A prospective randomized comparison of conventional mechanical ventilation and very early high frequency oscillatory ventilation in extremely premature newborns with respiratory distress syndrome. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant. High-frequency oscillatory ventilation versus conventional mechanical ventilation for very-low-birth-weight infants. Volume guarantee versus high-frequency ventilation: lung inflammation in preterm infants. The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome. HFOV in premature neonates: effects on pulmonary mechanics and epithelial lining fluid cytokines. A randomized controlled trial. Randomized comparison of high-frequency ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure. Effects of pressure support ventilation plus volume guarantee vs. high-frequency oscillatory ventilation on lung inflammation in preterm infants. High-frequency oscillatory ventilation for the prevention of chronic lung disease of prematurity. Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome. Early high-frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation in very low birth weight infants: a pilot study of two ventilation protocols.
To compare the effectiveness and safety of very early high-frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CMV) in treatment of the respiratory distress syndrome (RDS) and to evaluate their impact on the incidence of chronic pulmonary disease and early and late morbidity of very low-birthweight neonates.
                A prospective randomized clinical trial.
                Tertiary neonatal intensive care unit in the Perinatology Center in Prague.
                43 premature newborns, delivered in the Department of Obstetrics in the Perinatology Center, were randomly divided into two groups (HFOV and CMV) immediately after delivery; 2 patients in each group died, 2 fulfilled crossover criteria from CMV to HFOV, and 2 were excluded because of congenital malformations. Nineteen patients treated with HFOV were therefore compared with 18 infants in the CMV group.
                The two contrasting modes of ventilation were introduced immediately after intubation. Maintenance of optimal lung volume in HFOV to optimize oxygenation and the therapeutic administration of surfactant after fulfilling defined criteria are important points of the strategy and design of the study.
                Except for a higher proportion of males in the HFOV group (p<0.02), the basic clinical characteristics (gestational age, birthweight, Apgar score at 5 min, umbilical arterial pH), the two groups were similar. In the acute stage of RDS, infants treated with HFOV had higher proximal airway distending pressure with HFOV for 6 h after delivery (p<0.05). For a period of 12 h after delivery lower values for the alveolar-arterial oxygen difference (p<0.03) were noted. The number of patients who did not require surfactant treatment was higher in the HFOV group (11 vs. 1, p<0.001). In the HFOV group the authors found a lower roentgenographic score at 30 days of age (p<0.03) and a lower clinical score in the 36th postconceptional week (p<0.05), using these two scoring systems for assessing chronic lung disease according to Toce scale. The incidence of pneumothorax, pulmonary interstitial emphysema, intraventricular hemorrhage and retinopathy of prematurity in both groups was the same.
                HFOV, when applied early and when the clinical strategy of maintenance of optimal lung volume is used, improves oxygenation in the acute stage of RDS, reduces the need of surfactant administration, and can decrease the injury to lung tissue even in extremely immature newborns to whom surfactant is administered therapeutically. Inhaled nitric oxide improves gas exchange, decreases pulmonary vascular lability, and reduces pulmonary inflammation. We hypothesized that the use of inhaled nitric oxide would decrease the incidence of chronic lung disease and death in premature infants with the respiratory distress syndrome.
                We conducted a randomized, double-blind, placebo-controlled study of the effect of inhaled nitric oxide during the first week of life on the incidence of chronic lung disease and death in premature infants (less than 34 weeks' gestation) who were undergoing mechanical ventilation for the respiratory distress syndrome. Infants were randomly assigned to receive inhaled nitric oxide (10 ppm on day 1, followed by 5 ppm for six days) or inhaled oxygen placebo for seven days. We further randomly assigned the infants in each group to receive intermittent mandatory or high-frequency oscillatory ventilation.
                A total of 207 premature infants were enrolled. In the group given inhaled nitric oxide, 51 infants (48.6 percent) died or had chronic lung disease, as compared with 65 infants (63.7 percent) in the placebo group (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97; P=0.03). There was no significant difference between the nitric oxide and placebo groups in the overall incidence of intraventricular hemorrhage and periventricular leukomalacia (33.3 percent and 38.2 percent, respectively), but the group given inhaled nitric oxide had a lower incidence of severe intraventricular hemorrhage and periventricular leukomalacia (12.4 percent vs. 23.5 percent; relative risk, 0.53; 95 percent confidence interval, 0.28 to 0.98; P=0.04). The type of ventilation had no significant effect on the outcome.
                The use of inhaled nitric oxide in premature infants with the respiratory distress syndrome decreases the incidence of chronic lung disease and death.
                Copyright 2003 Massachusetts Medical Society To compare high-frequency oscillatory ventilation (HFOV) and intermittent positive pressure ventilation (IPPV) as a primary ventilation mode in preterm infants with respiratory distress syndrome. Primary end points were survival and maintenance of the randomized ventilation mode.
                Prospective, multicenter, randomized clinical trial.
                Level III neonatal intensive care units at three university children's hospitals.
                Ninety-six premature infants (gestational age < 32 weeks) randomly assigned to HFOV or IPPV within the first 2 hours of life. All patients received a natural surfactant. No differences were found between the study groups with respect to the demographic data or the severity of respiratory distress syndrome. Infants were stratified at randomization, by birth weight, into two groups: 750 to 1000 gm (n = 32) and 1001 to 1500 gm (n = 64). The centers involved complied with a study protocol that planned a reduction in respiratory pressures when the infant's oxygen requirement had reached a fractional concentration of inspired oxygen of 0.6.
                Five patients in the HFOV group died, and eight patients did not respond to the randomized ventilation mode; whereas four patients in the IPPV group died, and nine were switched to HFOV. No differences were found in gas exchange or ventilator support over the first 72 hours. Premature infants with a birth weight < 1000 gm had a significantly shorter course to reach fractional concentration of inspired oxygen of 0.21 while receiving IPPV than those receiving HFOV (9.3+/-4.5 days vs 27.5+/-10.2 days, p = 0.01). No differences were found between the groups in extraalveolar air (HFOV seven; IPPV, seven) and intracranial bleeding (HFOV, nine; IPPV, eight).
                After surfactant treatment, HFOV, as a primary ventilation mode in premature infants with respiratory distress syndrome, is as safe and efficacious as conventional ventilation. The efficacy and safety of early high-frequency oscillatory ventilation as compared with conventional synchronized intermittent mandatory ventilation for the treatment of infants with very low birth weight have not been established.
                We conducted a randomized, multicenter clinical trial to determine whether infants treated with early high-frequency oscillatory ventilation were more likely than infants treated with synchronized intermittent mandatory ventilation to be alive without requiring supplemental oxygen at 36 weeks of postmenstrual age. Eligible infants weighed 601 to 1200 g at birth, were less than four hours of age, had received one dose of surfactant, and required ventilation with a mean airway pressure of at least 6 cm of water and a fraction of inspired oxygen of at least 0.25. Infants were stratified according to birth weight and exposure to prenatal corticosteroids and then randomly assigned to high-frequency oscillatory ventilation or synchronized intermittent mandatory ventilation. Ventilation was managed according to protocols designed to optimize lung inflation and blood gas values.
                Five hundred infants were enrolled in the study. Infants randomly assigned to high-frequency oscillatory ventilation were successfully extubated earlier than infants assigned to synchronized intermittent mandatory ventilation (P<0.001). Of infants assigned to high-frequency oscillatory ventilation, 56 percent were alive without a need for supplemental oxygen at 36 weeks of postmenstrual age, as compared with 47 percent of those receiving synchronized intermittent mandatory ventilation (P=0.046). There was no difference between the groups in the risk of intracranial hemorrhage, cystic periventricular leukomalacia, or other complications.
                There was a small but significant benefit of high-frequency oscillatory ventilation in terms of the pulmonary outcome for very-low-birth-weight infants without an increase in the occurrence of other complications of premature birth.
                Copyright 2002 Massachusetts Medical Society Appropriate ventilation together with improvement of clinical care of premature babies can contribute to reducing lung inflammation, known to represent the "primum movens" of bronchopulmonary dysplasia (BPD). High-frequency oscillatory ventilation (HFOV) and volume-guarantee (VG) ventilation are effective in the treatment of neonatal respiratory distress syndrome (RDS).
                To assess the potential of HFOV and VG to prevent BPD in the acute phase of RDS, by a randomised clinical study evaluating lung inflammation in premature infants. Study design: Forty infants (gestational age 25-32 weeks) with RDS were assigned to assist-control ventilation plus VG (Vt = 5 ml/kg) or HFOV (both with a Dräger Babylog 8000 plus ventilator). Levels of interleukin (IL) 6, IL8 and tumour necrosis factor were determined in tracheal aspirate on days 1, 3 and 7 of life.
                In the HFOV group IL6 levels were significantly higher on day 3 (0.5 (0.2) vs assisted-control ventilation plus VG group 0.1 (0.2) ng/ml) and oxygen dependency was significantly longer (36 (23) vs assisted-control ventilation plus VG group 19 (11) days).
                VG ventilation is an effective lung-protective strategy to be used in acute RDS, inducing a lower expression of early inflammation markers than HFOV. Whether the use of this initial ventilatory strategy contributes to the prevention of BPD requires further studies. To compare the hospital course and clinical outcome of preterm infants with respiratory distress syndrome treated with surfactant and managed with high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CV) as their primary mode of ventilator support.
                A prospective randomized clinical trial.
                Three community-based level III neonatal intensive care units.
                A total of 125 neonates who were 35 weeks or less estimated gestation requiring intubation and assisted ventilation for respiratory distress syndrome with arterial to alveolar oxygen ratio less than .50.
                Patients were randomized to continue CV (61 patients) or be changed to HFOV (64 patients) after exogenous surfactant administration (100 mg/kg). HFOV was used in a strategy to promote lung recruitment and maintain lung volume. Protocol respiratory care guidelines were followed; otherwise routine care was provided by each neonatal intensive care unit.
                No differences were noted in demographic features between the two study groups. The study population birth weight was 1.51 +/- .47 kg (mean +/- SD), gestational age was 30.9 +/- 2.5 weeks, and study entry age was 2 to 3 hours. Patients randomized to HFOV demonstrated the following significant findings compared with CV-treated patients: vasopressor support was less intensive; surfactant redosing was not as frequent; oxygenation improved more rapidly and remained higher during the first 7 days; fewer infants required prolonged supplemental oxygen or ventilator support; treatment failure was reduced; more patients survived without chronic lung disease at 30 days; need for continuous supplemental oxygen at discharge was less; frequency of necrotizing enterocolitis illness was lower; there were fewer abnormal hearing tests; and hospital costs were decreased. No differences were seen between the two study groups in the frequency or severity of patent ductus arteriosus, air leak, retinopathy of prematurity, or intraventricular hemorrhage. Length of hospital stay and survival to discharge were similar for HFOV- and CV-treated infants.
                When used early with a lung recruitment strategy, HFOV after surfactant replacement resulted in clinical outcomes consistent with a reduction in both acute and chronic lung injury. Benefit was evident for preterm infants both less than or equal to 1 kg and more than 1 kg. In addition, early HFOV treatment may have had a more global effect on patient health throughout the hospitalization, resulting in reduced morbidity and decreased health care cost. Ventilation strategies for preterm neonates may influence the severity of pulmonary dysfunction and later development of chronic lung disease. The objective of this report is to compare the effects of high-frequency oscillatory ventilation (HFOV) versus synchronized intermittent mandatory ventilation (sIMV) from the points of views of biochemical and functional variables.
                Randomized controlled trial.
                Third level NICU.
                Forty preterm neonates with a gestational age of 24-29 weeks were randomly assigned to one of the two above-mentioned ventilation strategies within 30 min from birth.
                At 1, 3, 5, and 7 days, the babies were monitored by means of ventilator indices, pulmonary function, and eight pro-inflammatory or anti-inflammatory cytokines measured in bronchoalveolar lavage fluid. The neonates assigned to the HFOV procedure benefited from early and sustained improvement in pulmonary mechanics and gas exchange-significantly higher dynamic respiratory compliance values, significantly lower expiratory airway resistance and oxygenation index values-with earlier extubation as compared to the neonates assigned to sIMV treatment, and showed significantly lower transforming growth factor-beta1 concentrations in bronchoalveolar lavage fluid.
                The results of this randomized clinical trial support the hypothesis that early and exclusive use of HFOV, combined with optimum volume strategy, has a beneficial effect during the acute phase of lung injury. In a randomized, controlled, multicenter trial, we tested the hypothesis that high-frequency ventilation (HFV) with a high lung volume strategy results in fewer treatment failures than intermittent positive pressure ventilation (IPPV) with high rates and low peak inspiratory pressures.
                Infants with a gestational age between >/=24 weeks and <30 weeks, requiring mechanical ventilation within 6 hours of birth, were randomly assigned to receive either IPPV or HFV until 240 hours after randomization, extubation, or meeting treatment failure criteria. Treatment failure, the primary end point, was determined when air leaks, an oxygenation index >35 to 45 (depending on gestational age), death, or chronic lung disease occurred. Chronic lung disease was defined as persistent requirement of mechanical ventilation, continuous positive airway pressure, or supplemental oxygen at a postmenstrual age of 36 weeks. Secondary end points included the incidence of intracranial hemorrhage.
                The third scheduled interim analysis led to termination of the trial after recruitment of 284 infants. Treatment failure criteria were met by 46% of infants receiving IPPV and 54% of infants receiving HFV (1-tailed primary hypothesis, P =.92; 2-tailed chi2 test, P =.15). Air leaks occurred in 31% and 42% (P =.042), CLD in 23% and 25%, and grade 3-4 intracranial hemorrhage in 13% and 14% of IPPV-treated and HFV-treated patients, respectively. The mortality rate before discharge was 10% in both groups.
                HFV with a high lung volume strategy did not cause less lung injury in preterm infants than IPPV with a high rate and low peak inspiratory pressures. The aim of the present study was to evaluate if high-frequency oscillatory ventilation (HFOV) might reduce lung inflammation in preterm infants with infant respiratory distress syndrome (RDS) in comparison with the early application of another potentially lung-protective ventilation strategy, such as pressure support ventilation plus volume guarantee (PSV + VG). Infants at less than 30 weeks of gestation with RDS were enrolled consecutively in the study if they required mechanical ventilation, and were randomly allocated to receive HFOV or PSV + VG. Bronchial aspirate samples for the measurement of interleukin (IL)-1beta, IL-8, and IL-10 were obtained before surfactant treatment (T1), after 6-18 hr of ventilation (T2), after 24-48 hr of ventilation (T3), and before extubation (T4). Thirteen patients were enrolled in the HFOV group, and 12 in the PSV + VG group. The mean values of IL-1beta, IL-8, and IL-10 at T4 were lower in the HFOV group than in the PSV + VG group. The present study demonstrates that early treatment with HFOV is associated with a reduction of lung inflammation in comparison with PSV + VG in preterm infants with RDS.
                (c) 2005 Wiley-Liss, Inc. There remains uncertainty concerning the safety and efficacy of high-frequency oscillatory ventilation as compared with those of conventional ventilation for the respiratory support of very preterm infants. We conducted a multicenter trial to determine whether early intervention with high-frequency oscillatory ventilation reduced mortality and the incidence of chronic lung disease among newborns with a gestational age of 28 weeks or less.
                We randomly assigned preterm infants with a gestational age of 23 to 28 weeks to either conventional ventilation or high-frequency oscillatory ventilation within one hour after birth. Randomization was stratified according to center and gestational age (23 to 25 weeks or 26 to 28 weeks).
                A total of 400 infants were assigned to high-frequency oscillatory ventilation, and 397 were assigned to conventional ventilation. The composite primary outcome (death or chronic lung disease, diagnosed at 36 weeks of postmenstrual age) occurred in 66 percent of the infants assigned to receive high-frequency oscillatory ventilation and 68 percent of those in the conventional-ventilation group (relative risk in the group assigned to high-frequency oscillatory ventilation, 0.98; 95 percent confidence interval, 0.89 to 1.08). Similar proportions of infants died or had chronic lung disease in each gestational-age group. In both treatment groups treatment failure occurred in 10 percent of infants (relative risk in the group assigned to high-frequency oscillatory ventilation, 0.99; 95 percent confidence interval, 0.66 to 1.50). There were no significant differences between the groups in a range of other secondary outcome measures, including serious brain injury and air leak.
                The results obtained with high-frequency oscillatory ventilation and conventional ventilation do not differ significantly in the early treatment of respiratory disease in very preterm infants. Assessment of long-term effects will require additional follow-up.
                Copyright 2002 Massachusetts Medical Society Early use of high-frequency ventilation and exogenous surfactant is proposed as the optimal mode of ventilatory support in infants with respiratory distress syndrome. In very premature infants, we tested the hypothesis that high-frequency versus conventional ventilation could decrease exogenous surfactant requirements and improve pulmonary outcome, without altering the complication rate, including that of severe intraventricular hemorrhage.
                Preterm infants with a postmenstrual age of 24 to 29 weeks, presenting with respiratory distress syndrome were randomly assigned to high-frequency oscillatory ventilation (lung volume recruitment strategy) or conventional ventilation.
                Two hundred seventy-three infants were enrolled. One hundred fifty-three had a postmenstrual age of 24 to 27 weeks, and 143 had a birth weight </=1000 g. One hundred thirty-four infants were randomized at 142 minutes of life (median) to receive conventional ventilation (mean postmenstrual age at birth: 27. 6 +/- 1.5 weeks; mean birth weight: 997 +/- 245 g); and 139 infants were randomized at 145 minutes of life to receive high-frequency ventilation (mean postmenstrual age at birth: 27.5 +/- 1.4 weeks; mean birth weight: 976 +/- 219 g). High-frequency ventilation, compared with conventional ventilation, was associated with a twofold reduction in the requirement for >/=2 instillations of exogenous surfactant (30% vs 62%; odds ratio:.27; 95% confidence interval:.16-.44) and no difference in pulmonary outcome. The incidence of severe intraventricular hemorrhage was 24% in the high-frequency group and 14% in the conventional ventilation group (adjusted odds ratio: 1.50; 95% confidence interval:.68-3.30).
                Early use of high-frequency oscillatory ventilation in very premature infants decreases exogenous surfactant requirements, does not improve the pulmonary outcome, and may be associated with an increased incidence of severe intraventricular hemorrhage. To evaluate the feasibility of conducting a prospective, randomized trial comparing early high-frequency oscillatory ventilation (HFOV) to synchronized intermittent mandatory ventilation (SIMV) in very low birth weight (VLBW) premature infants. This pilot study evaluated two ventilator management protocols to determine how well they could be implemented in a multicenter clinical trial. Although this pilot study was not powered to detect differences in outcome, we also collected outcome data.
                Prospective, multicenter, randomized pilot study.
                Seven tertiary-level intensive care nurseries with previous experience with both HFOV and flow-triggered SIMV.
                Fifty infants weighing 501 to 1200 g, less than 4 hours of age, who had received one dose of surfactant and required ventilation with mean airway pressure > or =6 cm H2O and F(I)O2 > or =0.25, and had an anticipated duration of ventilation greater than 24 hours.
                Patients were stratified by birth weight and prenatal steroid status, then randomized to either HFOV or SIMV with tidal volume monitoring. Ventilator management for patients in both study arms was strictly governed by protocols that included optimizing lung inflation and blood gases, weaning strategies, and extubation criteria.
                Data were collected using the tools planned for the larger collaborative study. Protocol compliance was closely monitored, with successive changes in the protocol made as necessary to improve clarity and increase compliance. The incidence of major neonatal adverse outcomes was recorded.
                Data are presented for 24 HFOV and 24 SIMV infants (two infants, twins, were withdrawn from the study at parent's request). Nineteen of the 24 HFOV infants and 20 of the 24 SIMV infants survived to 36 weeks corrected age. Age at final extubation for survivors was 16+/-16 (mean+/-SD) days for HFOV infants and 24+/-24 days for SIMV infants. At 36 weeks corrected age, 14 of the 19 HFOV survivors were extubated and in room air, whereas 5 required supplemental oxygen. In comparison, 6 of the 20 SIMV survivors were extubated and in room air, whereas 14 required supplemental oxygen. Grade III/IV IVH and/or periventricular leukomalacia occurred in 2 HFOV and 2 SIMV patients. Overall compliance with the ventilator protocols was 82% for the SIMV protocol, and 88% for the HFOV protocol.
                The preliminary outcome data supports conducting the large randomized trial, which began in July of 1998. The protocols for the ventilator management of VLBW infants, both with HFOV and with SIMV were easily implemented and consistently followed, and are presented here.
There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.