High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669]. The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome. A prospective randomized comparison of conventional mechanical ventilation and very early high frequency oscillatory ventilation in extremely premature newborns with respiratory distress syndrome. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics. High-frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation. Plasma soluble intercellular adhesion molecule-1 (sICAM-1) in pediatric ARDS during high frequency oscillatory ventilation: a predictor of mortality.
To compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted.
                Patients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up.
                The study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22-2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43-3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI.
                No significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI. 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. 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. To compare the safety and efficacy of high-frequency oscillation (HFO) with conventional ventilation in the treatment of neonates with respiratory failure.
                We conducted a multicenter, prospective, randomized trial. Patients were stratified according to pulmonary diagnosis and then were randomly selected for conventional ventilation or HFO. A balanced crossover design offered patients who met criteria of treatment failure a trial of the alternative mode of ventilation.
                Four tertiary, level 3 neonatal intensive care units accepting regional referrals for extracorporeal membrane oxygenation.
                Neonates were eligible for enrollment if their gestational age was > 34 weeks, their birth weight was > or = 2 kg, they were < 14 days of age, they required fractional inspired oxygen > 0.50 and a mean airway pressure > 0.98 kPa (10 cm H2O) to support adequate oxygenation, and they required a peak inspiratory pressure > 2.9 kPa (30 cm H2O) and a rate > 40 breaths per minute to support adequate ventilation. Exclusion criteria were lethal congenital anomalies, profound shock, need for cardiopulmonary resuscitation, and failure to obtain consent.
                Of 79 patients studied, 40 were assigned to conventional ventilation and 39 to HFO. Neonates randomly assigned to HFO required higher peak pressure (3.8 +/- 0.5 vs 3.3 +/- 0.8 kPa, 39 +/- 5 vs 34 +/- 8 cm H2O; p = 0.004) and more often met extracorporeal membrane oxygenation criteria (67% vs 40%; p = 0.03) at study entry than did those given conventional ventilation. Twenty-four patients (60%) assigned to conventional ventilation met treatment failure criteria compared with 17 (44%) of those assigned to HFO (not significant). Of the 24 patients in whom conventional ventilation failed, 15 (63%) responded to HFO; 4 (23%) of the 17 in whom HFO failed responded to conventional ventilation (p = 0.03). There were no differences between the two groups with respect to outcome, need for extracorporeal membrane oxygenation, or complications.
                We conclude that HFO is a safe and effective rescue technique in the treatment of neonates with respiratory failure in whom conventional ventilation fails. Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed.
                To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2] < 60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater.
                Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p < 0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%).
                We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN. We previously reported improved oxygenation, but no change, in rates of extracorporeal membrane oxygenation (ECMO) use or death among infants with persistent pulmonary hypertension of the newborn who received inhaled nitric oxide (NO) with conventional ventilation, irrespective of lung disease. The goal of our study was to determine whether treatment with inhaled NO improves oxygenation and clinical outcomes in infants with persistent pulmonary hypertension of the newborn and associated lung disease who are ventilated with high-frequency oscillatory ventilation (HFOV).
                Single-center, prospective, randomized, controlled trial.
                Newborn intensive care unit of a tertiary care teaching hospital.
                We studied infants with a gestational age of > or =34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (PaO2 < or =100 mm Hg on FIO2 = 1.0), despite optimal medical management Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded.
                The treatment group received inhaled NO, whereas the control group did not. Adjunct therapies and ECMO criteria were the same in the two groups of patients. Investigators and clinicians were not masked as to treatment assignment, and no crossover of patients was permitted.
                Primary outcome variables were mortality and use of ECMO. Secondary outcomes included change in oxygenation and duration of mechanical ventilatory support and supplemental oxygen therapy. Forty-two patients were enrolled. Baseline oxygenation and clinical characteristics were similar in the two groups of patients. Infants in the inhaled NO group (n = 21) had improved measures of oxygenation at 15 mins and 1 hr after enrollment compared with infants in the control group (n = 20). Fewer infants in the inhaled NO group compared with the control group were treated with ECMO (14% vs. 55%, respectively; p = .007). Mortality did not differ with treatment assignment.
                Among infants ventilated by HFOV, those receiving inhaled NO had a reduced need for ECMO. We speculate that HFOV enhances the effectiveness of inhaled NO treatment in infants with persistent pulmonary hypertension of the newborn and associated lung disease. High-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) have been reported to improve oxygenation in children with acute hypoxemic respiratory failure (AHRF), but their roles in the treatment of AHRF remains unknown. The use of HFOV improves oxygenation by increasing lung recruitment. iNO can improve oxygenation in AHRF, but it may have limited efficacy in patients with poor lung inflation. Based on these findings, we hypothesized that the combined treatment of HFOV and inhalation of low-dose NO would improve oxygenation and survival in children with severe AHRF compared with children treated with conventional mechanical ventilation (CMV) or either treatment alone.
                Tertiary pediatric intensive care units at seven academic centers.
                Post hoc analysis of data from children enrolled in a multicenter, randomized, masked study of the use of iNO in the treatment of AHRF.
                A total of 108 pediatric patients with AHRF defined as an oxygenation index of >15 twice within 6 hrs. Mode of ventilation (HFOV or CMV) was determined by the patient's physician based on guidelines to maximize oxygenation. The patient was then randomized to treatment with or without iNO. Comparisons were made between patients who were treated with HFOV plus iNO (n = 14), HFOV alone (n = 12), CMV plus iNO (n = 35), and CMV alone (n = 38).
                Ventilation with CMV or HFOV with or without iNO.
                We found that the change in Pao /Fio ratio was greatest in the HFOV plus iNO group compared with the other treatment groups at 4 hrs (p =.02) and 12 hrs (p =.01). After 24 hrs of treatment, both HFOV plus iNO and HFOV alone resulted in greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.005). After 72 hrs, treatment with HFOV alone resulted in a greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.03). There was no difference in predefined treatment failures between treatment groups.
                We conclude that the combination of HFOV with iNO causes a greater improvement in oxygenation than either treatment strategy alone in children with severe AHRF. We speculate that the enhanced lung recruitment by HFOV enhances the effects of low dose iNO on gas exchange. The improvement in oxygenation with prone positioning is not persistent when patients with acute respiratory distress syndrome (ARDS) are turned supine. High-frequency oscillatory ventilation (HFOV) aims to maintain an open lung volume by the application of a constant mean airway pressure. The aim of this study was to show that HFOV is able to prevent the impairment in oxygenation when ARDS patients are turned back from the prone to the supine position.
                Prospective, comparative randomized study.
                A medical intensive care unit.
                Forty-three ARDS patients with a Pao2/Fio2 ratio <150 at positive end-expiratory pressure > or =5 cm H2O.
                After an optimization period, the patients were assigned to one of three groups: a) conventional lung-protective mechanical ventilation in the prone position (12 hrs) followed by a 12-hr period of conventional lung-protective mechanical ventilation in the supine position (CV(prone)-CV(supine)); b) conventional lung-protective mechanical ventilation in the supine position (12 hrs) followed by HFOV in the supine position (12 hrs) (CV(supine)-HFOV(supine)); or c) conventional lung-protective mechanical ventilation in the prone position (12 hrs) followed by HFOV in the supine position (CV(prone)-HFOV(supine) group).
                Pao2/Fio2 ratio was higher at the end of the study period in the CV(prone)-HFOV(supine) group than in the CV(prone)-CV(supine) group (p < .02). Venous admixture at the end of the study period was lower in the CV(prone)-HFOV(supine) group than in the two other groups.
                HFOV maintained the improvement in oxygenation related to prone positioning when ARDS patients were returned to the supine position. Soluble intercellular adhesion molecule-1 (sICAM-1), an important adhesion molecule that mediates leukocyte-endothelial interaction, has been identified as a marker for the outcome of acute respiratory tract infection. We postulate that plasma ICAM-1 may be a valuable marker for both biological and clinical severity of acute respiratory distress syndrome (ARDS). Sixteen pediatric patients (> 1 month and < 15 years of age) diagnosed with ARDS were recruited from the Pediatric Intensive Care Unit at King Chulalongkorn Memorial University Hospital, Bangkok. The patients were randomized to receive either high frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation. Plasma sICAM-1 was measured by enzyme linked immunosorbent assay (ELISA) on days 1, 3, 5 and 7 of ARDS. Plasma sICAM-1 levels in survivors and non-survivors of the HFOV and conventional treatment groups were compared. Nine and 7 patients constituted the control group receiving conventional treatment and HFOV group, respectively. Overall nine patients survived. The patients in the HFOV group had a better chance of survival compared to the controls (71% versus 31.5%), but it was not statistically significant (p = 0.2). The overall mortality was 45.7%. The mean plasma sICAM-1 levels (n = 13/16) were significantly elevated among non-survival patients as compared to survival patients at all time points, which indicates that an unfavorable outcome in ARDS is related to the degree of epithelial and endothelial alveolar cell injury. The elevation of plasma slCAM-1 on day 3 provided the best predictor of mortality (likelihood ratio 11.9, p < 0.001). It was concluded that HFOV facilitated a potentially better outcome compared to conventional treatment and it was associated with less lung injuries evidenced by lower plasma sICAM-1.
The findings of this systematic review suggest that HFO was a promising treatment for ALI and ARDS prior to the uptake of current lung protective ventilation strategies. These findings may not be applicable with current conventional care, pending the results of large multi-centre trials currently underway.