Respiratory Failure In Term Infants Research Articles

Neonatal Respiratory Care

Acute respiratory failure caused by different origins continues to be the major etiology of morbidity and mortality in critical neonates. There has been much advancement in neonatal respiratory care, but a few neonates with severe respiratory failure continue to be candidates for extracorporeal membrane oxygenation or survive with chronic lung diseases (CLD). Therefore, searching for ideal respiratory care strategies to reduce the morbidity and mortality rates is crucial for caring critical neonates. The main aim of this special issue was focused on the existing and potential strategies or techniques in neonatal respiratory care. In this special issue, we have invited a few papers that address such issues. Meconium aspiration syndrome (MAS) is a common cause of severe respiratory failure in term infants. The associations of persistent pulmonary hypertension of newborn (PPHN), pulmonary air leaks, and other morbidities sometimes make the respiratory care a difficult challenge to neonatologists. Three papers address current respiratory care in MAS. In a paper by K. Swarnam et al. they have a detail review on the epidemiology, pathophysiology, and managements in many different views of MAS. In another paper, P. Dargaville focuses on the application of mechanical respiratory supports in MAS, as well as the role of adjunctive respiratory therapies. In a paper, by C. Fischer et al., they demonstrate the epidemiology of MAS in term neonates using a population-based retrospective study for all births from 2000 to 2007 in a French region (Burgundy). In addition, bronchopulmonary dysplasia (BPD)/chronic lung disease (CLD) continues to be a major cause of neonatal morbidity in spite of significant progress in the treatment of preterm neonates. We have two articles discussing the pharmacologic approaches for prevention and treatment of BPD/CLD. S. Gupta et al. focus on the use of corticosteroids in one paper, and K. Tropea reviews all possible medications and the future potential stem cell therapy in another one. Furthermore, research papers discussing other important clinical issues in neonatal respiratory care are included. In a paper by S. Rastogi et al., they report their analysis on the factors associated with the successful weaning from nasal continuous positive airway pressure (NCPAP). In a paper by A. Gentili et al., they report their analysis on the duration of preoperative stabilization in predicting outcome of congenital diaphragmatic hernia. In a paper by K. Hole et al., they report the impact of neonatal resuscitation training in neonatal mortality rates in Malawi, Africa. Mei-Jy Jeng Tsu F. Yeh Peter A. Dargaville Thomas H. Shaffer Jen-Tien Wung

Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials

Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory. Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings. Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92-1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98-1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤ 5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74-0.98]) was found. Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.

Surfactant lavage for meconium aspiration syndrome

Meconium aspiration can cause lethal respiratory failure in term infants. Recent large trials have demonstrated that the interventions to prevent meconium aspiration syndrome (MAS) — intra-amniotic saline infusions prior to delivery, airway suction on the perineum at delivery, or intubation and tracheal suction of vigorous infants — do not prevent MAS. Nevertheless, in the US, the syndrome is disappearing, presumably because there are fewer post-dates deliveries, and asphyxia during labor is detected and treated more effectively.

Cochrane review: Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants

AbstractBackgroundNeonatal extracorporeal membrane oxygenation (ECMO) is a complex procedure of life support used in severe but potentially reversible respiratory failure in term infants. Although the number of babies eligible for ECMO is small and the use of ECMO invasive and potentially expensive, its benefits may be high.ObjectivesTo determine whether ECMO used for neonatal infants with severe respiratory failure is clinically and cost effective compared to conventional ventilatory support.Search strategyThe Cochrane Neonatal Group Specialised Register, the Cochrane Controlled Trials Register, and MEDLINE were searched for 1974 to 2007.Selection criteriaAll randomised trials comparing neonatal ECMO to conventional ventilatory support.Data collection and analysisThe authors independently evaluated the trials for methodological quality and appropriateness for inclusion in the Review (without consideration of their results) and independently extracted the data.Main resultsThe four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow‐up information. One study included economic evaluation.The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation.All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53).The UK trial provided follow up information about death or severe disability, and cost‐effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost‐effective as other intensive care technologies in common use.Authors' conclusionsA policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear.Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life.Plain Language SummaryExtracorporeal membrane oxygenation for severe respiratory failure in newborn infantsA complex life support procedure, called extracorporeal membrane oxygenation (ECMO), can be used in infants who are near term age to overcome severe, potentially reversible breathing problems. ECMO is similar to the technology used in cardiac bypass surgery. Blood is removed from the body of the patient, oxygen is added to the blood, and the blood is returned to the patient. Although the number of babies requiring ECMO is small, and ECMO is a very invasive and potentially expensive procedure, the benefits of this procedure are high. In this review, four randomized trials that compared the use of ECMO to the conventional approach to supporting these infants with severe breathing problems were identified. Overall, these trials showed a strong benefit for ECMO regarding survival at the time of hospital discharge. This is particularly true for infants without a specific problem of lung formation (congenital diaphragmatic hernia). The result implies that for every three babies with breathing problems and lung failure who were treated with ECMO rather than conventional ventilation, one more infant will survive. Although little information is available regarding long‐term follow‐up, one trial in the United Kingdom shows both benefits of ECMO and cost‐effectiveness of the use of ECMO.

Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants

Neonatal extracorporeal membrane oxygenation (ECMO) is a complex procedure of life support used in severe but potentially reversible respiratory failure in term infants. Although the number of babies eligible for ECMO is small and the use of ECMO invasive and potentially expensive, its benefits may be high. To determine whether ECMO used for neonatal infants with severe respiratory failure is clinically and cost effective compared to conventional ventilatory support. The Cochrane Neonatal Group Specialised Register, the Cochrane Controlled Trials Register, and MEDLINE were searched for 1974 to 2007. All randomised trials comparing neonatal ECMO to conventional ventilatory support. The authors independently evaluated the trials for methodological quality and appropriateness for inclusion in the Review (without consideration of their results) and independently extracted the data. The four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow-up information. One study included economic evaluation. The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation. All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53). The UK trial provided follow up information about death or severe disability, and cost-effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost-effective as other intensive care technologies in common use. A policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear. Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life.

Haplotype analysis of ABCA3: association with respiratory distress in very premature infants

Background. Adenosine triphosphate (ATP)‐binding cassette transporter A3 (ABCA3) gene mutations cause fatal respiratory failure in term infants, but common ABCA3 polymorphisms have remained uncharacterized at the population level.Aim. To define a subset of tagging single‐nucleotide polymorphisms (tSNPs) which capture most of the variation within the ABCA3 gene, and to assess ABCA3 as a novel candidate gene for susceptibility to respiratory distress syndrome (RDS) in preterm infants.Methods. Based on an initial screen, nine tSNPs were selected. These 9 tSNPs and a length variation, representing >90% of haplotypic variation of the gene, and 5 nonsynonymous coding SNPs were genotyped in 267 preterm infants. SNP rs13332514 was genotyped in an additional 48 infants.Results. The fourth common haplotype was overrepresented in very premature infants with RDS, being accounted for by SNP rs13332514 (F353F), with an increased minor allele frequency in RDS. Furthermore, rs13332514 associated significantly with chronic lung disease defined as a requirement for supplemental O2 at 28 postnatal days in very premature infants.Conclusions. The results are suggestive of an association of a synonymous SNP in the ABCA3 gene with a prolonged course of respiratory distress syndrome in very premature infants and serve as a reference for further population‐based studies of ABCA3.

Surfactant Protein B Deficiency: Insights into Surfactant Function through Clinical Surfactant Protein Deficiency

Surfactant protein B (SP-B) deficiency is a disorder of surfactant function with complete or transient absence of SP-B in term neonates. SP-B, 1 of 4 described surfactant-associated proteins, plays a key role in surfactant metabolism, particularly in intracellular packaging of surfactant components, formation of tubular myelin, and the presentation of the surfactant phospholipid monolayer to the air-fluid interface within the alveolus. Neonates with clinical SP-B deficiency best demonstrate the key role of SP-B in surfactant function. "Classic" deficiency results in severe respiratory failure in term infants and death unless lung transplantation is performed. Because the initial description of complete deficiency secondary to a homozygous frameshift mutation in codon 121 of the SP-B cDNA, partial deficiencies with differing genetic backgrounds and less severe clinical courses have been reported. These partial deficiency states may provide a clearer picture of genotype/phenotype relationships in SP-B function and surfactant metabolism. SP-B deficiency or dysfunction may be more common than once thought and may play a significant role in neonatal lung disease.

Inhaled Nitric Oxide and Hypoxic Respiratory Failure in Term Infants: Neurodevelopmental Follow-Up

Inhaled Nitric Oxide and Hypoxic Respiratory Failure in Term Infants: Neurodevelopmental Follow-Up

SURFACTANT PROTEIN-B (SP-B) PROMOTER IN REPLICATION DEFICIENT ADENOVIRUS(rAd) DIRECTS PULMONARY EPITHELIAL CELL-SPECIFIC GENE EXPRESSION. • 1986

Gene therapy using rAd shows promise in treating genetic pulmonary diseases. Inherited deficiency of SP-B, a proteolipid critical to pulmonary surfactant, results in severe respiratory failure in term infants. SP-B is produced by alveolar type II cells and bronchiolar Clara cells and may be harmful within other cells due to its fusogenic properties. A SP-B promoter(SPB; -640/+319 relative to transcription start site) shows lung epithelial cell line specificity in transient transfection of H441 pulmonary adenocarcinoma cells with promoter strength similar to the promiscuous viral RSV promoter. To explore cell-type specific gene therapy for SP-B deficiency, we compared expression of the lacZ reporter gene driven by the RSV or SP-B promoters in rAd. Dose-response and time course experiments in H441 cells demonstrated efficient rAd.SPB.lacZ and rAd.RSV.lacZ infection with 24h of virus exposure at a multiplicity of infection (MOI) of≈1-10 with high-level β-galactosidase activity after 72h. X-gal staining showed specificity of rAd.SPB.lacZ for pulmonary derived cell lines (A549 and H441 versus HeLa) whereas all cell lines stained extensively with rAd.RSV.lacZ. This finding was confirmed by quantitative β-gal assay: the ratios of rAd.SPB.lacZ to rAd.RSV.lacZ β-gal activities(average ± SEM) were A549 = 1.96 ± 0.69; H441 = 0.66 ± 0.13; HeLa = 0.05 ± 0.01; p<0.05; n=3). Human fetal lung explants(24wk gestation) infected with rAd.SPB.lacZ had preferential X-gal staining of airway lining cells versus interstitial cells. Epithelia of explanted trachea showed minimal staining. All lung and trachea explant cell types stained extensively with rAd.RSV.lacZ. rAd.SPB.lacZ infection of mixed cells isolated from lung explants showed staining of most epithelial cells and rare fibroblasts. Primary fibroblasts infected with rAd.SPB.lacZ (MOI 1-300) had very low β-gal activities (7-94 A420/min/mg protein) whereas β-gal activities of fibroblasts infected with rAd.RSV.lacZ increased in a dose-dependent manner (480-55200 A420/min/mg protein). These results indicate that the SP-B promoter in rAd maintains cell line specificity and may be useful for limiting transgene expression to type II and Clara cells. (supported by 5 P30 HD28815)

Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation

A blinded, randomized, controlled study was designed to test whether multiple-dose surfactant therapy would improve pulmonary outcome in term infants with respiratory failure, resulting in a shortened period of extracorporeal membrane oxygenation (ECMO). Infants > or = 34 weeks of gestational age in severe respiratory failure and receiving ECMO were stratified by diagnosis and then randomly assigned to the treatment or the control group. Four doses of modified bovine lung surfactant extract (beractant) were administered to the surfactant group (n = 28), and an equal volume of air was administered to the control group (n = 28). Lung compliance was initially low in both groups; after treatment, values were higher with time in the surfactant group (F = 5.40, p = 0.026). The ECMO treatment period was significantly shorter in the surfactant group (mean +/- SD: 107 +/- 33 hours vs 139 +/- 54 hours for the control group; U = 232, p = 0.023). Tracheal aspirate concentrations of surfactant protein A were low in both groups, and then increased steadily to a higher level in the surfactant group (F = 2.58, p = 0.04). The overall incidence of complications after ECMO was decreased in the surfactant group (18% vs 46% for the control group; chi-square value = 5.004, p = 0.025). Radiographic scores, echocardiographic findings, incidence of intracranial or pulmonary hemorrhage and bronchopulmonary dysplasia, time to extubation, duration of oxygen therapy, and duration of hospitalization did not differ between the two groups. Beractant in this population improved pulmonary mechanics, increased surfactant protein A content in tracheal aspirate, decreased time on ECMO duration, and reduced disease complications.