Use of surfactant for prophylaxis versus rescue treatment of respiratory distress syndrome: experience from an Italian-Bulgarian trial. A prospective randomized comparison of conventional mechanical ventilation and very early high frequency oscillatory ventilation in extremely premature newborns with respiratory distress syndrome. Randomized controlled trial of very early continuous distending pressure in the management of preterm infants. The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome. Volume guarantee versus high-frequency ventilation: lung inflammation in preterm infants. Early versus delayed surfactant administration in extremely premature neonates with respiratory distress syndrome ventilated by high-frequency oscillatory ventilation. Comparison of prophylaxis and rescue treatment with Curosurf in neonates less than 30 weeks' gestation: a randomized trial. A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant. Comparative efficacy of exosurf and survanta surfactants on early clinical course of respiratory distress syndrome and complications of prematurity.
To show if surfactant applied in different social-sanitary realities as prophylaxis of respiratory distress syndrome (RDS) is equally useful and able to reduce mortality and incidence of 3-4 radiological grade RDS.
                Two neonatal intensive care units (NICU) in Italy, one NICU in Bulgaria and one NICU in Romania were involved in a randomized controlled clinical trial of prophylaxis vs rescue treatment of RDS. Babies with gestational age 26-30 wks were randomized before birth to prophylaxis in the delivery-room with 200 mg/kg of porcine surfactant (prophylaxis) or to routine assistance (control). Subsequently the babies developing RDS requiring mechanical ventilation and fraction of inspired oxygen (FiO2) > or = 0.4 to maintain PaO2 about 50 mmHg were allowed to be treated rescue with 200 mg/kg of the same surfactant. To reach end-points of reducing mortality by 40% and incidence of radiological grade 3-4 RDS a total number of 174 patients were required.
                Due to logistic, practical and social-political problems the study was interrupted after enrollment of 93 babies (61 in Italy and 32 in Bulgaria). The Romanian centre did not start the study because it was impossible in the scheduled times to equip it for mechanical ventilation of the newborn infants. Analysis done on an intention to treat basis did not show significant reductions of mortality and 3-4 radiological grade RDS, even if there was a trend towards a reduction in the babies given prophylaxis. A significantly lower number of babies given prophylaxis required a subsequent rescue treatment compared to controls (p < 0.001). There was no difference in other complications such as intraventricular haemorrhage, air-leak syndromes and infections between prophylaxis and control infants. As regards pulmonary gas exchange, the PaO2/FiO2 ratio was significantly improved in the babies given prophylaxis for the first 12 hours of life vs the controls.
                Even if the study was terminated before term, the analysis of the data shows that prophylaxis with surfactant is equally effective in different social-clinical conditions to improve pulmonary gas-exchange, especially in the first critical hours of life of premature babies. 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. Application of continuous distending pressure at birth (very early CDP) should stabilize the immature airways and reduce the severity of respiratory distress syndrome (RDS) in preterm infants. Eighty-two preterm infants of less than 32 weeks gestation were randomly assigned at birth to early treatment group (TG), in which CDP of 6 cm water pressure was applied at birth by the nasopharyngeal route (NP-CDP), or to control group (CG), in which CDP was applied when indicated for established criteria (pO2 less than 50 mmHg in FiO2 greater than 0.5). Characteristics of the infants in the two groups were comparable. No statistically significant difference between the two groups was found in the incidence of RDS. The course of RDS, and oxygen and ventilatory requirements also did not appear to be changed. In blood gas parameters of most of the time frames, no significant difference was found between the two groups when the results were analyzed according to the assigned group. When the results were analyzed separately for the infants who developed RDS, infants in TG appear to have fared worse from the therapy in terms of oxygenation, as indicated by significantly higher FiO2 (P less than 0.01) and lower a/A (P less than 0.01) values on the third day of the course of RDS, as compared to infants in CG. The incidence of complications was comparable in the two groups. Four infants from TG (9.3%) and one from CG (2.6%) died (P = NS). We conclude that VECDP by nasopharyngeal route does not reduce the incidence of RDS and does not appear to improve the outcome and may worsen the severity of RDS when compared to application of CDP for established criteria. 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. 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 determine whether early surfactant administration is superior to selective delayed treatment in terms of improving survival and/or reducing chronic lung disease in extremely premature neonates with respiratory distress syndrome (RDS) treated by high-frequency oscillatory ventilation (HFOV).
                Prospective randomized clinical trial.
                Tertiary neonatal intensive care unit (NICU) in the Perinatology Center of Prague.
                Forty-three extremely premature infants who needed artificial ventilation within 3 h after delivery.
                Patients were randomly assigned to either early ( n=21) or delayed (n=22) administration of surfactant. All were ventilated by HFOV as the primary mode of ventilation using the high volume strategy aimed at optimizing lung volume. Curosurf at a dose of 100 mg/kg was given as a single bolus via the endotracheal tube within 1 min immediately after intubation in the early group (EARL), or during HFOV only when defined criteria were reached in the delayed (DEL) group.
                No differences were noted in demographic data between the two groups. Fewer infants randomized to the EARL group required oxygen use or died at 36 weeks (combined outcome 29% vs 64%, p=0.021), and there was a lower incidence of any intraventricular hemorrhage in this group (43 vs 82%, p=0.008).
                When compared to delayed dosing, early administration of surfactant followed by HFOV facilitates and accelerates respiratory stabilization during the acute phase of severe RDS, may reduce the incidence of chronic lung disease or death and may positively influence the incidence of severe intracranial pathology in extremely premature infants with primary surfactant insufficiency. The aim of this randomized clinical trial was to evaluate the immediate effects of prophylactic administration of Curosurf and to compare outcomes after prophylactic or expectant management.
                Porcine surfactant (Curosurf, 200 mg/kg body weight) was administered intratracheally within 10 minutes of birth to preterm neonates with a gestational age of 26 to 29 weeks (n = 75); rescue-eligible neonates (n = 72) were initially subjected to a sham maneuver. The primary end points of the trial, evaluated at the age of 6 hours, were to obtain (1) a 40% decrease in the ratio between transcutaneous oxygen tension (tcPO2) (kPa) and fraction of inspired oxygen (FIO2), and (2) a 50% decrease in the incidence of radiologically verified respiratory distress syndrome (RDS). After 6 to 24 hours, a similar dose of surfactant was given to the neonates of both the prophylaxis and the rescue-eligible group, if they needed mechanical ventilation with an FIO2 > or = 0.6.
                At 6 hours the prophylaxis group had, in comparison with the rescue-eligible group, significantly higher tcPO2/FIO2 ratios (mean +/- SD: 39.7 +/- 15.3 vs 28.1 +/- 18.1; P < .001) and less severe RDS by radiological scoring (chi 2 = 14.9; P = .005). Severe RDS was present in 19% of the prophylactically treated neonates versus 32% in the rescue-eligible group (P < .05). The prophylaxis group needed shorter periods of FIO2 > 0.40 than the rescue-eligible neonates (P < .01), and eight neonates of the prophylaxis group (11%) versus 23 of the rescue-eligible group (32%) qualified for rescue treatment with surfactant in the interval 6 to 24 hours (P < .01). There were no differences in the incidence or severity of pneumothorax, pulmonary interstitial emphysema, cerebral hemorrhage, periventricular leukomalacia, patent ductus arteriosus, in the duration of mechanical ventilation or time in supplemental oxygen, or in mortality.
                Subgroup analysis revealed (1) that administration of corticosteroids reduced the risk of developing neonatal RDS as effectively as did surfactant prophylaxis at birth, and (2) that prophylaxis was effective especially in neonates with gestational age < 28 weeks or birth weight < 1000 g, in male neonates, and in neonates who had received no antenatal treatment with corticosteroids. Our data indicate that prophylactic treatment with surfactant should be considered in high-risk neonates fulfilling these latter criteria. 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. To determine the comparative efficacy of Exosurf Neonatal and Survanta surfactants on the early course of respiratory distress syndrome (RDS), arterial blood gases, ventilatory support, outcome morbidity rate, and complications of prematurity and RDS.
                Medical records from 203 premature newborn infants undergoing mechanical ventilation for respiratory distress syndrome, and who received up to four rescue doses of either Exosurf or Survanta, were retrospectively reviewed.
                All groups were comparable for birth weight and gestational age. Although the two randomized groups were similar in severity of RDS based on fraction of inspired oxygen (FIO2) and ventilatory support, a significantly greater improvement in respiratory function as evidenced by FIO2, mean airway pressure, alveolar-arterial partial pressure of oxygen difference, and oxygen index, was observed in the Survanta group from 12 hours (p < 0.05) through 48 hours (p < 0.01). Comparison of outcome morbidity rate by gestational age showed a higher occurrence of retinopathy of prematurity (p < 0.02) among the older infants (28 to 32 weeks) who were treated with Exosurf.
                Survanta exerted a significantly faster response in the early clinical course of RDS compared with Exosurf. However, no difference in the impact on eventual respiratory outcome was observed. We therefore conclude that both surfactants are effective for the treatment of RDS.
There is insufficient information on the use of rescue HFOV to make recommendations for practice. The small amount of data that exists suggest that harm might outweigh any benefit. Any future use of HFOV as rescue therapy for preterm infants with severe RDS should be within randomised controlled trials and address important outcomes such as longer term pulmonary and neurological function.