N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial

Ahola, T; Lapatto, Risto; Raivio, Kari O.; Selander, Bo; Stigson, Lennart; Jónsson, Baldvin; Jonsbo, Finn; Esberg, Gitte; Stövring, Sören; Kjartansson, Sveinn; Stiris, Tom; Lossius, Kristin; Virkola, Kristina; Fellman, Vineta

doi:10.1067/s0022-3476(03)00419-0

Cited by 117 publications

(98 citation statements)

References 39 publications

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“…We carried out a randomized, multicenter, controlled trial to test the hypothesis that NAC administration during the first week of life would decrease the incidence of BPD in extremely low birth weight infants (ELBWIs). However, no difference was found in the incidence of BPD or death in the NAC-treated infants (n ϭ 194) compared with placebo-treated infants (n ϭ 197) (18).…”

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confidence: 95%

Plasma 8-Isoprostane Is Increased in Preterm Infants Who Develop Bronchopulmonary Dysplasia or Periventricular Leukomalacia

et al. 2004

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Our aim was to assess the plasma free 8-epi-prostaglandin F 2␣ (8-isoprostane) and ascorbyl radical as risk indicators for oxidative damage in extremely low birth weight infants (ELBWIs) and the effect of N-acetylcysteine (NAC) on these markers. Plasma samples were collected on days 3 and 7 of life from infants who were enrolled in a randomized, controlled trial in which i.v. NAC or placebo was administered to ELBWIs during the first week of life, with the aim of preventing bronchopulmonary dysplasia (BPD). Plasma 8-isoprostane was analyzed in 83 infants using an enzyme immunoassay kit. Ascorbyl radical concentration was measured in 61 infants with electron spin resonance spectroscopy. The 8-isoprostane concentrations were similar in the NAC and placebo groups. In infants who later developed BPD or died (n ϭ 29), the median (range) 8-isoprostane concentration was significantly higher (p ϭ 0.001) on day 3 and day 7 [50.0 pg/mL (19 -360) and 57.0 pg/mL (14 -460), respectively] than in survivors without BPD [n ϭ 54; 34.5 pg/mL (5-240) and 39.5 pg/mL (7-400), respectively]. The 8-isoprostane levels increased significantly more (p Ͻ 0.05) in infants who later developed periventricular leukomalacia. NAC treatment or the later development of BPD was not related to the ascorbyl radical levels. The ascorbyl radical level decreased significantly in all groups from day 3 to day 7, but the difference between the groups was not significant. The mean (SD) ascorbyl radical level on day 3 was significantly higher (p Ͻ 0.01) in infants who later developed periventricular leukomalacia [287 (124) Free radical generation and oxidative injury have been implicated as causal factors in several complications of prematurity, such as bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL) (1). Despite improved perinatal care, BPD remains one of the most important causes of long-term morbidity after preterm birth (2). Oxygen therapy and inflammatory neutrophil activation are considered important in increasing the production of reactive oxygen species (ROS) and the release of proinflammatory cytokines resulting in abnormal lung development. Evidence for increased oxidant production and oxidant-induced macromolecular damage has been demonstrated during the first week of life in infants who develop BPD (2,3). Increased levels of volatile lipid peroxidation products have been shown to correlate with poor respiratory outcome and death in very low birth weight infants (4).Preterm newborn infants are considered vulnerable to oxidative stress because of deficient antioxidant capacity. Even though the enzymatic antioxidant defenses of preterm infants seem relatively well developed, with the exception of catalase (5)

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Plasma 8-Isoprostane Is Increased in Preterm Infants Who Develop Bronchopulmonary Dysplasia or Periventricular Leukomalacia

et al. 2004

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“…Moreover, in preterm animals, in contrast with term, induction of antioxidative enzymes does not occur after oxidative stress (41,44). Randomized trials of antioxidant intervention in premature infants, with strong rationale and good study design, failed to demonstrate any improvement on BPD incidence (36,(45)(46)(47). In our study, we speculate that low-dose iNO probably did not act as an antioxidant by itself but by reducing the oxidative stress as a result of high oxygen concentration allowed a less dramatic consumption of GSH stores.…”

Section: Discussionmentioning

confidence: 99%

Early Inhaled Nitric Oxide Improves Oxidative Balance in Very Preterm Infants

Hamon

Fresson²,

Nicolas

et al. 2005

Pediatr Res

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Inhaled nitric oxide (iNO) improves oxygenation in premature infants, but concern has been raised about its potential oxidative toxicity. We designed this study to assess the oxidative balance in premature infants who were exposed to low dose iNO and the relationship with their clinical outcome on day 28 of life. A total of 274 infants who were Ͻ32 wk gestation were randomized at birth to receive 5 ppm of iNO if they presented with hypoxemic respiratory failure. Nonhypoxemic infants were studied as the reference group. Blood samples were withdrawn 24 h apart, within the first 4 d of life, to assess malondialdehyde (MDA) concentration as oxidative stress marker and total plasmatic glutathione (GSH), intraerythrocyte GSH peroxidase, and GSH reductase activities as antioxidant defenses. After 24 h, the rise in MDA was blunted in the iNO group compared with controls and was close to the reference infants. Conversely, GSH was more stable in the iNO group, when there was no difference for the GSH peroxidase and GSH reductase activities. On day 28, Oxygen dependence was linked with a higher increase in MDA as was the risk for death, whereas intraventricular hemorrhage was associated with a higher initial drop in GSH. Early low-dose iNO in hypoxemic preterm infants improves oxidative balance and seems to be clinically beneficial up to day 28 of life. Since 1992, several randomized trials have shown that inhaled nitric oxide (iNO) significantly improved oxygenation in term or near-term infants, with a significant reduction in the use of extracorporeal membrane oxygenation (1-6). In 1997, Skimming et al. (7) were the first to report a positive response of 23 premature infants with respiratory distress syndrome to low-dose iNO (5 ppm). Since then, a few clinical trials involving a small number of premature infants have shown that the initial improvement in oxygenation seemed to be transient (8 -10) because no improvement in mortality or in morbidity had been demonstrated (11). However, most of these studies were considering iNO therapy in premature infants who had severe hypoxemic respiratory failure or refractory hypoxemia (8,10,11) or were at an advanced stage of respiratory insufficiency (12). Most of them used a high dosage of iNO (10 -20 ppm).Finally, concerns have been raised about specific side effects of this new molecule that could worsen long-term outcome after an initial improvement in this high-risk population (13)(14)(15). Besides the risk for increased brain hemorrhage as a result of a prolonged bleeding time (16), neonatologists remain cautious in the use of this treatment because NO behaves as a "chameleon" molecule for the oxidative balance. Endogenous NO is incriminated in the cascade leading to cerebral lesions in perinatal experimental models of hypoxo-ischemic injuries (17). In addition, iNO may interact with oxygen to form nitrogen dioxide and peroxynitrites, which would enhance pulmonary toxicity. This is a main concern when dealing with Received May 20, 2004; accepted September 27, 2004

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“…Three hundred and ninety-one ELBW infants who were on mechanical ventilation or continuous positive airway pressure (CPAP) by the age of 36 hour were randomized to NAC or placebo. 41 There was no effect of the drug on death or need for supplementary oxygen at 28 postnatal days or 36 postmenstrual weeks. The study drug did not ameliorate lung function parameters assessed near term in 18 of the 197 infants in the intervention group compared to 15 who had received placebo.…”

Section: Methylxanthinesmentioning

confidence: 99%

“…40 Currently, only two antioxidants have been evaluated for prevention or amelioration of BPD in randomized controlled trials. Ahola et al 41 assessed the effect of a 6-day course of intravenous N-acetylcysteine (NAC) in ELBW infants. NAC is deacetylated to cysteine, the carrier of the active sulfhydryl residue in glutathione.…”

Section: Methylxanthinesmentioning

confidence: 99%

Prevention and treatment of bronchopulmonary dysplasia: current status and future prospects

Thomas

Speer

2007

J Perinatol

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This review summarizes the existing evidence for potential non-ventilatordependent strategies to prevent or ameliorate bronchopulmonary dysplasia (BPD). Oxygen plays an important pathogenetic and therapeutic role for BPD. Targeting infants with lower saturation of peripheral oxygen levels than traditionally used seems justified. Inhaled nitric oxide has not proven effective on pulmonary outcome in extremely low birth weight infants. Diuretics can ameliorate lung function transiently. High intramuscular doses of vitamin A reduce the risk of BPD. Prophylactic application of natural surfactant may also confer benefits. Recently, early administration of caffeine has been shown to decrease risk of BPD. However, assessment of long-term effects is needed before routine use can be recommended. Owing to potential short-and long-term effects, postnatal corticosteroids should be restricted to the most severe manifestations of BPD. Superoxide dismutase and a1-proteinase inhibitor have not shown efficacy in preventing BPD. The potential role of anti-inflammatory therapies like Clara Cell 10 kDa protein has yet to be defined.

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N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial

Cited by 117 publications

References 39 publications

Plasma 8-Isoprostane Is Increased in Preterm Infants Who Develop Bronchopulmonary Dysplasia or Periventricular Leukomalacia

Plasma 8-Isoprostane Is Increased in Preterm Infants Who Develop Bronchopulmonary Dysplasia or Periventricular Leukomalacia

Early Inhaled Nitric Oxide Improves Oxidative Balance in Very Preterm Infants

Prevention and treatment of bronchopulmonary dysplasia: current status and future prospects

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