Distress Syndrome In Preterm Infants Research Articles

Phospholipid components of the synthetic pulmonary surfactant CHF5633 probed by fluorescence spectroscopy

CHF5633 (Chiesi Farmaceutici, Italy) is a synthetic pulmonary surfactant currently under clinical development for the treatment of Respiratory Distress Syndrome in premature infants. The product is composed of phospholipids in liposomal organization, together with two peptide analogues of human surfactant proteins B and C. Phospholipids in liposomes can undergo oxidation of unsaturated lipids and hydrolysis, with formation of fatty acids and lysolipids, both affecting the physico-chemical properties of the formulation. We exploited two fluorescence probes, Prodan and ADIFAB, to evaluate the stability of the phospholipid components of CHF5633. While Prodan enters the phospholipid bilayer and probes the polarity of this environment, ADIFAB binds free fatty acids in the aqueous phase, allowing to determine their concentration. Changes of Prodan fluorescence emission indicated an increase in the polarity of the phospholipid bilayer as a function of time. This behavior is coupled with an increase in fatty acids concentration in the aqueous phase, as determined by ADIFAB, and an increase in lysolipids concentration, as determined by HPLC-MS. Prodan and ADIFAB resulted efficient probes to monitor phospholipids hydrolysis in liposomes, reporting an increased stability of CHF5633 at pH values higher than 6.5.

Noteworthy Professional News

POSTPARTUM DEPRESSION AND THE NEONATAL INTENSIVE CARE UNIT Postpartum depression is a medical diagnosis given to a woman within the first year after childbirth. Symptoms are very similar to depression including feelings of sadness, hopelessness, or worthlessness.1,2 These symptoms are more severe than common “baby blues” that present more mildly in nature such as tearfulness, frequent worrying, and tiredness. Postpartum depression affects approximately 20% of mothers3 and is estimated to be much higher in those women with a child in the neonatal intensive care unit (NICU).4 There are suggestions that women should be assessed for postpartum depression at time points other than their postpartum follow-up appointments with their obstetrician, including in the emergency department with a fussy child younger than 1 year.1,2 Often when the infant is medically cleared, it is the mother who needs medical attention. Although a NICU is the primary unit caring for ill and premature infants, it is the exact place where additional assessing and services for postpartum depression could occur. When the exciting day for that child to be discharged home from the NICU presents itself, it is imperative that we evaluate the entire home situation prior to discharge.3 Many times, NICU staff may not feel that they can control the environment these infants experience when going home. Examining that a mother's health is adequate to take on newborn care tasks and dealing with extensive, medically challenging situations is necessary to safeguard a child's initial entrance to home life. What is your NICU doing today to identify mothers who may present with symptoms of postpartum depression while visiting their infant? Is there sufficient skilled staffing support to add this responsibility within the NICU setting? A topic to consider when the goal is to send infants into the arms of competent and self-sufficient families. STABLE MICROBUBBLE TEST USING ORAL FLUID SAMPLES TO IDENTIFY RESPIRATORY DISTRESS SYNDROME For decades, as technology and medicine have allowed premature infants to live beyond the NICU walls, the desire to predict the immaturity of lung development has also increased. Since the late 1900s, tests such as the stable microbubble test have been proposed, analyzed, and tested to be a sensitive and specific predictor for respiratory immaturity in infants from amniotic samples taken during an amniocentesis.5,6 Since this time, the use of the stable microbubble test has been an underutilized prenatal laboratory test result in the United States for pregnancies anticipated to end prematurely compared with the lecithin/sphingomyelin ratio test. Not all premature deliveries are expected, not every healthcare facility may have the technology to conduct a lecithin/sphingomyelin ratio test, and for those women, with little to no prenatal care, what is the best way to determine the risk for respiratory distress syndrome when an amniocentesis is no longer an option? Recently, research has shown that the use of the stable microbubble test performed as well as other samples types (ie, amniotic or gastric) in predicting respiratory distress syndrome in premature infants.7 In 64 patients born less than 34 weeks of gestation, a minimum of 0.2 mL of oral secretions was collected by the obstetrician in the delivery room. Test results were available within 5 minutes and at a low cost8 to assist in assessing whether a premature infant needed surfactant. A small microbubble test result less than 25 small microbubble (SM)/mm2 demonstrated a sensitivity of 81.4% and specificity of 85.7% on oral secretion samples in being able to predict surfactant deficiency.8 As a result, the stable microbubble test may be a bedside test to consider for any delivering hospital facility at the time of a premature birth when other sample types or tests are not available.

A Comparative Study of Treatment Response of Respiratory Distress Syndrome in Preterm Infants: Early Nasal Intermittent Positive Pressure Ventilation versus Early Nasal Continuous Positive Airway Pressure

Background Infant respiratory distress syndrome (IRDS) is one of the main causes of serious complications and death in preterm infants. Both Nasal Continuous Positive Airway Pressure (NCPAP) and Nasal Intermittent Positive Pressure Ventilation (NIPPV) are known as the most common treatment strategies for IRDS. The present study intended to compare NCPAP and NIPPV in the treatment of preterm infants with respiratory distress syndrome. Materials and Methods To this double blind clinical trial study during a one-year period (2016 to 2017) in Fatemieh Hospital in Hamadan city (Iran), about 60 preterm RDS infants were randomly assigned into two treatment groups; the NIPPV group received the PIP (14–20 cmH2O), RR: 30-50/min, PEEP (5–6 cmH2O), FiO2 up to 60%. The NCPAP group received PEEP (5-6 cmH2o), Flow: 6-7 L/min, and FiO2 up to 60% Results There was not any significant difference in the mean values of gestational age (30.07±1.50 vs. 30.07±2.05; P>0.05), birth weight (1259±263 vs. 1235±285; P>0.05), and 1-minute Apgar score (5.53±1.13 vs. 5.33±1.34; P>0.05) between NIPPV and NCPAP treatment groups. Besides, the rate of recovery, mortality and disease complications was not significantly different between both groups. However, the duration of respiratory support was less in NIPPV than NCPAP (34.9±33.8 vs. 68.4±32 h; P=0.001). Conclusion According to the results, there was not significant advantage between the NIPPV vs. NCPAP methods in the treatment of RDS in preterm infants with very low birth weight.

Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation

Nasal continuous positive airway pressure (nCPAP) is a well-established treatment of respiratory distress syndrome in preterm infants. Suboptimal weaning from nCPAP may be associated with lung injury, pulmonary morbidity, and infant weight gain. To our knowledge, the best weaning strategy from nCPAP is unknown. To compare the effect of sudden wean and pressure wean from nCPAP in very preterm infants. A randomized, clinical, open-label, multicenter trial was conducted at 6 neonatal intensive care units in Denmark from September 2012 to December 2016 and included infants born before 32 weeks of gestation. Sudden wean with discontinuation of nCPAP without a prior reduction in pressure. Pressure wean with gradual pressure reduction prior to the discontinuation of nCPAP. The primary outcome was weight gain velocity from randomization to postmenstrual age 40 weeks. Secondary outcomes included other measures of growth, nCPAP and the duration of oxygen supplementation, postmenstrual age at successful wean and at discharge, successful wean at the first attempt, the number of attempts to wean, and the length of the hospital stay. Prespecified subgroup analyses by gestational age were performed. Of the 372 randomized infants, 185 (49.7%) were randomized to sudden wean and 187 infants (50.3%) to pressure wean. A total of 177 infants in both groups completed the trial (median gestational age for sudden and pressure wean, 30 weeks [interquartile range, 29-31]; male: sudden wean, 89 [50%]; pressure wean, 96 [54%]). There was no difference in mean [SD] weight gain velocity from randomization to 40 weeks postmenstrual age between the 2 groups (22 [6] g/kg/day). No difference was found in any of the secondary outcomes. More infants born before 28 weeks of gestation were successfully weaned from nCPAP during the first attempt in the pressure wean group compared with the sudden wean group (risk difference, 31%; 95% CI, 13%-50%), but there was no difference in the duration of nCPAP and oxygen supplementation. Overall, we found no difference in weight gain velocity or any of the secondary outcomes between very preterm infants who were randomized to sudden wean or pressure wean from nCPAP. However, among infants born before 28 weeks' gestation, infants from the pressure wean group were more often successfully weaned during the first attempt without a longer total duration of nCPAP treatment. ClinicalTrials.gov Identifier: NCT01721629.

Audit on the Application of Surfactant in Premature Babies in Assiut University Children Hospital

Abstract Background: To evaluate the use of exogenous natural surfactant for Respiratory Distress Syndrome (RDS) in pre-mature babies, identify areas where European Consensus Guidelines on the Management 2013 Update, modified by The Egyptian Consensus on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants 2014 are applied to as a reference standard in Assiut University Children Hospital and identify those points to be targeted for improve-ment.Patients and Methods: A retrospective audit was under-taken over a 12-month period between 1st of January, 2016 to the 31st of December 2016. It included all babies less than 37 weeks gestation with respiratory distress syndrome who received surfactant as a rescue treatment, guided by European Consensus Guidelines on the Management 2013 Update, modified by The Egyptian Consensus on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants 2014 and admitted to Neonatal Intensive Care Unit of Assiut University Children Hospital during this period. Results: All cases with severe respiratory distress that needed surfactant injection and admitted in Assiut university children hospital from 1st of January to 3 1th of December 2016 were included in the study. The study included 50 patients with severe respiratory distress syndrome.Conclusion: Surfactant replacement therapy has been available for about 37 years, revolutionizing neonatal respi-ratory care after its introduction in the 1980s. Along with antenatal steroids, surfactants improve survival for preterm babies and they are now recommended routinely as early in the course of Respiratory Distress Syndrome (RDS) as possible. The present study aimed to evaluate the use of surfactant for Respiratory Distress Syndrome (RDS) in premature babies admitted at NICU of Assiut university children hospital during the period from 1st of January to 31st of December 2016 using European Consensus Guidelines on the Management 2013 Update, modified by The Egyptian Consensus on the Manage-ment of Neonatal Respiratory Distress Syndrome in Preterm Infants 2014.The study included 50 cases with respiratory distress syndrome who received surfactant therapy.Data of the study showed that treatment regimens for cases of RDS in Assiut University Children Hospital partially followed the reference standard of the study concerning application of surfactant in premature babies.•Data of the gestational age and weight and sex were recorded in 100% of cases.•Data concerning clinical evaluation of the studied group were recorded in 100% cases.•Data concerning obstetric history and prenatal care were fulfilled well but there were no records concerning receiving a course of antibiotics if there is preterm, pre-labor rupture of membranes nor short term tocolytic drugs. Also, the data showed that only 28% of mothers received a course of prenatal steroids if preterm labor was expected.•Data concerning delivery room stabilization were fulfilled well but there were no records concerning delayed cord clamping and there was no available CPAP at the delivery room nor plastic bag for stabilization of preterm baby with respiratory distress syndrome.•Data concerning surfactant therapy were fulfilled well but there was no data that any case received prophylactic surfactant therapy neither with nor without INSURE tech-nique.•Data concerning respiratory support were fulfilled well but no cases received CPAP as a 1st line respiratory support for any spontaneously breathing preterm with RDS at delivery room and no cases received CPAP with early rescue surfactant which is now considered the optimal management for babies with RDS.•Data concerning supportive care were fulfilled in 100% of cases but no cases received enteral feeding from the 1st day which is strongly recommended with careful fluid balance for early aggressive nutritional support.•Data concerning prognosis showed that the vast majority of dead cases were below 32 weeks and below 1KG.

The Effect of Antenatal Corticosteroid Therapy to Respiratory Distress Syndrome Event on Preterm Infants in Surabaya

ABSTARCTIntroductions: One of the most common cause of morbidity and mortality in premature infants is respiratory distress syndrome (RDS). Several studies have shown that a single dose administration of antenatal corticosteroid therapy in women who are at high risk for premature delivery was associated with decreased incidence of RDS. The study aims to determine the effect of antenatal corticosteroid therapy on the incidence of RDS in prematurity in the Department of Child Health Hospital Dr. Soetomo.Methods: Analytic observational case-control design study was used for this research. Samples were taken from the medical records of RDS patients in premature baby and non-RDS with 36 samples in each group.Results: Antenatal corticosteroid therapy has effect in RDS incidence (p = 0.016). While the results of the odds ratio was 0.298 (with 95% CI 0.110 to 0.810), it means that premature infants with antenatal corticosteroid therapy has 0.298 times lower risk than those who were not given antenatal corticosteroid therapy.Conclusion: Antenatal corticosteroid therapy did not provide a direct relathionship to the incidence of respiratory distress syndrome in premature infants, but it a protective factor that can reduce the incidence of RDS in prematurity.

Results of INSSURE Method in the Treatment of Respiratory Distress Syndrome in Premature Infants at Bac Ninh Obstetric Pediatric Hospital

OBJECTIVES: To evaluate the results of the INtubate-SURfactant-Extubate (INSURE) method in the treatment of respiratory distress syndrome in premature infants at Bac Ninh obstetric pediatric hospital from March to September 2017. METHODS: A descriptive study was conducted on 50 preterm infants with respiratory distress syndrome. The infants were treated with INSURE method . RESULTS: Of the 50 infants, 29 (58.0%) were male. All of infants, 49 (98.0%) gestational age under 32 weeks, of which 56.0% was less than 30 weeks. The infants birth weight less than 1500 grams accounted for 78.0%, of which 28.0% under 1000 grams. Only 40.0% of mothers were injected with corticosteroid before giving birth. The most common symptoms are cyanosis , apnea neoatorum > 10 seconds; lower temperature. X.ray III is 92.0%. All infants were pumped pulsed surfactant before 6 hours, intubated endotracheal tube and was removed within 50 minutes. There were 13 children (26.0%) had to have mechanical ventilation, the highest rate of reintroduction in infants birth weight less than 1000 grams. The rate of SpO2 increased, the FiO2 and Siverman index decreased and remained stable significantly after 6 hours of treatment. The complication rate was 4.0%. Treatment outcomes were only associated with birth weight (p<0.05). CONCLUSIONS: INtubate-SURfactant-Extubate is effective methods in treatment of infants with respiratory distress syndrome (RDS).

Effective Factors of INSURE Method Failure in Treatment of Respiratory Distress Syndrome in Preterm Infants

Background INtubate-SURfactant-Extubate (INSURE) method is one of the effective methods in treatment of infants with respiratory distress syndrome (RDS). This study was performed to predict risk factors for the failure of INSURE method in treatment of RDS in preterm infants. Materials and Methods: In this cross-sectional study, 192 infants who born between July 2011 and April 2016 at women and children's hospital of Amiralmoemenin in Semnan, Iran, were included to the study. Inclusion criteria were infants with moderate to severe RDS, 26 to 38 gestational weeks and weighted 500 to 3,500 grams. All patients were treated with INSURE method, then were divided to success and failure INSURE. Severity of RDS was determined by RDS scoring system. The collected data including gender status, gestational age (GA), birth weight (BW), maternal diabetes mellitus, delivery type and neonatal morbidity (including intraventricular haemorrhage (IVH), Necrotizing enterocolitis (NEC) stage 1, sepsis, chronic lung disease (CLD), pneumothorax, and pulmonary bleeding. Statistical analysis was done using SPSS software, version 22.0. Results: Of the 192 patients, 82 (42.7%) infants were females. The mean GA and BW were 30.25 ± 1.85 weeks and 1950 ± 270 grams, respectively. Of all the patients, 156 infants (81.25%) were born via cesarean section. INSURE failure was observed in 79 infants (41.1 %) and INSURE success was observed in 113 (58.9%). Among the factors, INSURE method failure had a significant relationship with GA, BW, RDS severity and increased probability of IVH, CLD, pneumothorax and pulmonary bleeding (p<0.05). Based on logistic regression analysis, there was a significant relationship between the failure of INSURE method and RDS severity (odds ratio [OR]= 6.31, 95% 95%CI [CI]= 2.07-19.19, P=0.001), and GA OR=0.78, 95% CI= 0.67-0.91, P=0.001). Conclusion According to the finding, among the risk factors, only higher severity of RDS and GA were able to predict INSURE method failure in treatment of RDS in preterm infants. Additional studies are recommended in this regard.

Poractant alfa in respiratory distress syndrome in preterm infants: a profile of its use

Poractant alfa (Curosurf®) is a natural, porcine-derived surfactant that is well established as an effective and generally well-tolerated agent in the treatment of respiratory distress syndrome (RDS) in preterm infants. The efficacy of poractant alfa in RDS is better than that of early-generation synthetic surfactants, and limited data are available regarding its efficacy versus new-generation synthetic agents. Poractant alfa 200 mg/kg is more effective than poractant alfa 100 mg/kg or bovine-derived beractant 100 mg/kg. Techniques for administering poractant alfa include via an endotracheal tube or less invasive techniques [e.g. less invasive surfactant administration (LISA)] performed during non-invasive ventilation of spontaneously breathing infants via nasal continuous positive airway pressure (CPAP). Administration of poractant alfa 200 mg/kg in early rescue [i.e. fraction of inspired oxygen (FiO2) ≥ 0.3] via LISA is associated with increased successful management on continuous positive airway pressure, as well as reductions in the incidence of bronchopulmonary dysplasia (BPD) and death/BPD.

Comparing the Effect of Inhaler N-Acetyl Cysteine and Intravenous Dexamethasone on Respiratory Distress Syndrome in Premature Infants: A Randomized Clinical Trial

Background: Respiratory distress syndrome (RDS) is one of the most common respiratory disorders among premature infants. Despite recent developments in the application of corticosteroids for preventing RDS, their superiority and possible complications have remained controversial. Methods: In this randomized clinical trial, infants with confirmed diagnosis of RDS were randomly allocated into 2 groups. The first group underwent treatment with intravenous dexamethasone (0.15 mg/kg every 12 hours), and the second group received NAC nebulizer (400 mg every 8 hours) as well as intravenous dexamethasone for 3 to 5 days. Treatment duration, disease and drug complications, number of received doses as well as response to treatment (based on oxygen dependency and need for reintubation), and mortality rates were recorded in a checklist. Results: Finally we evaluated 60 (33 males and 27 females) infants in 2 dexamethasone and N-Acetyl Cysteine groups. Mean arterial oxygen saturation was 88.70% ± 4.31% in NAC and 87.90% ± 5.96% in dexamethasone group before intervention (P = 0.553). In the fifth day of the intervention, the mean arterial oxygen saturation was 93.80 ± 3.86 in NAC and 93.4% ± 3.79% in dexamethasone group (P = 0.321). Prior to the intervention, infants in NAC group had a mean respiratory rate (RR) of 66.33 ± 8.33, and this was 65 ± 12.66 in infants in dexamethasone group (P = 0.656). In the fifth day of intervention, infants had a mean RR of 46.67 ± 9.21 in NAC and 49 ± 12.66 in dexamethasone groups (P = 0.454). Conclusions: No significant difference was obtained between intravenous dexamethasone alone and intravenous dexamethasone with N-Acetyl cysteine nebulizer in the treatment of infantile respiratory distress syndrome. However, a significant response to treatment was observed in both groups.

EFFECTIVENESS OF EARLY USE OF SPONTANEOUS RESPIRATION UNDER CONTINUOUS POSITIVE AIRWAY PRESSURE IN PREMATURE INFANTS WITH VERY LOW BODY WEIGHT AT BIRTH

The article presents the results of a comparative analysis of various methods of respiratory therapy for the treatment of respiratory distress syndrome in premature infants with very low body weight at birth. The studies were conducted in the Republican perinatal center of the Ministry of health of the Republic of Uzbekistan. The study included newborns with very low body weight (1000-1500 g) and with a gestation age of 29-31 weeks, with respiratory distress syndrome at birth. Two groups of newborns were compared. Children of the 1st group have been treated by early, stage delivery room use of CPAP technique; premature infants of the 2nd group were born prior to the application of this technique. In a compative study of the cohorts of newborns treated in the department for two time periods, characterized by different approaches to respiratory therapy, results have been obtained indicating that the majority of premature infants with very low body weight and respiratory distress can be successfully treated with nasal CPAP, without the use of mechanical ventilation, especially in its early use.

Different ventilation modes combined with ambroxol in the treatment of respiratory distress syndrome in premature infants.

The aim of the present study was to compare the effectiveness of different modes of mechanical ventilation in combination with secretolytic therapy with ambroxol in premature infants with respiratory distress syndrome. Seventy-three premature infants with hyaline membrane disease (HMD) (stage III–IV), also known as respiratory distress syndrome, who were supported by mechanical ventilation in the neonatal intensive care unit (NICU) of Xuzhou Central Hospital, were involved in the present study, between January 2013 and February 2015. Forty cases were randomly selected and treated with high frequency oscillatory ventilation (HFOV), forming the HFOV group, whereas 33 cases were selected and treated with conventional mechanical ventilation (CMV), forming the CMV group. Patients in the two groups were administered ambroxol intravenously at a dosage rate of 30 mg/kg body weight at the beginning of the study. The present study involved monitoring the blood gas index as well as changes in the respiratory function index in the two groups. Additionally, the incidence of complications in the premature infants in the two groups was observed prior to and following the ventilation. Pulmonary arterial oxygen tension (PaO2), the PaO2/fraction of inspired oxygen (FiO2) ratio, the oxygenation index [OI = 100 × mean airway pressure (MAP) × FiO2/PaO2], as well as the arterial/alveolar oxygen partial pressure ratio (a/APO2) = PaO2/(713 × FiO2 partial pressure of carbon dioxide (PaCO2)/0.8) of the patients in the HFOV group after 1, 12 and 24 h of treatment were significantly improved as compared to the patients of the CMV group. However, there was no significant difference between patients in the two groups with regard to the number of mortalities, complications such as pneumothorax, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and the time of ventilation. In conclusion, combining HFOV with ambroxol secretolytic therapy is a more viable option, as the combined treatment resulted in significant improvements in arterial blood gas levels, oxygenation and the respiratory function of lungs in preterm infants.

The new generation synthetic reconstituted surfactant CHF5633 suppresses LPS-induced cytokine responses in human neonatal monocytes

BackgroundNew generation synthetic surfactants represent a promising alternative in the treatment of respiratory distress syndrome in preterm infants. CHF5633, a new generation reconstituted agent, has demonstrated biophysical effectiveness in vitro and in vivo. In accordance to several well-known surfactant preparations, we recently demonstrated anti-inflammatory effects on LPS-induced cytokine responses in human adult monocytes. The present study addressed pro- and anti-inflammatory effects of CHF5633 in human cord blood monocytes. MethodsPurified neonatal CD14+ cells, either native or simultaneously stimulated with E. coli LPS, were exposed to CHF5633. TNF-α, IL-1β, IL-8 and IL-10 as well as TLR2 and TLR4 expression were analyzed by means of real-time quantitative PCR and flow cytometry. ResultsCHF5633 did not induce pro-inflammation in native human neonatal monocytes and did not aggravate LPS-induced cytokine responses. Exposure to CHF5633 led to a significant decrease in LPS-induced intracellular TNF-α protein expression, and significantly suppressed LPS-induced mRNA and intracellular protein expression of IL-1β. CHF5633 incubation did not affect cell viability, indicating that the suppressive activity was not due to toxic effects on neonatal monocytes. LPS-induced IL-8, IL-10, TLR2 and TLR4 expression were unaffected. ConclusionOur data confirm that CHF5633 does not exert unintended pro-apoptotic and pro-inflammatory effects in human neonatal monocytes. CHF5633 rather suppressed LPS-induced TNF-α and IL-1β cytokine responses. Our data add to previous work and may indicate anti-inflammatory features of CHF5633 on LPS-induced monocyte cytokine responses.

Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress

Neonatal respiratory distress syndrome in preterm infants is a leading cause of neonatal death. Pulmonary insufficiency-related infant mortality rates have improved with antenatal glucocorticoid treatment and neonatal surfactant replacement. However, the mechanism of glucocorticoid-promoted fetal lung maturation is not understood fully, despite decades of clinical use. We previously have shown that genetic deletion of Erk3 in mice results in growth restriction, cyanosis, and early neonatal lethality because of pulmonary immaturity and respiratory distress. Recently, we demonstrated that the addition of postnatal surfactant administration to antenatal dexamethasone treatment resulted in enhanced survival of neonatal Erk3-null mice. To better understand the molecular underpinnings of corticosteroid-mediated lung maturation, we used high-throughput transcriptomic and high-resolution morphologic analysis of the murine fetal lung. We sought to examine the alterations in fetal lung structure and function that are associated with neonatal respiratory distress and antenatal glucocorticoid treatment. Dexamethasone (0.4 mg/kg) or saline solution was administered to pregnant dams on embryonic days 16.5 and 17.5. Fetal lungs were collected and analyzed by microCT and RNA-seq for differential gene expression and pathway interactions with genotype and treatment. Results from transcriptomic analysis guided further investigation of candidate genes with the use of immunostaining in murine and human fetal lung tissue. Erk3(-/-) mice exhibited atelectasis with decreased overall porosity and saccular space relative to wild type, which was ameliorated by glucocorticoid treatment. Of 596 differentially expressed genes (q < 0.05) that were detected by RNA-seq, pathway analysis revealed 36 genes (q<0.05) interacting with dexamethasone, several with roles in lung development, which included corticotropin-releasing hormone and surfactant protein B. Corticotropin-releasing hormone protein was detected in wild-type and Erk3(-/-) lungs at E14.5, with significantly temporally altered expression through embryonic day 18.5. Antenatal dexamethasone attenuated corticotropin-releasing hormone at embryonic day 18.5 in both wild-type and Erk3(-/-) lungs (0.56-fold and 0.67-fold; P< .001). Wild type mice responded to glucocorticoid administration with increased pulmonary surfactant protein B (P= .003). In contrast, dexamethasone treatment in Erk3(-/-) mice resulted in decreased surfactant protein B (P= .012). In human validation studies, we confirmed that corticotropin-releasing hormone protein is present in the fetal lung at 18 weeks of gestation and increases in expression with progression towards viability (22 weeks of gestation; P < .01). Characterization of whole transcriptome gene expression revealed glucocorticoid-mediated regulation of corticotropin-releasing hormone and surfactant protein B via Erk3-independent and-dependent mechanisms, respectively. We demonstrated for the first time the expression and temporal regulation of corticotropin-releasing hormone protein in midtrimester human fetal lung. This unique model allows the effects of corticosteroids on fetal pulmonary morphologic condition to be distinguished from functional gene pathway regulation. These findings implicate Erk3 as a potentially important molecular mediator of antenatal glucocorticoid action in promoting surfactant protein production in the preterm neonatal lung and expanding our understanding of key mechanisms of clinical therapy to improve neonatal survival.

Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4+ Lymphocytes.

BackgroundNatural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown.AimThe aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4+ lymphocytes.MethodsPurified human CD4+ T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry.ResultsNeither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4+ lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4+ lymphocytes.ConclusionFor the first time, the immunomodulatory capacity of CHF5633 on CD4+ lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4+ cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance.

Evaluation of a practice guideline for the management of respiratory distress syndrome in preterm infants: A quality improvement initiative

The use of mechanical ventilation to treat respiratory distress syndrome in preterm infants has been associated with the development of bronchopulmonary dysplasia. As part of a quality improvement initiative to reduce the incidence of bronchopulmonary dysplasia in preterm infants, a new practice guideline for the management of respiratory distress syndrome was developed and adopted into practice in a neonatal intensive care unit in February 2012. To evaluate the effects of implementing the new guideline in regard to the use of mechanical ventilation and surfactant, and the incidence of bronchopulmonary dypslasia. An historical cohort of very preterm infants (gestational age 26(0) to 32(6) weeks) born one year before guideline implementation was compared with a similar cohort of infants born one year following guideline implementation. Data were collected retrospectively from the local neonatal intensive care unit database. A total of 272 preterm infants were included in the study: 129 in the preguideline cohort and 143 in the postguideline cohort. Following the implementation of the guideline, the proportion of infants treated with ongoing mechanical ventilation was reduced from 49% to 26% (P<0.001) and there was a trend toward a reduction in bronchopulmonary dysplasia (27% versus 18%; P=0.07). There was no difference in the proportion of infants treated with surfactant (54% versus 50%). The implementation of the practice guideline helped to minimize the use of ongoing mechanical ventilation in preterm infants.

Success of Bubble CPAP in Treatment of Respiratory Distress Syndrome in Preterm Infants

Background: To observe the survival of preterm infants with respiratory distress syndrome treated with bubble CPAP in a tertiary care hospital. Methods: This prospective observational study was conducted in the NICU of Civil hospital Sukkur from 1st July 2013 to 18th August 2015. All consecutively born preterm neonates with gestational age between 27 weeks to 36 weeks of gestation, admitted to the neonatal intensive care unit with respiratory distress are included in the study. These neonates were managed by Bubble continuous positive airway pressure (bCPAP) in combination with surfactant (bovine derivative) via intubation, Surfactant replacement, extubation (INSURE) protocol Success was considered when neonates were clinically stable and required 90% and PaCO2 <40-45 mmHg. Results: Mean age of enrolled infants was 1.35 ± 0.60 days, 70 (57.9%) were males and 51 (42.1%) were female, mean weight was 1.76 ± 0.37 kg and mean gestational age was 33 ± 2.3 weeks. Overall 77 (63.6%) preterm infants were successfully weaned off from CPAP. Multivariable analysis showed weight of infant less than 1.5 kg or 8.63 (95% CI: 1.71-43.57), respiratory rate of more than 70 breaths per minute, or 9.59 (95% CI: 2.59-35.52), nasal flaring or 3.35 (95% CI: 1.08-10.31) and typical findings of RDS on chest X-rays 12.04 (95% CI: 1.89-76.52) are independent risk factors for failure of bCPAP. However, gestational age 0.70 (95% CI: 0.54-0.89) is protective against failure. Conclusion: bCPAP has a high proportion of success in the management of respiratory distress syndrome in preterm. It could be most useful in resource-constrained settings.

Evaluation of a practice guideline for the management of respiratory distress syndrome in preterm infants: A quality improvement initiative

Evaluation of a practice guideline for the management of respiratory distress syndrome in preterm infants: A quality improvement initiative

Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants.

Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants.

The Haplotype TGGAG in the ABCA3 Gene Increases the Risk of Respiratory Distress Syndrome in Preterm Infants in Southern China

Rare mutations in the ATP-binding cassette (ABC) transporter A3 (ABCA3) gene are associated with neonatal respiratory distress syndrome (RDS). The contribution of common single nucleotide polymorphisms (SNPs) to preterm RDS differs between ethnicities and remains unclear in Chinese infants. This study evaluated whether common SNPs and consequent haplotypes increase susceptibility to RDS in a population of preterm infants from the Guangxi Zhuang Autonomous Region of China. Using a tagging SNP (tSNP) strategy and real-time polymerase chain reaction, we genotyped four tSNPs (i.e., rs150929, rs4787273, rs11867129, and rs17135889) and one coding SNP (p.F353F) of the ABCA3 gene in preterm infants with RDS (n=83) and without RDS (n=83). We predicted the haplotypes. Minor allele frequencies (MAFs) and haplotype distributions were compared between the two groups. We analyzed correlations between the clinical data and the genotypes. Seven haplotypes existed at a frequency of 0.01 or greater. The haplotype TGGAG was significantly more frequent in RDS infants than in non-RDS infants (p=0.026; odds ratio 3.41; 95% confidence interval 1.088-10.685). The MAF of rs17135889 SNP, a crucial SNP of the haplotype TGGAG located in the transcription factor binding site of ABCA3, was significantly higher in RDS infants (p<0.05); however, the Bonferroni correction test showed no significant difference (p>0.05). No significant correlation existed between the rs17135889 genotypes (AG/GG) and any clinical characteristic (e.g., oxygen supplementation duration and hospitalization, requirement for ventilation, bronchopulmonary dysplasia complications, and mortality rate). The TGGAG haplotype may be a risk factor for RDS in preterm infants in this Chinese population. Further study is needed with a larger sample size to verify the association between the rs17135889 SNP and increased risk of RDS in preterm infants, and to determine whether rs17135889 can be a reference in further population-based studies of ABCA3.