Randomized trial of permissive hypercapnia in preterm infants. Efficacy of nocturnal nasal ventilation in stable, severe chronic obstructive pulmonary disease during a 3-month controlled trial. Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Impact of volume guarantee ventilation on arterial carbon dioxide tension in newborn infants: a randomised controlled trial. Volume guarantee: stability of tidal volume and incidence of hypocarbia. Inhaled nitric oxide in term infants with hypoxemic respiratory failure. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.
To determine whether a ventilatory strategy of permissive hypercapnia (PHC) reduces the duration of assisted ventilation in surfactant-treated neonates weighing 601 to 1250 g at birth.
                Forty-nine surfactant-treated preterm infants (birth weight: 854 +/- 163 g; gestational age: 26 +/- 1.4 weeks) receiving assisted ventilation were randomized during the first 24 hours of age to a PHC group (PaCO(2): 45-55 mm Hg) or to a normocapnia group (NC; PaCO(2): 35-45 mm Hg). The primary outcome measure was the total number of days on assisted ventilation. Uniform extubation and reintubation criteria were used for both groups. All patients received aminophylline before extubation.
                The total number of days on assisted ventilation expressed as median (25th-75th percentiles) was 2.5 (1.5-11.5) in the PHC group and 9.5 (2.0-22.5) in the NC group (Mann-Whitney U test). The number of patients on assisted ventilation throughout the first 96 hours after randomization was lower in the PHC group (log rank test). During that period, the ventilated patients in the PHC group had a higher PaCO(2) and lower peak inspiratory pressure, mean airway pressure, and ventilator rate than did those in the NC group. The percentage of patients requiring reintubation within 24 hours postextubation (PHC 17% vs NC 28%) and supplemental oxygen at 28 days of life (PHC 43% vs NC 64%) and the total days of oxygen supplementation (PHC 15 [4-53] vs NC 32 [17-50]) did not differ between the groups. There were no differences in mortality, air leaks, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or patent ductus arteriosus.
                A ventilatory strategy of PHC in preterm infants who receive assisted ventilation is feasible, seems safe, and may reduce the duration of assisted ventilation. assisted ventilation, respiratory distress syndrome, gentle ventilation, lung injury. To evaluate the efficacy of nocturnal nasal ventilation (NNV) in patients with rigidly defined, severe but stable chronic obstructive pulmonary disease (COPD) and hypercapnia.
                By randomization, eligible patients were assigned to an active or a sham treatment arm. Data from these two groups were analyzed statistically.
                Initially, 35 patients with severe COPD (forced expiratory volume in 1 second [FEV1] of less than 40% predicted) and daytime hypercapnia (arterial carbon dioxide tension [PaCO2] of more than 45 mm Hg) were enrolled in a 3-month NNV trial. After a minimal observation period of 6 weeks, 13 patients were judged to be clinically stable and were randomized to NNV (N = 7) or sham (N = 6) treatment, consisting of nightly use of a bilevel positive airway pressure (PAP) device set to deliver an inspiratory pressure of either 10 or 0 cm of water (H2O). The device was used in the spontaneous or timed mode and set to a minimal expiratory pressure of 2 cm H2O. Patients underwent extensive physiologic testing including polysomnography and were introduced to the bilevel PAP system during a 2.5-day hospital stay.
                The NNV and sham treatment groups were similar in mean age (71.0 versus 66.5 years), PaCO2 (54.7 versus 48.5 mm Hg), and FEV1 (0.62 versus 0.72 L). Only four of seven patients in the NNV group were still using the bilevel PAP device at the completion of the trial, as opposed to all six patients in the sham group. Only one patient had a substantial reduction in PaCO2 - from 50 mm Hg at baseline to 43 mm Hg after 3 months of NNV. He declined further NNV treatment with bilevel PAP. Sham treatment did not lower PaCO2. Lung function, nocturnal oxygen saturation, and sleep efficiency remained unchanged in both groups.
                Disabled but clinically stable patients with COPD and hypercapnia do not readily accept and are unlikely to benefit from NNV. 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. To compare the effects of the two modes of ventilation, synchronous intermittent positive pressure ventilation (SIPPV) and SIPPV with Volume Guarantee (VG), on arterial carbon dioxide tension (PaCO(2)) immediately after neonatal unit admission.
                Randomised study of ventilation mode for premature inborn infants admitted to two tertiary neonatal units. After admission, infants were randomised to receive either SIPPV or VG using a Dräger Babylog 8000 plus ventilator. In the SIPPV group, peak airway pressure was set clinically. In the VG group, desired tidal volume was set at 4 ml/kg, with the ventilator adjusting peak inspiratory pressure to deliver this volume. The study was completed once the first arterial PaCO(2) was available, with the desirable range defined as 5-7 kPa.
                PaCO(2) was significantly higher in the VG group (VG: 5.7 kPa, SIPPV: 4.9 kPa; p=0.03). The VG group had fewer out-of-range PaCO(2) values (VG: 42%, SIPPV: 57%) and fewer instances of hypocarbia <5 kPa (VG: 32%, SIPPV: 57%) but neither difference achieved statistical significance. Regression analysis showed PaCO(2) was negatively correlated with gestation (r=-0.41, p=0.01) and also with the mode of ventilation (r=0.32, p<0.05). In the VG group, all infants 23-25 weeks' gestation had out-of-range PaCO(2) values. VG significantly reduced the incidence of out-of-range PaCO(2) and hypocarbia in infants over 25 weeks' gestation (VG: 27%, SIPPV: 61%; p<0.05).
                Using this strategy, VG appears feasible in the initial stabilisation of infants over 25 weeks' gestation, with a halving of the incidence of hypocarbia. In the small number of babies studied below this gestation, VG was not found to be effective. Excessive tidal volume (V(T)) can lead to lung injury, hypocarbia, and neurologic damage. Volume guarantee (VG) uses exhaled V(T) as the control variable to reduce the risk of volutrauma and more closely control PaCO(2). Our objective was to test the hypothesis that VG combined with assist/control (A/C) will maintain PaCO(2) and V(T) within target range more consistently than assist/control alone during the first 72 hr of life in ventilated preterm infants. Eligible infants were randomly assigned to A/C + VG or A/C alone. Data were recorded directly from the pressure and volume module of the Draeger Babylog 8000+ ventilator. Arterial blood gases were obtained every 2-6 hr, as clinically indicated. In A/C, inspiratory pressure was adjusted to achieve a V(T) of 4-6 ml/kg. In VG, the target V(T) was 5 ml/kg. Subsequent adjustments were made by the clinical team in response to arterial blood gas measurements (ABG). Proportion of breaths and PaCO(2) values outside the target range were compared by chi(2), and continuous variables by t-test. There were no differences in demographic or baseline ventilator variables between the 18 infants in the two groups. For 1,805/11,950 breaths (15.1%), V(T) was > target with A/C + VG, vs. 2,503/9,853 (25.4%) with A/C (P < 0.001). V(T) was < target for 21.7% of breaths with A/C + VG, vs. 35.7% with A/C (P < 0.001). Twenty percent of PaCO(2) values were < target, with A/C + VG vs. 36.3% with A/C, P < 0.05. The proportion of PaCO(2) values > target was similar in the two groups. Oxygenation and mean pH were not different. No complications related to mechanical ventilation were observed. In conclusion, VG significantly reduced hypocarbia and excessively large V(T). This suggests the potential to reduce pulmonary and neurologic complications of mechanical ventilation. Larger studies are needed to establish safety and demonstrate such benefits.
                Copyright 2004 Wiley-Liss, Inc. To determine whether inhaled nitric oxide (NO) administered during conventional mechanical ventilation could produce improvements in oxygenation and reduce the incidence of meeting extracorporeal membrane oxygenation (ECMO) criteria in infants with hypoxemia.
                Prospective, randomized, controlled trial. Enrolled infants were assigned to conventional treatment with or without adjunctive inhaled NO. Control infants meeting failure criteria (partial pressure of arterial oxygen (PaO2)<80 mm Hg (10.7 kPa)) were allowed to cross over. Caregivers were not masked to group assignment.
                Neonatal intensive care units at the University of Alabama Hospital and the Children's Hospital of Alabama, October 1993 to May 1994.
                Newborn infants, both term and near-term, with PaO2 less than 100 mm Hg (13.3 kPa) who were receiving mechanical ventilation with 100% oxygen. Exclusion criteria included major congenital anomalies, diaphragmatic hernia, profound asphyxia, and significant bleeding.
                Inhaled NO was initiated in the NO group at a dose of 20 to 40 ppm and advanced stepwise to 80 ppm if PaO2 remained less than 100 mm Hg (13.3 kPa).
                Primary outcome variables were treatment failure and meeting of ECMO criteria before crossover. Improvement in oxygenation and ultimate use of ECMO or high-frequency oscillatory ventilation were secondary outcome variables.
                Seventeen neonates with hypoxemia were enrolled; 16 had echocardiographic evidence of pulmonary hypertension, and eight had extrapulmonary shunting. At 1 hour of treatment, two infants in the NO group responded with increases in PaO2 of more than 100 mm Hg (13.3 kPa); after crossover, two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) and one control infant had an increase in PaO2 of more than 10 mm Hg (1.3 kPa). All control infants met failure criteria and crossed over to receive NO; two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) with NO treatment. Despite initial responses, all subjects in both groups eventually met failure criteria. There were no differences between groups in primary outcome variables.
                Although inhaled NO produced a transient improvement in oxygenation in some infants, it did not reduce the incidence of meeting ECMO criteria in this population. 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. 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. 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.
This review does not demonstrate any significant overall benefit of a permissive hypercapnia/minimal ventilation strategy compared to a routine ventilation strategy. At present, therefore, these ventilation strategies cannot be recommended to reduce mortality, or pulmonary and neurodevelopmental morbidity. Ventilatory strategies which target high levels of PCO2 (> 55 mmHg) should only be undertaken in the context of well-designed controlled clinical trials. These trials should aim to establish the safe, or ideal, range for CO2 in ventilated newborns, and examine the role of protective ventilatory techniques in achieving this target.