Jonathan M. Davis

A Comparison of Surfactant as Immediate Prophylaxis and as Rescue Therapy in Newborns of Less Than 30 Weeks' Gestation

BACKGROUNDnExogenous pulmonary surfactants are administered into the trachea either to prevent respiratory distress syndrome in premature infants or to treat it. In a randomized, multicenter trial, we compared the results of surfactant therapy initiated as prophylaxis with the results of rescue therapy with surfactant.nnnMETHODSnBefore birth, 479 infants with an estimated gestational age of less than 30 weeks were randomly assigned to receive surfactant as prophylaxis (n = 235) or rescue therapy (n = 244). The infants in the prophylaxis group received a 90-mg intratracheal dose of an exogenous calf-lung surfactant extract at the time of delivery, whereas the infants in the rescue-therapy group received 90 mg of the surfactant several hours after delivery if the fractional inspiratory oxygen concentration was at least 0.40 or if the mean airway pressure was at least 0.686 kPa (7 cm of water), or both. Infants in both groups received additional doses of surfactant at intervals of 12 to 24 hours if these criteria were met.nnnRESULTSnThe proportion of infants surviving until discharge to their homes was significantly higher in the prophylaxis group than in the rescue-therapy group (88 vs. 80 percent, P = 0.028). This difference was due primarily to the longer survival of very premature infants (less than or equal to 26 weeks gestation) in the prophylaxis group than in the rescue-therapy group (75 vs. 54 percent, P = 0.006). According to proportional-hazards regression analysis, the distribution of survival times was better for all infants in the prophylaxis group (P = 0.007) and for the subgroup of infants in the prophylaxis group who were delivered at 26 weeks gestation or earlier (P = 0.0048). Infants in the prophylaxis group who were delivered at 26 weeks gestation or earlier had a lower incidence of pneumothorax than similar infants in the rescue-therapy group (7 vs. 18 percent, P = 0.03).nnnCONCLUSIONSnWe found a significant advantage to the administration of the initial dose of surfactant as prophylaxis rather than as rescue therapy in very premature infants.

Changes in Pulmonary Mechanics after the Administration of Surfactant to Infants with Respiratory Distress Syndrome

We assessed pulmonary mechanics in 35 premature infants with respiratory distress syndrome just before and one hour after the administration of 90 mg of surfactant to each infant. Transpulmonary pressure was measured between the airway opening and an esophageal balloon with use of a differential transducer, and flow rates were measured by a pneumotachometer. Values for pulmonary mechanics were then calculated by microcomputer processing. The administration of surfactant produced a large decrease (56 percent) in the mean (+/- SEM) ratio of alveolar to arterial oxygen, from 7.1 +/- 0.5 to 3.1 +/- 0.2 (P less than 0.0001)--a change that indicates improvement in gas exchange. Associated changes in pulmonary mechanics were not demonstrable when 10 of the infants were studied during continuous mechanical ventilation. However, in the 25 infants examined during spontaneous breathing with continuous positive airway pressures (identical airway pressures before and after treatment), large and consistent improvements in pulmonary mechanics were found after the administration of surfactant. Tidal volume increased by 32 percent (P less than 0.03), minute ventilation by 38 percent (P less than 0.02), dynamic compliance by 29 percent (P less than 0.004), and inspiratory flow rates by 54 percent (P less than 0.01). We conclude that significant improvement in pulmonary mechanics results from surfactant-replacement therapy for respiratory distress syndrome, but that these mechanical changes are apparent only during spontaneous respiration and can be masked if measurements are made during mechanical ventilation.

Hyperoxia-induced cell death in the lung--the correlation of apoptosis, necrosis, and inflammation.

Prolonged exposure to hyperoxia causes tissue damage in many organs and tissues. Since the entire surface area of lung epithelium is directly exposed to O2 and other inhaled agents, hyperoxia leads to the development of both acute and chronic lung injuries. These pathologic changes in the lung can also be seen in acute lung injury (ALI) in response to other agents. Simple strategies to mitigate hyperoxia‐induced ALI might not be effective by virtue of merely reducing or augmenting the extent of apoptosis of pulmonary cells. Identification of the specific cell types undergoing apoptosis and further understanding of the precise timing of the onset of apoptosis may be necessary in order to gain a greater understanding of the connection between apoptosis and tolerance to hyperoxia and ALI. Attention should also be focused on other forms of non‐apoptotic programmed cell death.

Hyperoxia Inhibits Oxidant-induced Apoptosis in Lung Epithelial Cells

It has previously been shown that hyperoxia induces nonapoptotic cell death in cultured lung epithelial cells, whereas hydrogen peroxide (H2O2) and paraquat cause apoptosis. To test whether pathways leading to oxidative apoptosis in epithelial cells are sensitive to molecular O2, A549 cells were exposed to 95% O2 prior to exposure to lethal concentrations of H2O2. The extent of H2O2-induced apoptosis was significantly reduced in cells preexposed to hyperoxia compared with room-air controls. Preexposure of the hyperoxia-resistant HeLa-80 cell line to 80% O2 also inhibited oxidant-induced apoptosis, suggesting that this inhibition is not due to O2toxicity. Because hyperoxia generates reactive oxygen species and activates the redox-sensitive transcription factor nuclear factor κB (NF-κB), the role of antioxidant enzymes and NF-κB were examined in this inhibitory process. The onset of inhibition appeared to be directly related to the degradation of IκB and subsequent activation of NF-κB (either by hyperoxia or TNF-α), whereas no significant up-regulation of endogenous antioxidant enzyme activities was found. In addition, suppression of NF-κB activities by transfecting A549 cells with a dominant-negative mutant construct of IκB significantly augmented the extent of H2O2-induced apoptosis. These data suggest that hyperoxia inhibits oxidant-induced apoptosis and that this inhibition is mediated by NF-κB.

Superoxide dismutase for preventing chronic lung disease in mechanically ventilated preterm infants.

BACKGROUNDnFree oxygen radicals have been implicated in the pathogenesis of chronic lung disease in preterm infants. Superoxide dismutase is a naturally occurring enzyme which provides a defence against such oxidant injury. Exogenously administered superoxide dismutase has been tested in clinical trials to prevent chronic lung disease in preterm infants.nnnOBJECTIVESnTo determine if exogenously administered superoxide dismutase is efficacious in the prevention of chronic lung disease in preterm infants who are mechanically ventilated, and efficacious in decreasing the following outcomes: bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, patent ductus arteriosus and mortality. To determine the frequency and nature of adverse effects of superoxide dismutase.nnnSEARCH STRATEGYnWe searched Medline (1966 - 2000) and the Cochrane Controlled Trials Register (CCTR) using the following keywords: [bronchopulmonary dysplasia OR chronic lung disease] AND superoxide dismutase, limited to human studies in newborn infants (infant, newborn). We hand searched the reference lists of articles located and the abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) from 1980 - 2000.nnnSELECTION CRITERIAnRandomized controlled trials where subjects were preterm infants who had developed or were at risk of developing respiratory distress syndrome requiring assisted ventilation and who were randomly allocated to receive either superoxide dismutase (in any form, by any route) or placebo or no treatment. We included studies which reported any of the following outcomes: chronic lung disease, bronchopulmonary dysplasia, any intraventricular hemorrhage, intraventricular hemorrhage grades III/IV, patent ductus arteriosus, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, neonatal mortality, death prior to discharge and neurodevelopmental outcome.nnnDATA COLLECTION AND ANALYSISnWe extracted and assessed separately all data for each study and entered final data into RevMan. We did not perform subgroup analyses (which were originally planned) because only two studies were eligible for inclusion. We assessed the methodological quality of the studies by assessing the risk for bias. We pooled the outcomes of infants who had developed bronchopulmonary dysplasia at 28 days with those who had died at 28 days to derive the combined outcome of bronchopulmonary dysplasia or death at 28 days. Similarly we pooled the outcomes of infants who had respiratory problems after discharge with those who had died prior to discharge to derive the combined outcome of respiratory problems after discharge or death. We used the standard method of the Cochrane Neonatal Review Group for statistical analysis, using a fixed effect model.nnnMAIN RESULTSnTwo randomized controlled trials were included for analysis. No differences were found in either study or in the pooled data in death prior to discharge, oxygen dependency at 36 weeks corrected age, oxygen dependency at 28 days of life or in other outcomes. In one study (Rosenfeld 1984), survivors who had been treated with superoxide dismutase had a shorter duration of continuous positive airway pressure (4.9 vs 9.7 days), a lower frequency of respiratory problems after discharge (relative risk 0.33, 95% confidence limits 0.11, 0.96) and a lower frequency of chest radiograph abnormalities (relative risk 0.30, 95% confidence limits 0.11, 0.87) compared to survivors who received placebo. A third study was available only in abstract form and will be evaluated for inclusion after publication.nnnREVIEWERS CONCLUSIONSnBased on currently available published trials, there is insufficient evidence to draw firm conclusions about the efficacy of superoxide dismutase in preventing chronic lung disease of prematurity. Data from a small number of treated infants suggest that it is well tolerated and has no serious adverse effects.

Role of oxidant injury in the pathogenesis of neonatal lung disease

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in newborn infants treated with oxygen and mechanical ventilation for a primary lung disorder. With significant improvements in survival of many critically ill infants, BPD has become an extremely important complication of newborn intensive care. The pathogenesis of BPD is complex and involves a variety of causative factors. However, increasing evidence has suggested that an oxidative insult could be an extremely important component of the injury process. Premature infants are especially sensitive to oxidant injury since they are exposed to supraphysiological concentrations of oxygen at birth while endogenous antioxidant enzyme activity may be relatively deficient.

Improved pulmonary distribution of recombinant human Cu/Zn superoxide dismutase, using a modified ultrasonic nebulizer

Prophylactic, intratracheal instillation of recombinant human Cu/Zn superoxide dismutase (rhSOD) has been shown to lessen lung injury produced by 48 h of hyperoxia and mechanical ventilation in neonatal piglets. However, instillation of small volumes of rhSOD intratracheally would not be expected to result in uniform pulmonary distribution. Aerosolization is a technique that may improve pulmonary distribution of drugs, but is limited by the poor efficiency of most nebulizers. A newly modified ultrasonic nebulizer was tested to assess pulmonary distribution of rhSOD compared to that achieved by intratracheal instillation. rhSOD was dual‐labeled with technetium‐99m (99mTc) and a fluorescent analog (permitting quantitative and qualitative assessments of pulmonary distribution), and administered to neonatal piglets by intratracheal instillation or by aerosolization.

Prevention of oxygen radical disease in the newborn: Possible therapeutic approaches

Free radical injury has been implicated in the pathogenesis of a wide variety of conditions that may affect newborn infants. This is not surprising since newborns (especially premature infants) are uniquely susceptible to free radical injury. At birth, newborns are exposed to significantly higher oxygen concentrations compared to the intrauterine environment and may develop medical conditions that require treatment with prolonged hyperoxia. In addition, newborns may experience reperfusion injury following periods of hypoxia or ischaemia and may have inadequate antioxidant defences to handle these oxidant challenges. As interest in free radical injury in the newborn has grown, so too has research examining possible methods of prevention and treatment. Antioxidant therapy has great potential to further reduce morbidity and mortality in the newborn period by influencing multiple organ systems and disease states. We will now review current strategies for the prevention and treatment of free radical injury in the newborn.

Effects of granulocyte colony-stimulating factor on hyperoxia-induced lung injury in newborn piglets.

Granulocyte colony-stimulating factor (G-CSF) increases the concentration and activation of neutrophils in the peripheral blood and has been used to prevent late-onset infection in premature infants. However, if G-CSF also augmented the inflammatory response in the lung, the incidence and severity of acute and chronic lung injury might be expected to increase. Using a newborn piglet model of acute lung injury, we examined the effects of rhG-CSF (recombinant-metHuG-CSF) on lung injury. Thirty-three newborn piglets were studied as follows: 1) Unventilated controls; 2) normally ventilated (PaCO2 = 35–45 torr) with room air(RA) for 48 h; 3) normally ventilated with RA for 48 h and received rhG-CSF (10 mg/kg/dose IV) at 0, 12, 24, and 36 h; 4) hyperventilated (PaCO2 = 15–25 torr) with 100% O2 for 48 h; 5) hyperventilated with 100% O2 for 48 h and received rhG-CSF (10 mg/kg/dose IV) at 0, 12, 24 and 36 h. Complete blood counts and and differentials were performed at 0, 24, and 48 h. Animals were sacrificed at 48 h, lungs were removed en bloc, and bronchoalveolar lavage (BAL) was performed. Total blood white blood cells and neutrophil counts increased significantly over 48 h in animals who received rhG-CSF either with normoventilation (p <0.0001) or hyperventilation with 100% O2 (p <0.003), and did not change significantly in the other experimental groups. However, there were no significant differences in BAL total cell counts, neutrophil chemotaxis activity, total protein, or albumin concentrations among the groups. Despite significantly increasing peripheral neutrophil counts, rhG-CSF did not potentiate acute lung injury or inflammation. This suggests that prophylactic administration strategies using rhG-CSF to prevent sepsis in premature infants should not increase the risk for developing acute and chronic lung disease.n

Perfluorochemical liquids enhance delivery of superoxide dismutase to the lungs of juvenile rabbits

Previous studies suggest acute lung injury (ALI) in premature newborns is associated with relative deficiency of antioxidant enzymes that may be ameliorated by recombinant human superoxide dismutase (rhSOD). Perfluorochemicals (PFCs) are distributed homogeneously and support gas exchange in diseased lungs. We investigated whether PFCs could provide an effective delivery system for rhSOD. Juvenile rabbits were lung-lavaged, treated with surfactant, and randomized: group I: fluorescently labeled rhSOD (5 mg/kg in 2 mL/kg saline); group II: fluorescently labeled rhSOD (5 mg/kg in 18 mL/kg PFC). Animals were ventilated with oxygen for 4 h; the lungs were harvested for analysis of SOD distribution and oxidative injury. Cardiopulmonary indices remained stable and similar between groups. Qualitative assessment (QA) showed a more homogeneous lung SOD distribution in group II and a better histologic profile. QA of lung SOD distribution showed significant increase in SOD concentrations in group II (7.37 ± 1.54 μg/mg protein) compared with group I (1.65 ± 0.23 μg/mg protein). Oxidative injury as assessed by normalized protein carbonyl was 149.1 ± 26.8% SEM in group II compared with 200.5 ± 7.3% SEM in group I. Plasma SOD was significantly higher in group II. Administration of rhSOD with or without PFCs does not compromise cardiovascular function or impede lung recovery after ALI. PFCs enhance rhSOD delivery to the lungs by 400% while decreasing lung oxidative damage by 25% compared with rhSOD alone. These data suggest that PFCs optimize lung rhSOD delivery and might enhance the beneficial effects of rhSOD in preventing acute and chronic lung injury.