantage to HFV. A serious attempt was made to maintain adequate lung volume in the HFV-treated group without overdistention, despite the difficulty in achieving this in the face of dynamic illnesses. In addition, extraordinarily small patients were enrolled, and the study entry was stratified for gestational age. Infants with birth weights as low as 370 g were included, and 31% of the enrolled infants weighed less than 750 g. There was a very high rate of enrollment of eligible patients, suggesting adherence to the goals of the trial by investigators at all 6 study sites. Few could argue with the assertion that the study design promoted a definitive comparison of the 2 modes of assisted ventilation.Randomized clinical trials can never be perfect, because they are conducted by humans for humans with inevitably heterogenous forms of medical disorders. There are important limitations to the study of Thome et al.8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Perhaps the most important is the complex primary outcome variable. It is actually a summary of 4 different outcomes. Two are clinically important end points (death or development of CLD). Two are radiologic or physiologic surrogates, development of any air leak including pulmonary interstitial edema or development of an excessive oxygenation index. Thus the “primary” outcome variable seems unnecessarily confusing. The high-frequency ventilator used has many of the features of an oscillator but does not permit varying the ratio of inspiratory to expiratory time, as is possible with one HFOV device widely used in the United States. Some will question the use of the “gentle ventilation” protocol, allowing PaCO2 to rise to 60 mm Hg during the first week and to 70 mm Hg thereafter. However, that feature, taken with the study’s allowing PaO2 to fall to 40 mm Hg, and arterial oxygen saturation to fall to 85%, should have helped minimize unnecessarily aggressive positive-pressure ventilation. Readers are not told the results of the “third group” of patients in this study. This group constitutes patients eligible but not enrolled. In this study, however, this third group represents only about 20% of eligible infants. Knowledge about outcomes in this group could have addressed the recent observation that the act of participating in definitive clinical trials may itself confer benefits.9Schmidt B Gillie P Caco C Roberts J Roberts R. Do sick newborn infants benefit from participation in a randomized clinical trial?.J Pediatr. 1999; 134: 151-155Abstract Full Text Full Text PDF PubMed Scopus (63) Google ScholarAt the end, there were no important differences in respiratory outcomes between patients in the 2 arms of the study and almost no likelihood of finding an important difference with the enrollment of the additional planned 100 patients. This clinical result is consistent with an earlier report by Thome et al10Thome U Gotze-Speer B Speer C Pohlandt F. Comparison of pulmonary inflammatory mediators in preterm infants treated with intermittent positive pressure ventilation or high frequency oscillatory ventilation.Pediatr Res. 1998; 44: 330-336Crossref PubMed Scopus (46) Google Scholar in which no differences were detected in tracheal aspirate pro-inflammatory cytokines obtained from a subset of patients in each arm of the study. Is this then a case of “back to the future”? Are we back to 1989, with no apparent advantage with the oscillator? Even if one believes that there is no obvious advantage for HFOV, this belief should not produce anxiety, because the results for both groups are encouraging. Key findings here included a low mortality rate (combined 10% to discharge) and, given the population at risk, a modest incidence of CLD of 25%, defined as need for supplemental oxygen or for assisted ventilation at 36 weeks’ postmenstrual age. The results represent significant improvement from those of 10 years ago. There is still a disturbingly large incidence of intracranial hemorrhage (13.5% of all patients). Other problems of extreme prematurity, such as necrotizing enterocolitis and retinopathy of prematurity, were not banished from either group.These results provide an important new benchmark for neonatologists worldwide. The work also reminds us that paying attention to the minutiae of assisted ventilation is crucial. Their results also confront us with our limits of understanding the mechanisms of injury in these half-formed lungs and of the limits of our understanding of the long-term consequences of therapy with positive-pressure ventilation. It is crucial that Thome et al provide longer-term follow-up data, using sophisticated pulmonary function tests, to help answer questions about ultimate pulmonary growth and differentiation after exposure to these 2 modes of ventilation.In conclusion, both techniques of assisted ventilation used in this report appear to be winners. But an even bigger success awaits the reduction in the incidence of extreme prematurity. That is now neonatology’s Holy Grail. See related article, p. 39 Two phenomena, one clinical and one experimental, emerged and converged in the early 1980s. The clinical phenomenon was the increasingly successful application of time-cycled, pressure-limited ventilators to the treatment of premature infants with respiratory failure. The experimental phenomenon was the successful application of subphysiologic tidal volume delivered in an oscillating pattern at supraphysiologic rates to sustain pulmonary gas exchange in experimental animals. The clinical success of a decreased neonatal mortality rate was purchased at the price of an increased number of surviving infants demonstrating airway and lung parenchymal injury, then called bronchopulmonary dysplasia and now called chronic lung disease of prematurity . Extending the observations in the 1970s by Jonzon et al,1Jonzon A Öberg PO Sedin G Sjöstrand U. High frequency positive-pressure ventilation by endotracheal insufflation.Acta Anaesthesiol Scand Suppl. 1971; 43: 1-43Crossref Scopus (10) Google Scholar Bohn et al2Bohn DJ Miyasaka K Marchak BE Thompson WK Froese AB Bryan AC. Ventilation by high-frequency oscillation.J Appl Physiol. 1980; 48: 710-716PubMed Google Scholar showed that one form of high-frequency ventilation, namely high-frequency oscillatory ventilation with its active exhalation pattern, could sustain apneic dogs at low positive airway pressures. Bohn et al2Bohn DJ Miyasaka K Marchak BE Thompson WK Froese AB Bryan AC. Ventilation by high-frequency oscillation.J Appl Physiol. 1980; 48: 710-716PubMed Google Scholar raised the possibility that oscillatory ventilation might be useful for the treatment of infants with pulmonary disorders. The science and art of applying ventilatory strategies to immature lungs of premature infants were now changed fundamentally. Maintaining pulmonary gas exchange without inducing lung injury became neonatology’s Holy Grail, long sought but never quite achieved. To help approach that goal, additional types of HFV, as well as a multitude of more sophisticated forms of conventional rate positive-pressure ventilation, continue to become available—often before clinical trials defining the utility of these systems are conducted. The fertile field of comparison of HFOV with conventional ventilation has nurtured 6 studies published over the last 10 years, beginning with the HIFI study.3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar After this came studies by Clark et al,4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar Ogawa et al,5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar Gerstmann et al,6Gerstmann DR Minton SD Stoddard RA Meredith KS Monaco F Bertrand JM et al.The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.Pediatrics. 1996; 98: 1044-1057PubMed Google Scholar and more recently Rettwitz-Volk et al.7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Each study attempted to investigate the early application of HFOV in low birth weight infants to reduce chronic lung disease. Now comes the study by Thome et al,8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar published in this issue of The Journal. Some additional history is useful here. The HIFI study,3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar which enrolled 673 infants with birth weights between 750 and 2000 g under a complicated enrollment scheme, mandated immediate crossover in the event of failure of one form of ventilation and did not mandate a “high volume maintenance” strategy to the HFOV group. Because infants were enrolled at a mean age of 6 hours, those randomly assigned to receive HFOV underwent significant exposure to conventional treatment first. The HIFI study did not produce evidence of reduced CLD and/or death in the patients assigned to HFOV. The next 4 studies produced variable results. Clark et al4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar did show a reduction in incidence of CLD; Ogawa et al5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar did not show and could not have shown a reduction in deaths or CLD with HFOV because of the low incidence of these outcomes in the conventional group; Gerstmann et al6Gerstmann DR Minton SD Stoddard RA Meredith KS Monaco F Bertrand JM et al.The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.Pediatrics. 1996; 98: 1044-1057PubMed Google Scholar found improved outcome with HFOV, but the study was conducted in significantly larger infants than the other studies; and Rettwitz-Volk et al7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar failed to show improvement with HFV. Thome et al8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar have conducted a study in an attempt to eliminate the limitations perceived to be present in the earlier studies. Those limitations included the following: under-powered studies (Clark et al,4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar Ogawa et al,5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar and Rettwitz-Volk et al7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar); failure to use high volume strategy with HFOV (HIFI3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar and Ogawa et al5Ogawa Y Miyasaka K Kawano T Imura S Inukai K Okuyama K et al.A multicenter randomized trial of high frequency oscillatory ventilation as compared with conventional mechanical ventilation in preterm infants with respiratory failure.Early Hum Dev. 1993; 32: 1-10Abstract Full Text PDF PubMed Scopus (163) Google Scholar); failure to provide the most modern treatments as adjunctive therapy, for example, exogenous surfactant and antenatal corticosteroids (Clark et al4Clark R Gerstmann DR Null Jr, DM deLemos RA. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in respiratory distress syndrome.Pediatrics. 1992; 89: 5-12PubMed Google Scholar and HIFI3HIFI 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: 88-93Crossref PubMed Scopus (415) Google Scholar); failure to enroll very small infants who are most at risk for death and CLD (Gerstmann et al6Gerstmann DR Minton SD Stoddard RA Meredith KS Monaco F Bertrand JM et al.The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.Pediatrics. 1996; 98: 1044-1057PubMed Google Scholar and Rettwitz-Volk et al7Rettwitz-Volk W Veldman A Roth B Vierzig A Kachel W Varnholt V et al.A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.J Pediatr. 1998; 132: 249-254Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Thome et al8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar enrolled a large number of patients (284). Almost 80% received antenatal steroids to help induce lung maturation, and more than 70% received exogenous surfactant. Randomization occurred in the first hour after initiation of assisted ventilation so that there was minimal time for pulmonary injury to occur before institution of HFV. The study was multi-centered. It was adequately powered to demonstrate a small but still potentially clinically significant improvement in the HFV-treated infants and to provide additional data about adverse outcomes. Patients were treated according to a clearly specified protocol for assisted ventilation. The study was appropriately conducted with multiple interim evaluations. Thus any advantage to either treatment would be detected quickly, or as actually occurred, the study could be terminated when it became apparent that there would be no obvious advantage to HFV. A serious attempt was made to maintain adequate lung volume in the HFV-treated group without overdistention, despite the difficulty in achieving this in the face of dynamic illnesses. In addition, extraordinarily small patients were enrolled, and the study entry was stratified for gestational age. Infants with birth weights as low as 370 g were included, and 31% of the enrolled infants weighed less than 750 g. There was a very high rate of enrollment of eligible patients, suggesting adherence to the goals of the trial by investigators at all 6 study sites. Few could argue with the assertion that the study design promoted a definitive comparison of the 2 modes of assisted ventilation. Randomized clinical trials can never be perfect, because they are conducted by humans for humans with inevitably heterogenous forms of medical disorders. There are important limitations to the study of Thome et al.8Thome U Kössel H Lipowsky G Porz F Fürste H-O Genzel-Boroviczeny O et al.Randomized comparison of high-frequency oscillatory ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.J Pediatr. 1999; 135: 39-46Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Perhaps the most important is the complex primary outcome variable. It is actually a summary of 4 different outcomes. Two are clinically important end points (death or development of CLD). Two are radiologic or physiologic surrogates, development of any air leak including pulmonary interstitial edema or development of an excessive oxygenation index. Thus the “primary” outcome variable seems unnecessarily confusing. The high-frequency ventilator used has many of the features of an oscillator but does not permit varying the ratio of inspiratory to expiratory time, as is possible with one HFOV device widely used in the United States. Some will question the use of the “gentle ventilation” protocol, allowing PaCO2 to rise to 60 mm Hg during the first week and to 70 mm Hg thereafter. However, that feature, taken with the study’s allowing PaO2 to fall to 40 mm Hg, and arterial oxygen saturation to fall to 85%, should have helped minimize unnecessarily aggressive positive-pressure ventilation. Readers are not told the results of the “third group” of patients in this study. This group constitutes patients eligible but not enrolled. In this study, however, this third group represents only about 20% of eligible infants. Knowledge about outcomes in this group could have addressed the recent observation that the act of participating in definitive clinical trials may itself confer benefits.9Schmidt B Gillie P Caco C Roberts J Roberts R. Do sick newborn infants benefit from participation in a randomized clinical trial?.J Pediatr. 1999; 134: 151-155Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar At the end, there were no important differences in respiratory outcomes between patients in the 2 arms of the study and almost no likelihood of finding an important difference with the enrollment of the additional planned 100 patients. This clinical result is consistent with an earlier report by Thome et al10Thome U Gotze-Speer B Speer C Pohlandt F. Comparison of pulmonary inflammatory mediators in preterm infants treated with intermittent positive pressure ventilation or high frequency oscillatory ventilation.Pediatr Res. 1998; 44: 330-336Crossref PubMed Scopus (46) Google Scholar in which no differences were detected in tracheal aspirate pro-inflammatory cytokines obtained from a subset of patients in each arm of the study. Is this then a case of “back to the future”? Are we back to 1989, with no apparent advantage with the oscillator? Even if one believes that there is no obvious advantage for HFOV, this belief should not produce anxiety, because the results for both groups are encouraging. Key findings here included a low mortality rate (combined 10% to discharge) and, given the population at risk, a modest incidence of CLD of 25%, defined as need for supplemental oxygen or for assisted ventilation at 36 weeks’ postmenstrual age. The results represent significant improvement from those of 10 years ago. There is still a disturbingly large incidence of intracranial hemorrhage (13.5% of all patients). Other problems of extreme prematurity, such as necrotizing enterocolitis and retinopathy of prematurity, were not banished from either group. These results provide an important new benchmark for neonatologists worldwide. The work also reminds us that paying attention to the minutiae of assisted ventilation is crucial. Their results also confront us with our limits of understanding the mechanisms of injury in these half-formed lungs and of the limits of our understanding of the long-term consequences of therapy with positive-pressure ventilation. It is crucial that Thome et al provide longer-term follow-up data, using sophisticated pulmonary function tests, to help answer questions about ultimate pulmonary growth and differentiation after exposure to these 2 modes of ventilation. In conclusion, both techniques of assisted ventilation used in this report appear to be winners. But an even bigger success awaits the reduction in the incidence of extreme prematurity. That is now neonatology’s Holy Grail.