Lung Disease In Preterm Infants Research Articles

Changes in markers of bone metabolism during dexamethasone treatment for chronic lung disease in preterm infants

Aim: To characterise the change in serum and urinary bone markers in the early postnatal period, and to assess the effect of systemic corticosteroid on bone metabolism in preterm infants....

Review: early postnatal corticosteroids reduce chronic lung disease in preterm infants, but increase complications

Review: early postnatal corticosteroids reduce chronic lung disease in preterm infants, but increase complications

Effects of tapering neonatal dexamethasone on rat growth, neurodevelopment, and stress response.

Dexamethasone is commonly used to lessen the morbidity of chronic lung disease in premature infants, but little is known regarding neurological consequences of its prolonged use. To study neurological effects of dexamethasone, we have developed a rat model in which newborn pups are exposed to tapering doses of dexamethasone at a time corresponding neurodevelopmentally to human exposure in the neonatal intensive care unit. On postnatal day (PD) 2, litters were divided into three groups: 1) handled controls, 2) saline-injected animals, and 3) animals injected with tapering doses of intramuscular dexamethasone between PD 3 and 6. Somatic growth and brain weight were decreased in dexamethasone-treated animals. Dexamethasone-treated animals demonstrated delays in gross neurological development on PD 7 and 14 but not PD 20. In late adolescence (PD 33), dexamethasone-treated animals were less active in light and dark environments, while demonstrating a blunted serum corticosterone response to a novel stress. The dissociation between behavioral and hormonal stress responsiveness suggests that neonatal dexamethasone exposure permanently alters central nervous system function, particularly within the neuroendocrine stress axis. This may lead to increased risk for learning impairment and maladaptive responses to the environment.

Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants

This statement is intended for health care professionals caring for neonates and young infants. The objectives of this statement are to review the short and long term effects of systemic and inhaled postnatal corticosteroids for the prevention or treatment of evolving or established chronic lung disease, and to make recommendations for the use of corticosteroids in infants with very low birth weight. The routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended.

Identification and quantification of ureaplasmas colonizing the respiratory tract and assessment of their role in the development of chronic lung disease in preterm infants.

The role of Ureaplasma urealyticum in the development of chronic lung disease (CLD) in preterm infants continues to be disputed. Recently U. urealyticum has been found to consist of two species, U. urealyticum and Ureaplasma parvum, a finding that has not been considered in previous studies of CLD. This study examined the possible relationships between development of CLD and respiratory colonization by these newly redefined species, their concentrations in lower respiratory secretions and the effect of pulmonary surfactant treatment on these relationships in preterm infants with birth weights < 1500 g. Endotracheal aspirates (ETA) were collected from intubated infants when airway suctioning was medically required. ETA were stored at -80 degrees C until quantitative cultures for ureaplasmas and Mycoplasma hominis were performed. Culture results were correlated with development of CLD. Of 475 infants (birth weights < 1500 g) admitted during the 2-year study period, 272 were excluded because they were not intubated or were extubated before ETA could be obtained. An additional 28 infants died, were discharged or were transferred before they could be assessed for CLD. From the remaining 175 infants ureaplasmas were isolated from 66 (38%). No statistically significant associations were identified between development of CLD and the Ureaplasma species isolated, or concentration of ureaplasmas in lower respiratory secretions. These findings were not altered by treatment with pulmonary surfactant (Survanta). Lower respiratory colonization by ureaplasmas does not appear to be a contributory cause of CLD in preterm infants.

Alpha-1 proteinase inhibitor (a1PI) for preventing chronic lung disease in preterm infants.

Inflammation of the pulmonary parenchyma is one of the important mechanisms implicated in development of chronic lung disease (CLD) in preterm neonates. Release of enzymes and other anti - oxidants following cell damage is considered to be responsible for the damage to lung tissue. Various strategies have been attempted to counteract enzymatic damage to pulmonary parenchyma and to prevent CLD. This review examines the effectiveness of alpha 1 proteinase inhibitor (a1PI) for the prevention of CLD defined as requirement of supplemental oxygen at 36 weeks post menstrual age (PMA) in preterm neonates. A literature search was performed using the following databases: MEDLINE (1966 - February 2001), EMBASE (1980 -February 2001), CINAHL (1982 - February 2001), Cochrane Controlled Trials Register (Issue 1, 2001 of Cochrane Library) and abstracts from the annual meetings of the Society of Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2000). No language restrictions were applied. Selection criteria applied to the clinical trials were: 1. The population had to be preterm neonates 2. The intervention had to be administration of a1PI compared to placebo or no treatment within the first week of life 3. The eligible studies had to include any of the following outcomes: a. prevention of CLD b. reduction in duration of assisted ventilation c. reduction in the duration of oxygen requirement d. reduction in the need for systemic antiinflammatory therapy e. reduction in mortality or f. reduction in long term adverse neurological sequelae. 4. The trial had to be randomized or quasi-randomized. The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the authors. Data on relevant outcomes were extracted and the effect size was estimated and reported as pooled relative risk (RR), risk difference (RD) and weighted mean difference (WMD) as appropriate. Two strategies were used for analysis : 1. Comparison of 60 mg/kg/dose of a1PI administered for 4 days in first 2 weeks after birth, versus placebo and 2. Comparison of any dose of a1PI administered in first 2 weeks after birth, versus placebo. Two eligible studies were identified. The methodological qualities of identified studies were good. One study randomized infants to either placebo, or a1PI 60 mg/kg/dose for four doses while in the second study the same investigators explored the efficacy of different dose regimens of a1PI compared to placebo. There was no statistically significant difference in the development of CLD at 36 weeks PMA amongst all randomized infants. For 60 mg/kg/dose for four doses of a1PI compared to placebo the pooled RR was 0.64 [95% CI 0.35, 1.18] and RD was -0.10 [95% CI -0.23, 0.03] while for any doses of a1PI the pooled RR was 0.79 [95% CI 0.44, 1.41], RD was -0.05 [95% CI -0.17, 0.06]. There was a trend towards reduced risk of development of oxygen dependency at 28 days postnatal age, pooled RR 0.81 [95% CI 0.64, 1.01], RD -0.14 [95% CI -0.29, 0.00] for 60 mg/kg/dose for four doses of a1PI compared to placebo. The pooled RR was statistically significant, RR 0.80 [95% CI 0.65, 0.98], RD -0.15 (95 % CI -0.29, -0.01) when any doses of a1PI were combined. The number of patients needed to treat (NNT) with a1PI to prevent one infant developing oxygen dependency at 28 weeks was 7. The benefits of short-term outcomes did not remain for long-term outcomes such as CLD and/or death at 36 weeks post menstrual age (pooled RR 0.84 [95% CI 0.53, 1.34], RD -0.06 [95% CI -0.20, 0.09] for 60 mg/kg/dose and pooled RR 0.95 [95% CI 0.61, 1.49], RD -0.02 [95% CI -0.15, 0.12] for any dose) or risk of development of long term neurodevelopmental abnormalities (pooled RR 1.29 [95% CI 0.43, 3.90], RD 0.03 [95% CI -0.11, 0.18]). In addition, no statistically significant difference was noted in other respiratory parameters such as duration of oxygen requirement or respiratory support. Prophylactic administration of a1PI did not reduce the risk of CLD at 36 weeks or long term adverse developmental outcomes in preterm neonates.

Glucocorticoids and lung development in the fetus and preterm infant.

During the final prenatal period of fetal lung development in humans, important maturational processes occur, including the production of surfactant necessary to decrease surface tension at the air-liquid interface of the alveoli. During early gestation, the glucocorticoid receptor is expressed in the fetal lung, and glucocorticoids stimulate the production of surfactant-associated proteins and increase phospholipid synthesis by enhancing the activity of phosphatidylcholine. Other glucocorticoid-induced effects may include stimulation of cell maturation and differentiation, inhibition of DNA synthesis, changes in interstitial tissue components, stimulation of antioxidant enzymes, and regulation of pulmonary fluid metabolism. Recently, it was suggested that glucocorticoids are also important in postnatal pulmonary development, and may be related to the development of neonatal lung disease in preterm infants. Surfactant deficiency that can be prevented by antenatal corticosteroid treatment causes infant respiratory distress syndrome and requires mechanical ventilation. Ventilation by itself or in combination with high levels of oxygen, fluid overload, pulmonary infections, sepsis, and air leak syndrome causes an acute pulmonary inflammatory reaction that may result in chronic lung disease or bronchopulmonary dysplasia. Glucocorticoids are effective in the treatment of chronic lung disease of prematurity and regulate the inflammatory response by the interaction with transcription factors such as nuclear factor kappaB and activated protein 1. Indeed, inflammatory cells and the levels of chemokines and cytokines in bronchoalveolar fluid decrease after dexamethasone treatment. However, treatment of fetuses and preterm infants with repeated and/or high doses of corticosteroids may have considerable long-term side effects on somatic, brain, and lung growth. The difficult balance between short-term gain and the possible long-term side effects of glucocorticoids in preterms remains a difficult issue.

Aerosolized diuretics for preterm infants with (or developing) chronic lung disease.

Lung disease in preterm infants is often complicated with lung edema. The aim of this review is to assess the risks and benefits of aerosolized diuretic administration in preterm infants with or developing chronic lung disease (CLD). Primary objectives are to assess effects on short term outcome (changes in need for oxygen or ventilatory support) and effects on long-term outcome. Secondary objectives are to assess changes in pulmonary mechanics and potential complications of therapy. We used the standard search method of the Cochrane Neonatal Review Group. We used the following keywords: ¿<bronchopulmonary dysplasia> or <chronic lung disease>¿ and <explode diuretics>, limited to <human> and limited to <infant, newborn> or <infant>. We searched Medline (1966-1998), Embase (1974-1998) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (1998, Issue 4). In addition, we hand searched several abstract books of national and international American and European Societies. We included in this analysis trials in which preterm infants with or developing chronic lung disease and at least five days of age were all randomly allocated to receive an aerosolized loop diuretic. Eligible studies needed to assess at least one of the outcome variables defined a priori for this systematic review. Primary outcome variables included important clinical outcomes, and secondary outcome variables included pulmonary mechanics and potential complications of therapy. We used the standard method for the Cochrane Collaboration which is described in the Cochrane Collaboration Handbook. Two investigators extracted, assessed and coded separately all data for each study, using a form that was designed specifically for this review. Any disagreement was resolved by discussion. We combined parallel and cross-over trials and, whenever possible, transformed baseline and final outcome data measured on a continuous scale into change scores using Follmann's formula. We identified eight studies which met selection criteria. Most studies focused on pathophysiological parameters and did not assess effects on important clinical outcomes defined in this review or the potential complications of diuretic therapy. No study assessed the amount of diuretic effectively delivered to the patient. Furosemide was the only diuretic used in the eight studies included in this review. Among preterm infants < 3 weeks of age developing CLD, not enough information is available to assess the effect of aerosolized furosemide on outcome or lung function. Among infants > 3 weeks with CLD, a single aerosolized dose of 1 mg/kg of furosemide may transiently improve pulmonary mechanics. Not enough information is available to assess the effect of chronic administration of aerosolized furosemide on oxygenation and pulmonary mechanics. In preterm infants > 3 weeks with CLD administration of a single dose of aerosolized furosemide improves pulmonary mechanics. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of aerosolized loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence. More double-blinded randomized trials are needed (1) to analyze factors likely to affect the response to aerosolized furosemide, e.g. , washout period and delivery of furosemide to distal airways, and (2) to assess the effects of chronic administration of aerosolized furosemide on mortality, O2 dependency, ventilator dependency, length of hospital stay and long-term outcome.

Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

Chronic lung disease (CLD) occurs frequently in preterm infants (< 37 weeks gestational age) and has a multifactorial etiology. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increase in compliance and tidal volume and decrease in pulmonary resistance have been documented with use of bronchodilators in short term studies of pulmonary mechanics in infants with CLD. Therefore it is possible that bronchodilators might have a role in the prevention and treatment of CLD. To evaluate the effect of bronchodilators, given prophylactically or as treatment for chronic lung disease, on mortality and other complications of preterm births. The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group. Searches were made of MEDLINE 1966 to December 2000, EMBASE 1980 to January 2001, CINAHL 1982 to December 2000, the Cochrane Library Issue 1, 2001, personal files and reference lists of identified trials. The following terms were used: bronchopulmonary dysplasia, chronic lung disease, bronchodilator agents, adrenergic agents, anticholinergic agents, albuterol, aminophylline, atropine, caffeine, clenbuterol, cromakalim, ephedrine, epinephrine, fenoterol, hexoprenaline, ipratropium, isoetharine, isoproterenol, orciprenaline, procaterol, terbutaline, theophylline, tretoquinol. newborn, infant; human, clinical trial or controlled clinical trial, meta analysis, multicenter study or randomised controlled trial. No language restrictions were applied. Randomised controlled clinical trials involving preterm infants. Initiation of bronchodilator therapy had to occur within two weeks of birth for prevention of CLD. For treatment of CLD treatment should have been initiated before discharge from the neonatal unit. The intervention had to include the randomised administration of a bronchodilator either by nebulisation, metered dose inhaler with or without a spacer device, intravenously or orally, versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: mortality, CLD at 28 days or at 36 weeks corrected GA, number of days on oxygen, number of days on ventilator, patent ductus arteriosus (PDA), pulmonary interstitial emphysema (PIE), pneumothorax, any grade of intraventricular haemorrhage, necrotizing enterocolitis (NEC), sepsis and adverse effects of bronchodilators. We used the standard method for the Cochrane Collaboration as described in the Cochrane Collaboration handbook. Two investigators (GN, AO) extracted and assessed all data for each study. Any disagreement was resolved by discussion. Relative risk (RR) and risk difference (RD) with 95% confidence intervals (CI) are reported for dichotomous outcomes and mean difference (WMD) for continuous data. One eligible study was found dealing with prevention of CLD; this study used salbutamol and enrolled 173 infants. No eligible studies were found dealing with treatment of CLD. Prophylaxis with salbutamol did not show a statistically significant difference in mortality [RR 1.08 (95% CI 0.50, 2.31); RD 0.01 (95% CI -0.09, 0.11)], CLD (mild, moderate or severe) [RR 1.03 (95% CI 0.78, 1.37); RD 0.02 (95% CI -0.13, 0.17)], need for iv dexamethasone [RR 0.77 (95% CI 0.49, 1.19); RD -0.08 (95% CI -0.22, 0.05)], respiratory infections [RR 0.61 (95% CI 0.27, 1.39); RD -0.06 (95% CI -0.16, 0.04)] or positive blood culture [RR 1.06 (95% CI 0.54, 2.06); RD 0.01 (95% CI -0.10, 0.12)]. There was no statistically significant difference in duration of ventilatory support [MD -1.63 days (95% CI -5.63, 2.37)], duration of oxygen supply [MD -2.82 days (95% CI -11.91, 6.27)] or age of weaning from respiratory support (defined as assisted ventilation or oxygen supplementation) [MD -2.87 days (95% CI -11.28, 5.54)]. No side effects due to salbutamol were commented on in this study. There are insufficient data to reliably assess the use of salbutamol for the prevention of CLD. Further clinical trials are necessary to assess the role of salbutamol or other bronchodilator agents in prophylaxis or treatment of CLD.

Special Nutritional Needs of Infants for Prevention of and Recovery from Bronchopulmonary Dysplasia

Extremely low birth weight infants who develop severe respiratory disease may have special nutrient requirements imposed by a combination of enhanced utilization of nutrients or the need for epithelial cell repair resulting from the disease process, as well as to support catch-up growth. Inositol, free fatty acids, vitamin E and vitamin A are proposed as nutrients for which infants at risk of chronic pulmonary insufficiency may have special requirements. Of these nutrients, only for vitamin A does suggestive evidence exist that high doses when given intramuscularly may reduce the incidence of death or chronic lung disease. Exogenous steroid therapy (dexamethasone), which is often used to improve pulmonary compliance in ventilated premature infants, may compromise vitamin A status and induce restricted somatic and bone mineral growth. Supplemental nutrition by means of enriched infant formulas has provided benefits in growth and bone mass accretion to infants recovering from bronchopulmonary dysplasia up to 3-mo corrected age. This growth advantage was not sustained over the subsequent 9 mo, suggesting that prolonged nutritional support is required until catch-up growth is complete. Further studies are required to delineate the needs for specific nutrients such as antioxidant vitamins and minerals or vitamin A that may play a role in preventing severe chronic lung disease in premature infants. As well, the role of supplemental nutrition (beyond the requirements of term infants) to support catch-up growth and maintenance during the critical stages of early development requires further investigation before evidence-based nutrient recommendations can be developed for this special population of infants.

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

Free 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. To 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. We 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. Randomized 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. We 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. Two 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. Based 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.

Cromolyn sodium for the prevention of chronic lung disease in preterm infants.

Chronic lung disease (CLD) frequently occurs in preterm infants (< 37 weeks gestational age) and has a multifactorial etiology including inflammation. Cromolyn sodium is a mast cell stabiliser that inhibits neutrophil activation and neutrophil chemotaxis. Therefore it is possible that cromolyn sodium might have a role in the prevention of CLD. in preterm infants, does the prophylactic administration of cromolyn sodium reduce the incidence of CLD, mortality or the combined outcome of mortality or CLD at 28 days of life without undue side effects? The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group. Searches were made of MEDLINE, EMBASE, CINAHL up to and including December 2000, the Cochrane Library 2000 Issue 4, personal files and reference lists of identified trials. The following terms were used: chronic lung disease, cromolyn sodium or cromoglycate. newborn, infant; human, clinical trial or controlled clinical trial or meta analysis or randomised controlled trial. No language restrictions were applied. Randomised or quasi-randomised controlled clinical trials involving preterm infants. Initiation of cromolyn sodium administration during the first two weeks of life. The intervention had to include administration of cromolyn sodium by nebulizer or metered dose inhaler with or without spacer device, versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: overall mortality, CLD at 28 days, CLD at 36 weeks corrected gestational age, or the combined outcome mortality or CLD at 28 days. Secondary outcomes included number of days on oxygen, number of days on mechanical ventilation, patent ductus arteriosus (PDA), air leaks [pulmonary interstitial emphysema (PIE), pneumothorax], any grade of intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), sepsis and adverse effects due to cromolyn sodium. We used the standard method for the Cochrane Collaboration as described in the Cochrane Collaboration handbook. Both investigators extracted and assessed all data for each study. Any disagreement was resolved by discussion. Relative risk (RR) and risk difference (RD) with 95% confidence intervals (CI) are reported for dichotomous outcomes and weighted mean difference (WMD) for continuous data. Number needed to treat was not calculated as no outcome showed a statistically significant RD. A fixed effect model was used for meta-analysis. Two eligible studies were identified with small numbers of infants enrolled. Prophylaxis with cromolyn sodium did not result in a statistically significant effect on the combined outcome, death or CLD at 28 days [RR 1.05 (95% CI 0.73, 1.52); RD 0.03 (95% CI -0.20, 0.27)], CLD at 28 days [RR 0.93 (95% CI 0.53, 1.64; RD -0.03 (95% CI -0.27, 0.20)], CLD at 36 weeks corrected gestational age [RR 1.25 (95% CI 0.43, 3.63); RD 0.08 (95% CI -0.29, 0.44)], CLD in survivors at 28 days [RR 0.97 (95% CI 0.58, 1.63); RD -0.02 (95% CI -0.29, 0.26)] or CLD in survivors at 36 weeks corrected gestational age [RR 1.04 (95% CI 0.38, 2.87); RD 0.02 (95% CI -0.40, 0.43)]. Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall mortality [RR 1.31 (95% CI 0.52, 3.29); RD 0.06 (95% CI -0.13, 0.26)]. There were no statistically significant differences in the incidence of air leaks, NEC, IVH, sepsis, days on mechanical ventilation or PDA. No side effects were noted. There is currently no evidence from randomized trials that cromolyn sodium has a role in the prevention of CLD. Cromolyn sodium cannot be recommended for the prevention of CLD in preterm infants. Additional clinical trials do not appear to be justified using the protocols for drug administration used to date unless a more efficient type of delivery device than the jet nebulizer is employed.

Role of erythromycin for treatment of incipient chronic lung disease in preterm infants colonised with Ureaplasma urealyticum.

Ureaplasma urealyticum is frequently isolated from tracheal aspirates of very low birthweight infants who go on to develop chronic lung disease. The use of erythromycin has been advocated in ventilated very low birthweight infants who are colonised with U. urealyticum, although the association between U. urealyticum and chronic lung disease remains controversial. There are only two randomised, controlled trials involving a total of 37 U. urealyticum-positive very low birthweight infants. Both trials failed to demonstrate a reduction in the incidence of chronic lung disease after 7 or 10 days of erythromycin. On the other hand, there are reports of rare but serious adverse effects of erythromycin in newborn infants including sudden cardiovascular compromise and hypertrophic pyloric stenosis. We conclude that, at present, there is insufficient evidence to support the use of erythromycin for the treatment of incipient chronic lung disease in very low birthweight infants colonised with U. urealyticum.

Neonatal dexamethasone treatment increases susceptibility to experimental autoimmune disease in adult rats.

Major concern has emerged about the possible long term adverse effects of glucocorticoid treatment, which is frequently used for the prevention of chronic lung disease in preterm infants. Here we show that neonatal glucocorticoid treatment of rats increases the severity (p< or = 0.01) and incidence (p< or =0.01) of the inflammatory autoimmune disease experimental autoimmune encephalomyelitis in adult life. In search of possible mechanisms responsible for the increased susceptibility to experimental autoimmune encephalomyelitis, we investigated the reactivity of the hypothalamo-pituitary-adrenal axis and of immune cells in adult rats after neonatal glucocorticoid treatment. We observed that neonatal glucocorticoid treatment reduces the corticosterone response after an LPS challenge in adult rats (p< or =0.001). Interestingly, LPS-stimulated macrophages of glucocorticoid-treated rats produce less TNF-alpha and IL-1beta in adult life than control rats (p<0.05). In addition, splenocytes obtained from adult rats express increased mRNA levels of the proinflammatory cytokines IFN-gamma (p<0.01) and TNF-beta (p<0.05) after neonatal glucocorticoid treatment. Apparently, neonatal glucocorticoid treatment has permanent programming effects on endocrine as well as immune functioning in adult life. In view of the frequent clinical application of glucocorticoids to preterm infants, our data demonstrate that neonatal glucocorticoid treatment may be a risk factor for the development of (auto)immune disease in man.

Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease.

Lung disease in preterm infants is often complicated with lung edema. The aim of this review was to assess the risks and benefits of administration of a diuretic acting on the loop of Henle (loop diuretic) in preterm infants with or developing chronic lung disease (CLD). Primary objectives were to assess changes in need for oxygen or ventilatory support and effects on long-term outcome, and secondary objectives were to assess changes in pulmonary mechanics and potential complications of therapy. We used the standard search method of the Cochrane Neonatal Review Group. We used the following keywords: ¿<bronchopulmonary dysplasia> or <chronic lung disease>¿ and <explode diuretics>, limited to <human> and limited to <infant, newborn> or <infant>. We searched Medline (1966-1998), Embase (1974-1998) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (1998, issue 4). In addition, we hand searched several abstract books of national and international American and European Societies. We included in this analysis trials in which preterm infants with or developing chronic lung disease and at least 5 days of age were all randomly allocated to receive a loop diuretic either enterally or intravenously. Eligible studies needed to assess at least one of the outcome variables defined a priori for this systematic review. Primary outcome variables included important clinical outcomes, and secondary outcome variables included toxicity and pulmonary mechanics (e.g., lung compliance and airway resistance). We used the standard method for the Cochrane Collaboration which is described in the Cochrane Collaboration Handbook. Two investigators extracted, assessed and coded separately all data for each study, using a form that was designed specifically for this review. Any disagreement was resolved by discussion. We combined parallel and cross-over trials and, whenever possible, transformed baseline and final outcome data measured on a continuous scale into change scores using Follmann's formula. The only loop diuretic used in the studies which met the selection criteria was furosemide. Most studies focused on pathophysiological parameters and did not assess effects on important clinical outcomes defined in this review, or the potential complications of diuretic therapy. In preterm infants < 3 weeks of age developing CLD, furosemide administration has either inconsistent effects or no detectable effect. In infants > 3 weeks of age with CLD, a single intravenous dose of 1 mg/kg of furosemide improves lung compliance and airway resistance for 1 hour. Chronic administration of furosemide improves both oxygenation and lung compliance. In preterm infants > 3 weeks of age with CLD, acute and chronic administration of furosemide improve lung compliance. Chronic administration of intravenous or enteral furosemide improves oxygenation. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of systemic loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence. Randomized trials are needed to assess the effects of furosemide administration on survival, duration of ventilatory support and oxygen administration, length of hospital stay, potential complications and long-term outcome.

Investigation of Lung Disease in Preterm Infants Using Magnetic Resonance Imaging

Many preterm infants require ongoing respiratory support despite treatment with exogenous surfactant. The reasons for this are unclear, but may involve one or a combination of changes in water content or distribution within the lung. Detailed three-dimensional information with the potential to provide quantitation of water content may help to investigate this further. We aimed to determine if magnetic resonance (MR) imaging could be developed to study lung disease in preterm infants. Appropriate MR sequences and procedures were defined and we found that T1 and proton density weighted images could be successfully acquired. The images contained three-dimensional information that could not be obtained using chest radiograph. MR imaging may be a useful method for studying the pathology of respiratory distress syndrome and chronic lung disease in preterm infants.

Clinical use of antenatal corticosteroids: benefits and risks.

After completing this article, readers should be able to: 1. Describe the rationale for the use of antenatal corticosteroids for human fetal maturation. 2. Delineate recommendations of the 1994 National Institutes of Health Consensus Conference on Antenatal Corticosteroids. 3. Review areas of controversy in the clinical use of antenatal corticosteroids. 4. Describe the potential risks of multiple courses of antenatal corticosteroids. 5. Delineate current recommendations for clinical use of antenatal corticosteroids to promote fetal maturation. Glucocorticoid administration initially was appreciated as a method for accelerating development of the intestine more than 40 years ago. Since that time, developmental effects of these agents have been defined in at least 16 tissues of mammals. More than 30 years ago, while studying the mechanism of initiation of labor in sheep, Liggins made the observation that infusion of corticosteroids into fetal lambs was associated with improved survival and decreased lung disease in animals delivered preterm. Subsequently, numerous studies in cell culture, animal models, and human fetal tissue have delineated the multiple effects of glucocorticoids on the developing lung. These include increases in both the total tissue and alveolar surfactant pools; a decrease in vascular permeability, with less protein leak into the alveolar spaces; enhanced clearance of lung water; maturation of parenchymal structure; increase in lung compliance and maximal lung volume; enhanced response to surfactant treatment; and improvement in respiratory function, outcome, and survival. (See accompanying article on scientific rationale for use of antenatal glucocorticoids.) In 1972, the first randomized clinical trial of administration of antenatal corticosteroids (ANCS) in humans demonstrated decreased mortality and a decreased incidence of respiratory distress syndrome (RDS) in preterm infants born at less than 34 weeks’ gestation, who were treated with betamethasone for at least 24 hours before delivery. Over the ensuing 20 years, multiple clinical investigations continued to document the effectiveness of ANCS on …

Postnatal corticosteroids in preterm infants: systematic review of effects on mortality and motor function.

Postnatal corticosteroid therapy has been proved in randomized controlled trials to reduce ventilator dependence and the rate of chronic lung disease in preterm infants with few serious short-term side effects. However, there are other consequences that might follow postnatal corticosteroid therapy that are more important, including mortality or cerebral palsy. To review the evidence from reported randomized controlled trials on the effects of postnatal corticosteroid on long-term mortality and motor dysfunction, including cerebral palsy. The methods involved a meta-analysis of reported randomized controlled trials, following guidelines of the Cochrane Collaboration, including calculation of event rate differences (ERD) and 95% confidence intervals (CI). The mortality rate difference was non-significant both statistically and clinically (ERD - 0.1% favouring corticosteroids, 95% CI -2.9% to 2.8%). There were no subgroups in which a beneficial effect of postnatal corticosteroids on survival could be demonstrated. The rate of motor dysfunction in survivors was significantly higher in survivors from the postnatal corticosteroid group (ERD 11.9% favouring controls, 95% CI 4.6% to 19.2%). The rate of survival, free of motor dysfunction, was significantly lower in the postnatal corticosteroid group (ERD 7.8% favouring controls, 95% CI 0.5% to 15.1%). Although postnatal corticosteroids have short-term benefits, they do not increase the survival rate, and they may cause motor dysfunction in survivors. A large-scale, placebo-controlled randomized trial, with survival free of sensorineural impairments and disabilities as the major endpoint, is urgently needed.

Early (4–7 Days of Age) Dexamethasone Therapy for Prevention of Chronic Lung Disease in Preterm Infants

We conducted a comparative study to evaluate whether early (4–7 days of age) low-dose dexamethasone (DEX) therapy in preterm infants with surfactant-pretreated respiratory distress syndrome (RDS) would facilitate extubation and improve the clinical outcome. Twenty-six preterm infants with surfactant-pretreated RDS who were oxygen- and ventilator-dependent at 4 days of postnatal age were enrolled. Twelve infants were in the historical comparison group, and 14 infants were assigned to receive DEX 0.125 mg/kg i.v., every 12 h, for a total of 6 doses. At study entry, the two groups had a comparable clinical status. DEX therapy significantly facilitated weaning from mechanical ventilation (median interval, 6 vs. 24 days, p < 0.005) and shortened duration of oxygen supplementation (9 vs. 28 days, p < 0.05) as compared with the historical comparison group. At 28 days of age, the occurrence of chronic lung disease (CLD) was significantly lower (1/14 vs. 6/12, p < 0.05) and there was a significant decrease in the incidence of ventilator dependence (0/14 vs. 5/12, p < 0.05) in the DEX group. DEX therapy did not influence the incidence of significant complications such as infection, periventricular leukomalacia or retinopathy of prematurity. We conclude that in a selected high-risk group of preterm infants, early low-dose DEX treatment results in improvement in pulmonary outcome without significant side effects.

Meta‐analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants

Meta‐analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants