Respiratory Failure In Preterm Infants Research Articles

New developments in neonatal respiratory management.

Respiratory distress syndrome (RDS) is the major cause of respiratory failure in preterm infants due to immature lung development and surfactant deficiency. Although the concepts and methods of managing respiratory problems in neonates have changed continuously, determining appropriate respiratory treatment with minimal ventilation-induced lung injury and complications is crucially important. This review summarizes neonatal respiratory therapy's advances and available strategies (i.e., exogenous surfactant therapy, noninvasive ventilation, and different ventilation modes), focusing on RDS management.

Recent research on the mechanism of mesenchymal stem cells in the treatment of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease due to impaired pulmonary development and is one of the main causes of respiratory failure in preterm infants. Preterm infants with BPD have significantly higher complication and mortality rates than those without BPD. At present, comprehensive management is the main intervention method for BPD, including reasonable respiratory and circulatory support, appropriate enteral nutrition and parenteral nutrition, application of caffeine/glucocorticoids/surfactants, and out-of-hospital management after discharge. The continuous advances in stem cell medicine in recent years provide new ideas for the treatment of BPD. Various pre-clinical trials have confirmed that stem cell therapy can effectively prevent lung injury and promote lung growth and damage repair. This article performs a comprehensive analysis of the mechanism of mesenchymal stem cells in the treatment of BPD, so as to provide a basis for clinical applications.

Does surfactant nebulization prevent early intubation in preterm infants? A protocol for a systematic review and meta-analysis

BackgroundRespiratory distress syndrome (RDS) is the most common cause of respiratory failure in preterm infants. Treatment consists of respiratory support and exogenous surfactant administration. Commonly, surfactant is administered intratracheally. However, this requires airway instrumentation and subsequent fluid instillation which may be harmful. Surfactant nebulization (SN) may offer a safe and effective alternative for surfactant administration, but the clinical efficacy is not yet established. Thus, this systematic review and meta-analysis of randomized controlled trials will summarize the available evidence to determine the effectiveness and safety of SN for the prevention of intubation and subsequent mechanical ventilation at 72 h after birth.MethodsA systematic literature search in Medline, Embase, and The Cochrane Library will be performed, and all randomized controlled trials (RCTs) and quasi-RCTs from published articles, presentations, and trial registries will be included in this meta-analysis. Titles and abstracts of all records identified in the search will be screened by two reviewers independently.Data on preterm infants (≤ 37 weeks) receiving nebulized surfactant in the first 72 h after birth for the treatment or prevention of RDS will be evaluated. Primary outcome is the intubation rate by 72 h after birth, and secondary outcomes include peridosing safety effects as well as major neonatal morbidities.Risk of bias will be assessed using the revised Cochrane ROB tool, and subgroup analyses will be performed to evaluate potential confounding factors. Publication bias will be assessed by examining a funnel plot. The meta-analysis will be performed using a fixed-effects model.DiscussionThis review will provide an evidence-based tool for information about surfactant nebulization, illustrating the current knowledge and hopefully revealing potential novel avenues for researchers and clinicians alike.Systematic review registrationThis review is registered with the publicly available resource PROSPERO (CRD42020175625).

Study protocol for the POPART study—Prophylactic Oropharyngeal surfactant for Preterm infants: A Randomised Trial

IntroductionMany preterm infants develop respiratory distress syndrome (RDS), a condition characterised by a relative lack of surfactant. Endotracheal surfactant therapy revolutionised the care of preterm infants in the 1990s. However,...

Diaphragm-triggered non-invasive respiratory support in preterm infants.

Diaphragm-triggered non-invasive respiratory support, commonly referred to as NIV-NAVA (non-invasive neurally adjusted ventilatory assist), uses the electrical activity of the crural diaphragm to trigger the start and end of a breath. It provides variable inspiratory pressure that is proportional to an infant's changing inspiratory effort. NIV-NAVA has the potential to provide effective, non-invasive, synchronised, multilevel support and may reduce the need for invasive ventilation; however, its effects on short- and long-term outcomes, especially in the preterm infant, are unclear. To assess the effectiveness and safety of diaphragm-triggered non-invasive respiratory support in preterm infants (< 37 weeks' gestation) when compared to other non-invasive modes of respiratory support (nasal intermittent positive pressure ventilation (NIPPV); nasal continuous positive airway pressure (nCPAP); high-flow nasal cannulae (HFNC)), and to assess preterm infants with birth weight less than 1000 grams or less than 28 weeks' corrected gestation at the time of intervention as a sub-group. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 5), MEDLINE via PubMed (1946 to 10 May 2019), Embase (1947 to 10 May 2019), and CINAHL (1982 to 10 May 2019). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. Randomised and quasi-randomised controlled trials that compared diaphragm-triggered non-invasive versus other non-invasive respiratory support in preterm infants. Two review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs). We used the generic inverse variance method to analyse specific outcomes for cross-over trials. We used the GRADE approach to assess the certainty of evidence. There were two small randomised controlled trials including a total of 23 infants eligible for inclusion in the review. Only one trial involving 16 infants included in the analysis reported on either of the primary outcomes of the review. This found no difference in failure of modality between NIV-NAVA and NIPPV (RR 0.33, 95% CI 0.02 to 7.14; RD -0.13, 95% CI -0.41 to 0.16; 1 study, 16 infants; heterogeneity not applicable). Both trials reported on secondary outcomes of the review, specific for cross-over trials (total 22 infants; 1 excluded due to failure of initial modality). One study involving seven infants reported a significant reduction in maximum FiO₂ with NIV-NAVA compared to NIPPV (MD -4.29, 95% CI -5.47 to -3.11; heterogeneity not applicable). There was no difference in maximum electric activity of the diaphragm (Edi) signal between modalities (MD -1.75, 95% CI -3.75 to 0.26; I² = 0%) and a significant increase in respiratory rate with NIV-NAVA compared to NIPPV (MD 7.22, 95% CI 0.21 to 14.22; I² = 72%) on a meta-analysis of two studies involving a total of 22 infants. The included studies did not report on other outcomes of interest. Due to limited data and very low certainty evidence, we were unable to determine if diaphragm-triggered non-invasive respiratory support is effective or safe in preventing respiratory failure in preterm infants. Large, adequately powered randomised controlled trials are needed to determine if diaphragm-triggered non-invasive respiratory support in preterm infants is effective or safe.

Turkish Neonatal Society guideline on the management of respiratory distress syndrome and surfactant treatment.

Respiratory distress syndrome is the leading cause of respiratory failure in preterm infants. The incidence and severity of respiratory distress syndrome are inversely related to the gestational age of the newborn. The major underlying pathophysiologic mechanisms are surfactant deficiency and anatomic, structural immaturity of the lung. Recent improvements such as antenatal steroid treatment to enhance pulmonary maturity, appropriate resuscitation facilitated by placental transfusion and immediate use of continuous positive airway pressure for alveolar recruitment, early rescue administration of surfactant, ventilation with gentler modes to minimize damage to the immature lungs, and the other supportive therapies have significantly decreased respiratory distress syndrome-related morbidity and mortality. This guideline was addressed to overview the mentioned improvements in order to standardize respiratory distress syndrome management in neonatal intensive care units in Turkey.

A sulfur-free peptide mimic of surfactant protein B (B-YL) exhibits high in vitro and in vivo surface activities.

Background: Animal-derived surfactants containing surfactant proteins B (SP-B) and C (SP-C) are used to treat respiratory distress syndrome (RDS) in preterm infants. SP-B (79 residues) plays a pivotal role in lung function and the design of synthetic lung surfactant. Super Mini-B (SMB), a 41-residue peptide based on the N- and C-domains of SP-B covalently joined with a turn and two disulfides, folds as an α-helix hairpin mimicking the properties of these domains in SP-B. Here, we studied 'B-YL', a 41-residue SMB variant that has its four cysteine and two methionine residues replaced by tyrosine and leucine, respectively, to test whether these hydrophobic substitutions produce a surface-active, α-helix hairpin. Methods: Structure and function of B-YL and SMB in surfactant lipids were compared with CD and FTIR spectroscopy, and surface activity with captive bubble surfactometry and in lavaged, surfactant-deficient adult rabbits. Results: CD and FTIR spectroscopy of B-YL in surfactant lipids showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to SMB in lipids. B-YL in surfactant lipids demonstrated excellent in vitro surface activity and good oxygenation and dynamic compliance in lavaged, surfactant-deficient adult rabbits, suggesting that the four tyrosine substitutions are an effective replacement for the disulfide-reinforced helix-turn of SMB. Here, the B-YL fold may be stabilized by a core of clustered tyrosines linking the N- and C-helices through non-covalent interactions involving aromatic rings. Conclusions: 'Sulfur-free' B-YL forms an amphipathic helix-hairpin in surfactant liposomes with high surface activity and is functionally similar to SMB and native SP-B. The removal of the cysteines makes B-YL more feasible to scale up production for clinical application. B-YL's possible resistance against free oxygen radical damage to methionines by substitutions with leucine provides an extra edge over SMB in the treatment of respiratory failure in preterm infants with RDS.

A sulfur-free peptide mimic of surfactant protein B (B-YL) exhibits high in vitro and in vivo surface activities

Background: Animal-derived surfactants containing surfactant proteins B (SP-B) and C (SP-C) are used to treat respiratory distress syndrome (RDS) in preterm infants. SP-B (79 residues) plays a pivotal role in lung function and the design of synthetic lung surfactant. Super Mini-B (SMB), a 41-residue peptide based on the N- and C-domains of SP-B covalently joined with a turn and two disulfides, folds as an α-helix hairpin mimicking the properties of these domains in SP-B. Here, we studied ‘B-YL’, a 41-residue SMB variant that has its four cysteine and two methionine residues replaced by tyrosine and leucine, respectively, to test whether these hydrophobic substitutions produce a surface-active, α-helix hairpin. Methods: Structure and function of B-YL and SMB in surfactant lipids were compared with CD and FTIR spectroscopy, and surface activity with captive bubble surfactometry and in lavaged, surfactant-deficient adult rabbits. Results: CD and FTIR spectroscopy of B-YL in surfactant lipids showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to SMB in lipids. B-YL in surfactant lipids demonstrated excellent in vitro surface activity and good oxygenation and dynamic compliance in lavaged, surfactant-deficient adult rabbits, suggesting that the four tyrosine substitutions are an effective replacement for the disulfide-reinforced helix-turn of SMB. Here, the B-YL fold may be stabilized by a core of clustered tyrosines linking the N- and C-helices through non-covalent interactions involving aromatic rings. Conclusions: ‘Sulfur-free’ B-YL forms an amphipathic helix-hairpin in surfactant liposomes with high surface activity and is functionally similar to SMB and native SP-B. The removal of the cysteines makes B-YL more feasible to scale up production for clinical application. B-YL’s possible resistance against free oxygen radical damage to methionines by substitutions with leucine provides an extra edge over SMB in the treatment of respiratory failure in preterm infants with RDS.

An oxidation-resistant peptide mimic of surfactant protein B (B-YL) forms an amphipathic helix-hairpin in liposomes with high surface activity

Background: Animal-derived surfactants containing surfactant proteins B (SP-B) and C (SP-C) are used to treat respiratory distress syndrome (RDS) in preterm infants. SP-B (79 residues) plays a pivotal role in lung function and the design of synthetic lung surfactant. Super Mini-B (SMB), a 41-residue peptide based on the N- and C-domains of SP-B joined with a turn and two disulfides, folds as an α-helix hairpin mimicking the properties of these domains in SP-B. Here, we studied ‘B-YL’, a 41-residue oxidation-resistant SMB variant that has its four Cys and two Met residues replaced by Tyr and Leu, respectively, to test whether these hydrophobic substitutions produce a surface-active, α-helix hairpin.Methods:Structure and function of B-YL and SMB in surfactant lipids were compared with CD and FTIR spectroscopy and molecular dynamic (MD) simulations, and surface activity with captive bubble surfactometry and in lavaged, surfactant-deficient adult rabbits.Results:CD and FTIR spectroscopy of B-YL in surfactant lipids showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to SMB in lipids. MD simulations confirmed that B-YL maintained its α-helix hairpin in a lipid bilayer, matching the hairpin obtained from MD of SMB. Unlike the disulfide-reinforced helix-turn of SMB, the B-YL fold was stabilized by a core of clustered Tyr linking the N- and C-helices through noncovalent interactions involving aromatic rings. B-YL in surfactant lipids demonstrated excellentin vitrosurface activity and good oxygenation and dynamic compliance in lavaged, surfactant-deficient adult rabbits.Conclusions:‘Sulfur-free’ and ‘oxidation-resistant’ B-YL forms an amphipathic helix-hairpin in surfactant liposomes with high surface activity and is functionally similar to SMB and native SP-B. B-YL’s resistance against free oxygen radical damage provides an extra edge over oxidized SMB in the treatment of respiratory failure in preterm infants with RDS and children and adults with acute lung injury.

Diaphragm-triggered non-invasive respiratory support for preventing respiratory failure in preterm infants

Diaphragm-triggered non-invasive respiratory support for preventing respiratory failure in preterm infants

Inhaled nitric oxide for respiratory failure in preterm infants.

Inhaled nitric oxide (iNO) is effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure and the potential risks of iNO differ substantially in preterm infants, necessitating specific study in this population. To determine effects of treatment with inhaled nitric oxide (iNO) on death, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH) or other serious brain injury and on adverse long-term neurodevelopmental outcomes in preterm newborn infants with hypoxic respiratory failure.Owing to substantial variation in study eligibility criteria, which decreases the utility of an overall analysis, we divided participants post hoc into three groups: (1) infants treated over the first three days of life because of defects in oxygenation, (2) preterm infants with evidence of pulmonary disease treated routinely with iNO and (3) infants treated later (after three days of age) because of elevated risk of BPD. We used standard methods of the Cochrane Neonatal Review Group. We searched MEDLINE, Embase, Healthstar and the Cochrane Central Register of Controlled Trials in the Cochrane Library through January 2016. We also searched the abstracts of the Pediatric Academic Societies. Eligible for inclusion were randomised and quasi-randomised studies in preterm infants with respiratory disease that compared effects of iNO gas versus control, with or without placebo. We used standard methods of the Cochrane Neonatal Review Group and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. We found 17 randomised controlled trials of iNO therapy in preterm infants. We grouped these trials post hoc into three categories on the basis of entry criteria: treatment during the first three days of life for impaired oxygenation, routine use in preterm babies along with respiratory support and later treatment for infants at increased risk for bronchopulmonary dysplasia (BPD). We performed no overall analyses.Eight trials providing early rescue treatment for infants on the basis of oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD (typical risk ratio (RR) 0.94, 95% confidence interval (CI) 0.87 to 1.01; 958 infants). Four studies examining routine use of iNO in infants with pulmonary disease reported no significant reduction in death or BPD (typical RR 0.94, 95% CI 0.87 to 1.02; 1924 infants), although this small effect approached significance. Later treatment with iNO based on risk of BPD (three trials) revealed no significant benefit for this outcome in analyses of summary data (typical RR 0.92, 95% CI 0.85 to 1.01; 1075 infants).Investigators found no clear effect of iNO on the frequency of all grades of IVH nor severe IVH. Early rescue treatment was associated with a non-significant 20% increase in severe IVH.We found no effect on the incidence of neurodevelopmental impairment. iNO does not appear to be effective as rescue therapy for the very ill preterm infant. Early routine use of iNO in preterm infants with respiratory disease does not prevent serious brain injury or improve survival without BPD. Later use of iNO to prevent BPD could be effective, but current 95% confidence intervals include no effect; the effect size is likely small (RR 0.92) and requires further study.

Randomized Control Trial: Heated Humidity High Flow Nasal Cannula in Comparison with NCPAP in the Management of RDS in Extreme Low Birth Infants in Immediate Post Extubation Period

Background: Respiratory failure in neonates remains a difficult challenge and is associated with high morbidity and mortality. Current practice reflects the belief that limited exposure to invasive mechanical ventilation and careful use of oxygen support, results in less lung injury and improved long term pulmonary outcomes in preterm infants. Respiratory Distress Syndrome (RDS) is a common cause of respiratory failure in preterm infants and occurs in most preterm infants less than 28 weeks gestation. Standard of care involves surfactant administration and providing respiratory support. Objective: To compare the primary outcome, failure of extubation defined by the need for re-intubation and mechanical ventilation within 5 days of initial extubation and secondary outcomes, morbidities and mortality after using of heated humidity high flow nasal cannula (HHHFNC) and Nasal Continuous Positive Airway Pressure (NCPAP) in the immediate post-extubation period for preterm infants between 24 and 28 weeks gestation with respiratory distress syndrome. Methods: 60 preterm infants with gestational ages between 24 and 28 weeks were randomized in this study to either HHHFNC or NCPAP. The primary outcome measured was failed extubation defined by the need for reintubation and mechanical ventilation within 5 days of initial extubation after receiving at least 2 doses of surfactant. Secondary outcome measures included: 1. Duration of respiratory support using HHHFNC/NCPAP. 2. Duration of oxygen requirement. 3. Incidence of complications i.e. Nasal breakdown, Sepsis, Intraventricular hemorrhage, Retinopathy of prematurity and Patent Ductus Arteriosis. Preterm infants who remained intubated for more than 24 hours were excluded from the study. Results: 17.2% of neonates placed on HHHFNC failed extubation and required re-intubation within 5 days of initial extubation compared with 20.8% of neonates placed on NCPAP (p value 1.000). Mean duration of respiratory support using HHHFNC was 37.45 days compared with 40.04 days using NCPAP (p value 0.66). Duration of oxygen requirement for infants placed on HHHFNC was 49.41 days compared with 43.75 days for infants placed on NCPAP (p value 0.58). 25% of infants placed on NCPAP suffered nasal trauma, 12.5% developed sepsis, 12.5% had grades III and IV IVH, 41.67% were reported to have a PDA and 41.67% were reported to have varying stages of ROP. No nasal trauma was reported for infants placed on HHHFNC, 3.5% developed sepsis, 13.79% had grades III and IV IVH, 31.03% were reported to have a PDA and 24.14% were reported to have varying stages of ROP. Conclusion: HHHFNC use is comparable to the use of NCPAP in the immediate post-extubation period for preterm infants between 24 and 28 weeks gestations with Respiratory Distress Syndrome without an increased risk for co-morbid conditions.

Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future.

Respiratory distress syndrome (RDS) due to surfactant deficiency is the most common cause of respiratory failure in preterm infants. Tremendous progress has been made since the original description that surfactant deficiency is the major cause of RDS. Surfactant therapy has been extensively studied in preterm infants and has been shown to significantly decrease air leaks and neonatal and infant mortality. Synthetic and animal-derived surfactants from bovine as well as porcine origin have been evaluated in randomized controlled trials. Animal-derived surfactants generally result in faster weaning of respiratory support, shorter duration of invasive ventilation, and decreased mortality when compared to first- or second-generation of synthetic surfactants, but some of the second-generation synthetic surfactants are at least not inferior to the animal-derived surfactants. Using a higher initial dose of porcine derived surfactant may provide better outcomes when compared with using lower doses of bovine surfactants, likely, due to compositional difference and/or the dose. Third-generation synthetic surfactant containing peptide analogs of surfactant protein B and C are currently being studied. Less invasive intra-tracheal surfactant administration techniques in spontaneously breathing neonate receiving noninvasive ventilator support are also being evaluated. In the present era, prophylactic surfactant is not recommended as it may increase the risk of lung injury or death. In the future, surfactants may be used as vector to deliver steroids, or used in combination with molecules, such as, recombinant Club Cell Protein-10 (rhCC-10) to improve pulmonary outcomes. Also, noninvasive surfactant administration techniques, such as aerosolization or atomization of surfactant may play a greater role in the future.

Impact of targeted-volume ventilation on pulmonary dynamics in preterm infants with respiratory distress syndrome.

Mechanical ventilation is an essential therapy in the treatment of respiratory failure in preterm infants. However, optimal ventilation strategy continues to be difficult to define. To compare the effects of volume guarantee (VG) combined with intermittent mandatory ventilation (SIMV) and VG combined with pressure support ventilation (PSV) on the pulmonary mechanics and short term prognosis in preterm infants with respiratory distress syndrome. Infants of <32 weeks gestational age ventilated for respiratory distress syndrome were randomized to receive either SIMV + VG or PSV + VG. The patient characteristics, ventilator variables including PIP, PEEP, MAP, VT, dynamic compliance, resistance, C20/C, and neonatal outcomes (IVH, ROP, oxygen dependency at 28th postnatal day and 36 weeks of PMA), mortality and extubation failure were recorded in each groups. Thirty-four infants were enrolled in to the study: 19 patients were randomized to the SIMV + VG group, and 15 patients to the PSV + VG group. No significant differences were observed between the two groups in terms of the birth weight, gestational age, gender, multiple pregnancy, delivery mode, and antenatal steroid treatment. The respiratory and ventilatory parameters were similar in the groups. The need for reintubation were common in SIMV + VG group (P < 0.01). Volume guaranteed ventilation combined with PSV may be a convenient method for preterm infants with RDS in terms of reducing postextubation atelectasis and the need for reintubation. Pediatr Pulmonol. 2017;52:213-216. © 2016 Wiley Periodicals, Inc.

Comparison of two kinds of noninvasive ventilation mode in premature infants with respiratory failure

Objective To investigate the difference of two models of respiratory failure in preterm infants with nasal continuous positive airway pressure(nCPAP) and nasal biphasic positive airway pressure(nBiPAP). Methods Comparative analysis of 81 cases of premature infants with respiratory failure requiring respiratory support was needed.They were applied nCPAP and nBiPAP ventilation mode treatment.The use of breathing machine and total oxygen inhalation time, the number of treatment failures, the PEEP parameters of the ventilator, the total number of recent complications and secondary infections were compared. Results In the nBiPAP treatment group, the average time of noninvasive ventilation was(96.34 ± 31.5)h, the total time of oxygen inhalation was(10.11 ± 9.39)d, 3 cases of treatment failure, the incidence of severe complications was 5.56%(2/36), PEEP(4.08±0.73)cmH2O(1 cmH2O=0.098 kPa). In the nCPAP group, the average time of noninvasive ventilation was(114.14±41.69)h, the total time of oxygen inhalation was(17.53±15.96)d, 15 cases were failed, the incidence of severe complications was 15.56%(7/45), PEEP(5.11±1.01)cmH2O.There were significant differences between the two groups(P 0.05). Conclusion nBiPAP as one of the first choice treatment for premature infants with respiratory failure significantly better than nCPAP, as soon as the proper use can avoid invasive ventilation. Key words: Positive airway pressure; Mechanical ventilation; Preterm infants; Newborn; Respiratory failure

Protocolo clínico de atención en el recién nacido con síndrome de dificultad respiratoria

Respiratory distress syndrome is the leading cause of respiratory failure in preterm infants. For three decades, the treatment with exogenous pulmonary surfactant and mechanical ventilation has been the standard treatment; however with the increased and systematic use of non-invasive ventilation devices the current position has changed. ObjectiveTo prepare a clinical protocol for the effective and safe management of neonatal respiratory distress syndrome, through the integration of clinical decision algorithms. Materials and methodsThe technique used was the adoption of existing clinical practice guidelines in the literature. Selected guides were evaluated with the AGREE II tool, and guidelines with highest score were selected. In the event that the information necessary to answer the clinical questions were not found in the selected guidelines, other sources and information, such as systematic reviews and meta-analyses were reviewed. ResultsAdoption of international clinical practice guidelines was carried out with the analysis of the evidence and recommendations in the selected guidelines. The clinical care algorithms were integrated in the context of México. ConclusionsThe systematic use of non-invasive ventilation and exogenous pulmonary surfactant in preterm infants with RDS optimises and reduces the need for mechanical ventilation.

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.

Fetal origins of neonatal lung disease: understanding the pathogenesis of bronchopulmonary dysplasia

Fetal origins of neonatal lung disease: understanding the pathogenesis of bronchopulmonary dysplasia

Surfactant, mechanical ventilation or CPAP for treatment of early respiratory failure in preterm infants: A continuing conundrum?

s2view.con/pas/view.php?nu=PAS10L1660. Accessed on January 25, 2010. 4. Sandri F, Plavka R, Simeoni U; CURPAP Advisory Board. The CURPAP study: an international randomized controlled trial to evaluate the efficacy of combining prophylactic surfactant and early nasal continuous positive airway pressure in very preterm infants. Neonatology. 2008;94:60-2. 5. Tsakalidis C, Kourti M, Karayianni P, Rallis D, Porpodi M, Nikolaidis N. Early rescue administration of surfactant and nasal continuous positive airway pressure in preterm infants <32 weeks gestation. Indian Pediatr. 2011;48:601-5.

Inhaled Nitric Oxide in Preterm Infants: A Systematic Review

Studies of the efficacy of inhaled nitric oxide (iNO) to prevent or treat respiratory failure in preterm infants have had variable and contradictory findings. To systematically review the evidence on the use of iNO in infants born at ≤ 34 weeks' gestation who receive respiratory support. Medline, Embase, the Cochrane Central Register of Controlled Studies, PsycInfo, ClinicalTrials.gov, and proceedings of the 2009 and 2010 Pediatric Academic Societies meetings were searched in June 2010. Additional studies from reference lists of eligible articles, relevant reviews, and technical experts were considered. Two investigators independently screened search results and abstracted data from eligible articles. We focus here on mortality, bronchopulmonary dysplasia (BPD), the composite outcome of death or BPD, and neurodevelopmental impairment. Fourteen randomized controlled trials, 7 follow-up studies, and 1 observational study were eligible for inclusion. Mortality rates in the NICU did not differ for infants treated with iNO compared with controls (risk ratio [RR]: 0.97 [95% confidence interval (CI): 0.82-1.15]). BPD at 36 weeks for iNO and control groups also did not differ for survivors (RR: 0.93 [95% CI: 0.86-1.003]). A small difference was found in favor of iNO in the composite outcome of death or BPD (RR: 0.93 [95% CI: 0.87-0.99]). There was no evidence to suggest a difference in the incidence of cerebral palsy (RR: 1.36 [95% CI: 0.88-2.10]), neurodevelopmental impairment (RR: 0.91 [95% CI: 0.77-1.12]), or cognitive impairment (RR: 0.72 [95% CI: 0.35-1.45]). There was a 7% reduction in the risk of the composite outcome of death or BPD at 36 weeks for infants treated with iNO compared with controls but no reduction in death alone or BPD. There is currently no evidence to support the use of iNO in preterm infants with respiratory failure outside the context of rigorously conducted randomized clinical trials.