Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 /=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). CONCLUSION: 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.

Curosurf modulates cAMP accumulation in human monocytes through a membrane-controlled mechanism.

The cellular mechanisms by which pulmonary surfactant exerts its effects, including anti-inflammatory or proinflammatory effects, have remained elusive. To address the issue of whether plasma membrane modifications represent a target for these mechanisms, we designed an experimental protocol involving the determination of changes in cAMP levels under membrane-dependent or -independent stimulatory pathways. The effects of a modified natural porcine surfactant, Curosurf, and the major surfactant protein A were evaluated on resting and stimulated cAMP levels of human monocytes. We found that agents that elevate intracellular cAMP exhibit different susceptibilities toward a preexposure to Curosurf. The rise in cAMP induced by membrane-active agents such as cholera toxin or the diterpene forskolin was significantly inhibited by monocyte preexposure to Curosurf. In contrast, the rise in cAMP induced by the membrane-permeant phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine or by the Bordetella pertussis toxin adenylate cyclase-hemolysin was unaffected by Curosurf. Surfactant protein A did not affect either cAMP levels or the inhibitory capacity of Curosurf. We suggest that a plasma membrane-associated event affecting the mechanism underlying the effects of cholera toxin or forskolin is involved in the inhibition of cAMP accumulation caused by Curosurf.

Modified natural porcine surfactant modulates tobacco smoke-induced stress response in human monocytes.

Tobacco smoke (TS) is a potent source of oxidants and oxidative stress is an important mechanism by which TS exerts its toxicity in the lung. We have shown that TS induces heat shock (HS)/stress protein (HSP) synthesis in human monocytes. Pulmonary surfactant (PS) whose major physiological function is to confer mechanical stability to alveoli, also modulates oxidative metabolism and other pro-inflammatory functions of monocytes-macrophages. In order to determine whether PS alters the stress response induced by TS, we incubated human peripheral blood monocytes overnight with modified natural porcine surfactant (Curosurf) (1 mg/ml) before exposure to TS. Curosurf decreased TS-induced, but not HS-induced, expression of the major cytosolic, inducible 72 kD HSP (Hsp70). Furthermore, TS-generated superoxide anions production was significantly decreased by Curosurf in an acellular system, suggesting a direct scavenging effect of PS. We also examined the effects of TS and PS on monocytes ultrastructure. Monocytes incubated with Curosurf presented smoother cell membranes than control monocytes, while TS-induced monocyte vacuolization was, at least in part, prevented by Curosurf. Taken together, our data suggest that PS plays a protective role against oxygen radical-mediated, TS-induced cellular stress responses.

Heliox tolerance in spontaneously breathing neonates with bronchopulmonary dysplasia.

The use of a gas mixture in which helium is substituted for nitrogen allows a decrease in pulmonary resistances and in resistive work of breathing. This treatment might allow a reduction in energy expenditure in infants with bronchopulmonary dysplasia (BPD) and spare calories for growth. In a preliminary study designed to assess tolerance to Heliox(R), 4 infants with BPD and 4 controls were studied firstly when breathing air and secondly when breathing Heliox(R), at 10, 20 and 30 min exposure (T10, T20, T30). The following parameters were recorded: respiratory and cardiac rates, room (RT) and skin temperatures (ST) and transcutaneous (Tc) blood gases. When breathing air, TcPO2 was normal in the two groups (mean +/- SEM: 70 +/- 4 mm Hg in BPD vs. 78 +/-4 in controls). TcPCO2 was higher in the BPD group (41 +/- 2 vs. 35 +/- 1 mm Hg in controls; p = 0.028). Spontaneously breathing Heliox had immediate consequences such as wakening, crying, decrease in ST and hypoxia. Hypoxia was more serious and more rapid in the BPD group. At the 10-min exposure, mean TcPO2 was 39 +/- 4 mm Hg in BPD vs. 69 +/- 7 in controls (p = 0.042). Hypoxia was immediately corrected when breathing room air. TcPCO2 was unchanged in both groups.

A risk-benefit assessment of natural and synthetic exogenous surfactants in the management of neonatal respiratory distress syndrome.

Alveolar surfactant is central to pulmonary physiology. Quantitative and qualitative surfactant abnormalities appear to be the primary aetiological factors in neonatal respiratory distress syndrome (RDS) and exogenous replacement of surfactant is a rational treatment. Available exogenous surfactants have a natural (mammal-derived lung surfactants) or synthetic origin. Pharmacodynamic and clinical studies have demonstrated that exogenous surfactants immediately improve pulmonary distensibility and gas exchange; however, this is achieved more slowly and with more failures with synthetic surfactants. The ensuing advantageous haemodynamic effects are not so striking and they include an inconvenient increased left to right ductal shunt. Two strategies of administration have been used: prophylactic or rescue therapy to treat declared RDS. All methods of instillation require intubation. In addition to the early benefits (improved gas exchange and reduced ventilatory support) the incidence of classical complications of RDS, especially air leak events, is decreased except for the uncommon problem of pulmonary haemorrhage. The incidence of bronchopulmonary dysplasia is neither uniformly nor significantly reduced although the severity appears to be lessened. The overall incidence of peri-intraventricular haemorrhages is not diminished although separate trials have shown a decreased rate. The most striking beneficial effect of exogenous surfactants is the increased survival (of about 40%) of treated very low birthweight neonates. A small number of adverse effects has been described. The long term outcome of survivor neonates with RDS treated with surfactants versus control neonates with RDS not treated with surfactants is similar in terms of physical growth, at least as good in terms of respiratory status, with a similar or slightly better neurodevelopmental outcome. There is not clear benefit of exogenous surfactant therapy in extremely premature infants (< 26 weeks gestational age, birthweight < 750 g). The potential risks of contamination, inflammatory and immunogenic reaction and the inhalation of platelet activating factor remain a theoretical concern of surfactant therapy which has not been confirmed in clinical practice. The optimal timing of treatment favours prophylaxis over rescue treatment and early rescue treatment rather than delayed therapy. Meta-analyses suggest the clinical superiority of natural surfactant extracts over a synthetic one (colfosceril palmitate). The economic impact of surfactant therapy is favourable and the costs per quality-adjusted life year (QALY) for surviving surfactant treated infants are low. In conclusion, the mid and long term benefit/risk ratio clearly favours the use of exogenous surfactants to prevent or to treat RDS in neonates who have a gestational age of > 26 weeks or a birthweight of > 750 g, especially with the prophylactic strategy using natural surfactant extracts.

Mortality, severe respiratory distress syndrome, and chronic lung disease of the newborn are reduced more after prophylactic than after therapeutic administration of the surfactant Curosurf.

OBJECTIVE: To test the hypothesis that prophylactic treatment with the surfactant Curosurf (Chiesi Farmaceutici SPA, Parma, Italy) improves survival and respiratory problems more than rescue treatment. DESIGN: Meta-analysis of three prophylaxis versus rescue treatment trials, conducted in four countries. METHODS: A meta-analysis was performed with the original, individual data of mortality, severe respiratory distress syndrome, and chronic lung disease of 671 newborns as outcomes. The random-effects logistic model (accounting for the trial-within-country structure) was applied and adjusted for imbalances in covariates. RESULTS: The probability of each outcome differed between the countries, but the actual treatment effect itself did not. The adjusted odds ratios (ORs) and confidence intervals (CIs) for prophylaxis versus rescue were as follows: mortality: OR, .47; 95% CI, .30 to .73; severe RDS: OR, .50; 95% CI, .33 to .74; and chronic lung disease of the newborn in the survivors at day 28 after birth: OR, .54; 95% CI, .34 to .86. Gender, birth weight, gestational age, and prenatal administration of glucocorticosteroids were significant confounding covariates. CONCLUSION: The analysis shows that for the porcine surfactant Curosurf, prophylactic administration of surfactant has significant advantages over rescue therapy.

Modified natural porcine surfactant inhibits superoxide anions and proinflammatory mediators released by resting and stimulated human monocytes.

Pulmonary surfactant has a potential role in modulating inflammation in normal and injured lungs. In lung injury, monocytes become activated and participate in lung inflammation. We therefore, investigated the proinflammatory functions of stimulated human blood monocytes after an overnight preincubation period with modified natural porcine surfactant (Curosurf) (500-1000 micrograms/mL). Monocytes were stimulated either with phorbol myristate acetate (PMA), bacterial extract OM-85, lipopolysaccharide (LPS), or Ca2+ ionophore A23187. The present study shows that Curosurf significantly inhibits: 1) the production of superoxide anions stimulated with OM-85 (1 mg/mL, 30 min), but not with PMA (100 ng/mL, 30 min); 2) the release of cyclooxygenase metabolites prostaglandin E2 and thromboxane B2 stimulated with OM-85 (1 mg/mL, overnight); 3) the release of lipoxygenase metabolite leukotriene C4 stimulated with A23187 (10 microM, 10 min); 4) the release of the cytokine TNF-alpha stimulated overnight with either OM-85 (1 mg/mL) or LPS (10 micrograms/mL)) in a dose-dependent fashion. In addition, Curosurf decreases the spontaneous adherence of monocytes to plastic culture wells in a dose-dependent fashion. Experiments performed with staurosporine, an inhibitor of protein kinase C (PKC) indicate that, in contrast with PMA, the production of superoxide anions stimulated by OM-85 is not related to PKC activation. Consequently, we propose that the mechanism involved in the suppressive effects of Curosurf is PKC-independent. In summary, the present study provides experimental evidence that favors the anti-inflammatory role of modified natural porcine surfactant (Curosurf) in human monocytes in vitro.

[Natural or artificial surfactants? Arguments in favour of natural surfactants]. / Surfactant naturel ou artificiel? Les arguments en faveur des surfactants naturels.

The use of exogenous surfactant (ES) is an essential component for prevention and treatment of hyaline membrane disease (HMD). The ES available for clinical use are of two therapeutic classes: natural surfactants prepared from mammalian lung and artificial surfactants. The choice between these two classes of ES is controversial. In this overview, we present the arguments in favour of the preferential use of natural ES. The presence of hydrophobic specific proteins (SP-B and SP-C) provides to natural ES better surface tension properties than artificial ES. The in vitro greater efficacy of natural ES has been confirmed in vivo in experimental models of surfactant deficiency, human pharmacodynamic studies, and comparative clinical trials. Furthermore, the excellent clinical tolerance and harmlessness of natural ES has been firmly established. A meta-analysis of the comparative clinical trials between natural ES and one artificial ES (enrolling as many as 4400 babies treated for HMD) suggests that the use of natural ES compared to this artificial ES significantly reduces the neonatal mortality by 20%. In conclusion, all these arguments are in favor of the preferential use of natural ES for prevention and treatment of HMD.

Porcine surfactant replacement therapy in newborns of 25-31 weeks' gestation: a randomized, multicentre trial of prophylaxis versus rescue with multiple low doses. The French Collaborative Multicentre Study Group.

The aim of the study was to determine if prophylaxis with multiple low doses of porcine surfactant would increase survival, without bronchopulmonary dysplasia, compared with rescue therapy, for respiratory distress syndrome in newborns of 25-31 weeks' gestation. Compared with rescue therapy (n = 122), prophylaxis (n = 134) decreased the need for oxygenation and ventilatory support within 3-72 h. It did not, however, increase survival without bronchopulmonary dysplasia (60% versus 46%) (odds ratio (OR) = 1.53, 95% confidence interval (CI) = 0.90-2.61). Furthermore, prophylaxis decreased the incidence of severe peri-intraventricular haemorrhage (3% versus 16%) (OR = 0.28, 95% CI = 0.09-0.84) and retinopathy of prematurity (2% versus 11%) (OR = 0.18, CI = 0.04-0.78). We conclude that prophylaxis did not increase survival without bronchopulmonary dysplasia. The decreased incidence of severe peri-intraventricular haemorrhage and retinopathy of prematurity after prophylaxis requires further study.

Immune response after surfactant treatment of newborn infants with respiratory distress syndrome.

We examined the sera of 68 newborn infants with respiratory distress syndrome; 49 were treated with a natural porcine-derived surfactant preparation and 19 were controls. Serum of the patients was collected before, 3 weeks and 3 months after surfactant treatment. To detect any antibody that had been raised, we applied diluted serum of the babies in an indirect immunoperoxidase staining technique on frozen pig lung tissue specimens. With light microscopy an immune response could be appreciated as a brown reddish deposit in the porcine lung tissue specimens in 4 out of the 49 surfactant-treated and not in the control babies.

Pulmonary functional outcome at one year of age in infants treated with natural porcine surfactant at birth.

This prospective study was designed to assess pulmonary function (functional residual capacity, FRC; dynamic lung compliance, CLdyn; and total pulmonary resistance, RL) at 1 year of corrected age in infants with neonatal respiratory distress syndrome treated with natural porcine surfactant (Curosurf) (n = 13), as compared to nontreated control infants (n = 9). Values from 21 healthy infants of similar age served as reference. We found similar pulmonary dysfunction (decreased CLdyn, elevated RL) in both patient groups. These results suggest that surfactant replacement therapy does not affect pulmonary function at 1 year of age in infants who survive respiratory distress syndrome.

Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels.

Thirteen newborn infants (five premature, eight full term) with severe seizures and not responding to phenobarbital and diazepam received a lidocaine (LD) infusion. The schedule was 4 mg/kg/h on the 1st day, 3 mg/kg/h on the 2nd day, 2 mg/kg/h on the 3rd day, and 1 mg/kg/h on the 4th day. The LD plasma levels were measured every 24 h just before decreasing the dose. The control of seizures was achieved in 11 of 13 patients, with plasma LD concentration ranging from 2.8 to 10.5 mg/L. The LD concentration was linearly correlated with the dose in each group. In the premature group, LD clearance was always smaller than in the full-term group. Although no side effects were observed on heart rate and blood pressure, it is suggested that the dose of LD be adjusted to maintain the LD concentrations between 3-6 mg/L.

[Treatment of severe hyaline membrane disease with a single-dose of natural exogenous surfactant of porcine origin. A randomized trial: immediate effects and outcome at 28 days of life]. / Traitement de formes sévères de la maladie des membranes hyalines par une dose unique d'un surfactant exogène naturel d'origine porcine. Un essai randomisé: effets immédiats et devenir à 28 jours de vie.

The results obtained with porcine surfactant (Curosurf) administration for the treatment of hyaline membrane disease (HMD) are reported. Thirty premature infants weighing 700 to 2,000 g with severe HMD (mechanical ventilation and oxygen requirement (FiO2) greater than 60% were randomly allocated at 2 to 15 hours postnatal age. Eight of the 30 patients included in this group participated in a multicenter european trial. The fifteen infants with mean gestational age (GA) of 29.5 weeks included in the treatment group (T), were treated at 8.6 hours of life with a single dose of 200 mg/kg Curosurf given intratracheally while 15 infants of mean GA 30 weeks formed the control group (C). Infants in the T group showed an immediate, dramatic and sustained improvement of oxygenation as reflected by increased PaO2/FiO2 and arterial to alveolar PO2 ratios within 1 hour. This significant improvement in favor of T group (p less than 0.005) persisted for 2 days when control infants began to recover. This improvement in oxygenation allowed a significant decrease of FiO2 (p less than 0.005) and mean airway pressure (p less than 0.01) in the T group within 1 hour and up till the second day. Despite this early improvement obtained with Curosurf the survival rate at 28 days of life and the incidence of associated HMD complications were not significantly modified. However the tendency was towards decreased respiratory morbidity. The discussion will consider the value of multiple doses.

[Effects of exogenous surfactants on mortality and main complications of hyaline membrane disease]. / Effets des surfactants exogènes sur la mortalité et les principales complications de la maladie des membranes hyalines.

The authors analyse the results of the different trials of exogenous surfactants for the treatment of hyaline membrane disease. Whether artificial and used for prevention, or of human or animal origin and used for prevention or treatment, exogenous surfactants appear to improve the survival of premature infants. The improvement does not occur at the expense of increased morbidity. Indeed, there seems to be no increase in the frequency of patent ductus arteriosus, broncho-pulmonary dysplasia appears to be less frequent, and results on the effects of the frequency of intraventricular hemorrhage are contradictory. Current trials using new therapeutic schemes with multiple doses may further improve the protective effects of exogenous surfactants in premature infants.

Persistent elastase/proteinase inhibitor imbalance during prolonged ventilation of infants with bronchopulmonary dysplasia: evidence for the role of nosocomial infections.

Acute imbalance between elastase and alpha-1-proteinase inhibitor (alpha 1Pi) may contribute to the development of bronchopulmonary dysplasia (BPD). The question of whether such an imbalance persists in BPD infants still requiring mechanical ventilation after 4 wk of life has not been previously addressed. We studied 14 infants still on mechanical ventilation at 4 wk of age: nine had BPD and five did not. Weekly (4 to 9 wk) serum and bronchoalveolar lavage (BAL) specimens were taken. alpha 1Pi and alpha-2-macroglobulin were measured in serum and BAL by immunoturbidimetric assay. BAL elastase activity was measured by cleavage of a synthetic substrate and expressed as ng of porcine pancreatic elastase equivalent. Infants with BPD had higher levels of serum alpha 1Pi and alpha-2-macroglobulin than those without BPD. In contrast, the corresponding BAL levels were either similar or even decreased (alpha 1Pi). Moreover, there was a 3-fold increase in elastase-1Pi imbalance expressed as the BAL ng of porcine pancreatic elastase equivalent/2 alpha 1Pi ratio. The role of nosocomial infections was evident in a subgroup of 11 infected BAL aspirates in BPD infants. In such cases we found a 3-fold increase in the BAL ng of porcine pancreatic elastase equivalent/alpha 1Pi ratio as compared to 35 noninfected BAL in BPD infants. These data suggest a persistent alveolitis with imbalance between elastase and proteinase inhibitors in prolonged severe BPD. Such an imbalance is, in part, explained by a local destruction and/or inactivation of alpha 1Pi. Our results also emphasize the increase in proteolysis with nosocomial pneumonia.

Neonatal diagnosis of respiratory distress syndrome.

After a brief historical recall, this review states the needs for an accurate diagnosis of the neonatal respiratory distress syndrome (RDS). The clinical features consist of disturbances of respiratory rate, grunting, intercostal retractions, and cyanosis, but early mechanical ventilation tends to suppress most of them. Laboratory findings include hypoxemia, hypercapnia, and mixed acidosis. Positive radiological diagnosis remains an important criterion but early ventilation with positive end-expiratory pressure has made grading obsolete. The biochemical diagnosis addresses the basic lung surfactant deficiency, by determination of the lecithin/sphingomyelin ratio and phosphatidylglycerol ("modified lung profile") in lung effluents at birth. If clinical and radiological diagnosis remains adequate for daily practice and epidemiological studies, biochemical diagnosis should be mandatory for therapeutic trials. However, the problem of atypical RDS in very low birth weight infants has not been totally solved. RDS has now been known for more than 80 years; yet its diagnosis is still a matter of controversy.

[Cardiovascular and digestive effects of 2 mydriatics in the low-birth-weight newborn infant]. / Effets cardiovasculaires et digestifs de deux mydriatiques chez le nouveau-né de faible poids de naissance.

We studied the pupillary cardiovascular and gastrointestinal effects of two parasympathetic blocker mydriatics. Thirty-four neonates were randomly assigned into 3 groups: A: Atropine sulfate 0.3%, B: Tropicamide 0.5%, C: placebo. Mydriasis was obtained in groups A and B (p less than 0.001). No hypertension was observed and only an increase in heart rate with atropine was significant (p less than 0.001). Gastrointestinal side-effects studied in 25 children revealed a disturbance in groups A and B as compared to placebo (p less than 0.01). Tropicamide is therefore a more useful drug in low birth weight infants due to the absence of cardiovascular and hypertensive side-effects. Those infants with gastrointestinal disease should be treated with caution due to the side-effects which may be encountered.