Use of surfactant beyond respiratory distress syndrome, what is the evidence?

Surfactant replacement therapy is currently approved by the United States Food and Drug Administration (FDA) for premature infants with respiratory distress syndrome (RDS) caused by surfactant deficiency due to immaturity. There is strong evidence that surfactant decreases mortality and air leak syndromes in premature infants with RDS. However, surfactant is also used "off-label" for respiratory failure beyond classic RDS. This review discusses current evidence for the use of off-label surfactant therapy for (1) term infants with lung disease such as meconium aspiration syndrome (MAS), pneumonia/sepsis, and congenital diaphragmatic hernia (2) premature infants after 72 h for acute respiratory failure, and (3) the use of surfactant lavage. At last, we briefly describe the use of surfactants for drug delivery and the current evidence on evaluating infants for surfactant deficiency.

Neonatal surfactant therapy beyond respiratory distress syndrome.

Whilst exogenous surfactant therapy is central to the management of newborn infants with respiratory distress syndrome, its use in other neonatal lung diseases remains inconsistent and controversial. Here we discuss the evidence and experience in relation to surfactant therapy in newborns with other lung conditions in which surfactant may be deficient or dysfunctional, including meconium aspiration syndrome, pneumonia, congenital diaphragmatic hernia and pulmonary haemorrhage. We find that, for all of these diseases, administration of exogenous surfactant as bolus therapy is frequently associated with transient improvement in oxygenation, likely related to temporary mitigation of surfactant inhibition in the airspaces. However, for none of them is there a lasting clinical benefit of surfactant therapy. By virtue of interrupting disease pathogenesis, lavage therapy with dilute surfactant in MAS offers the greatest possibility of a more pronounced therapeutic effect, but this has yet to be definitively proven. Lavage therapy also involves a greater degree of procedural risk.

Efficacy of synthetic surfactant (CHF5633) bolus and/or lavage in meconium-induced lung injury in ventilated newborn rabbits.

BACKGROUND: The pathogenesis of neonatal meconium aspiration syndrome (MAS) involves meconium-induced lung inflammation and surfactant inactivation. Bronchoalveolar lavage (BAL) with diluted surfactant facilitates the removal of meconium. CHF5633, one of the most promising synthetic surfactants, is effective in neonatal respiratory distress syndrome. Here we investigated its efficacy via BAL in an experimental MAS model. METHODS: Experimental MAS was induced at birth in near-term newborn rabbits by intratracheal instillation of reconstituted human meconium. First, undiluted CHF5633 was compared with a porcine-derived surfactant (Poractant alfa) via intratracheal bolus (200 mg/kg). Second, the efficacy of BAL with diluted CHF5633 (5 mg/mL, 20 ml/kg) alone, or followed by undiluted boluses (100 or 300 mg/kg), was investigated. RESULTS: Meconium instillation caused severe lung injury, reduced endogenous surfactant pool, and poor survival. CHF5633 had similar benefits in improving survival and alleviating lung injury as Poractant alfa. CHF5633 BAL plus higher boluses exerted better effects than BAL or bolus alone in lung injury alleviation by reversing phospholipid pools and mitigating proinflammatory cytokine mRNA expression, without fluid retention and function deterioration. CONCLUSIONS: CHF5633 improved survival and alleviated meconium-induced lung injury, the same as Poractant alfa. CHF5633 BAL plus boluses was the optimal modality, which warrants further clinical investigation. IMPACT: To explore the efficacy of a synthetic surfactant, CHF5633, in neonatal lung protection comparing with Poractant alfa in a near-term newborn rabbit model with meconium-induced lung injury. Similar effects on improving survival and alleviating lung injury were found between CHF5633 and Poractant alfa. Optimal therapeutic effects were identified from the diluted CHF5633 bronchoalveolar lavage followed by its undiluted bolus instillation compared to the lavage or bolus alone regimens. Animals with CHF5633 lavage plus bolus regimen exerted neither substantial lung fluid retention nor lung mechanics deterioration but a trend of higher pulmonary surfactant-associated phospholipid pools.

The Effects of Different Types of Steroids on Clinical Outcomes in Neonates with Meconium Aspiration Syndrome: A Systematic Review, Meta-Analysis and GRADE Assessment.

Background and Objectives: Meconium aspiration syndrome (MAS) is a condition caused by the aspiration of meconium-stainted amniotic fluid into the lungs, resulting in pulmonary inflammation, neonatal morbidity, and mortality. It is important that these MAS infants receive appropriate care to avoid further complications. Steroids have an anti-inflammatory effect and may be effective in the management of MAS. The objective of the this study was to evaluate the effect of different steroids on clinical outcomes in infants with MAS. Materials and Methods: We systematically searched of PubMed/Medline, Scopus, Embase, Clinical Trials.gov, and Cochrane Library databases from inception to 24 January 2021 without language restriction. Only randomized controlled trials (RCTs) evaluating the effects of steroids in neonates with MAS were included. We calculated relative risks and weighted mean differences (MDs) with 95% confidence intervals (CIs) using a random-effects model to determine the associations between MAS and steroids and GRADE approach was employed for quality of evidence. The main outcomes measures were duration of respiratory distress, oxygen requirement, hospitalization, need for mechanical ventilation, death, and adverse drug reactions. Results: Seven RCTs involving 397 patients were analyzed. Nebulized budesonide and intravenous (IV) methylprednisolone shortened the duration of respiratory distress (MD, -2.46 days; 95% CI, -3.09 to -1.83 and MD, -3.30 days; 95% CI, -4.07 to -2.52, respectively) (moderate certainty). There was a reduction in duration of oxygen requirement in nebulized budesonide use (MD, -2.40 days; 95% CI, -3.40 to -1.40) (low certainty) and IV methylprednisolone use (MD, -3.30 days; 95% CI, -4.07 to -2.52) (moderate certainty). Nebulized budesonide shortened hospitalization stay (MD, -4.47 days; 95% CI, -8.64 to -0.30 days) (low certainty) as IV methylprednisolone use (MD, -7.23 days; 95% CI, -8.19 to -6.07 days) (moderate certainty). None of steroids benefits in death (low certainty). Conclusions: Certain types of steroids may benefit the respiratory aspect, but there was no decrease in mortality in MAS infants.

Association of Adherence to Surfactant Best Practice Uses With Clinical Outcomes Among Neonates in Sweden.

Importance: While surfactant therapy for respiratory distress syndrome (RDS) in preterm infants has been evaluated in clinical trials, less is known about how surfactant is used outside such a framework. Objective: To evaluate registered use, off-label use, and omissions of surfactant treatment by gestational age (GA) and associations with outcomes, mainly among very preterm infants (GA <32 weeks). Design, Setting, and Participants: This population-based cohort study used registry data for 97 377 infants born in Sweden between 2009 and 2018. Infants did not have malformations and were admitted for neonatal care. Data analysis was conducted from June 2019 to June 2020. Exposures: Timing and number of surfactant administrations, off-label use, and omission of use. Registered use was defined by drug label (1-3 administrations for RDS). Omissions were defined as surfactant not administered despite mechanical ventilation for RDS. Main Outcome and Measures: In-hospital survival, pneumothorax, intraventricular hemorrhage grade 3 to 4, duration of mechanical ventilation, use of postnatal systemic corticosteroids for lung disease, treatment with supplemental oxygen at 28 days' postnatal age and at 36 weeks' postmenstrual age. Odds ratios (ORs) were calculated and adjusted for any prenatal corticosteroid treatment, cesarean delivery, GA, infant sex, Apgar score at 10 minutes, and birth weight z score of less than -2. Results: In total, 7980 surfactant administrations were given to 5209 infants (2233 [42.9%] girls; 2976 [57.1%] boys): 629 (12.1%) born at full term, 691 (13.3%) at 32 to 36 weeks' GA, 1544 (29.6%) at 28 to 31 weeks' GA, and 2345 (45.0%) at less than 28 weeks' GA. Overall, 977 infants (18.8%) received off-label use. In 1364 of 3508 infants (38.9%) with GA of 22 to 31 weeks, the first administration of surfactant was given more than 2 hours after birth, and this was associated with higher odds of pneumothorax (adjusted OR [aOR], 2.59; 95% CI, 1.76-3.83), intraventricular hemorrhage grades 3 to 4 (aOR, 1.71; 95% CI, 1.23-2.39), receipt of postnatal corticosteroids (aOR, 1.57; 95% CI, 1.22-2.03), and longer duration of assisted ventilation (aOR, 1.34; 95% CI, 1.04-1.72) but also higher survival (aOR, 1.45; 95% CI, 1.10-1.91) than among infants treated within 2 hours of birth. In 146 infants (2.8%), the recommended maximum of 3 surfactant administrations was exceeded but without associated improvements in outcome. Omission of surfactant treatment occurred in 203 of 3551 infants (5.7%) who were receiving mechanical ventilation and was associated with lower survival (aOR, 0.49; 95% CI, 0.30-0.82). In full-term infants, 336 (53.4%) of those receiving surfactant had a diagnosis of meconium aspiration syndrome. Surfactant for meconium aspiration was not associated with improved neonatal outcomes. Conclusions and Relevance: In this study, adherence to best practices and labels for surfactant use in newborn infants varied, with important clinical implications for neonatal outcomes.

Steroids for the Management of Neonates With Meconium Aspiration Syndrome: A Systematic Review and Meta-analysis.

BACKGROUND: Steroids are a potential treatment for pulmonary inflammation in meconium aspiration syndrome (MAS). OBJECTIVE: To assess the efficacy and safety of steroids for the management of neonates with MAS. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCT). DATA SOURCES AND SELECTION CRITERIA: A systematic search of PubMed, Embase, Cochrane, and CINAHL was performed from database inception to May 2020 for trials assessing the efficacy of steroids (inhaled/systemic or both) in neonates with MAS. The primary outcome was in-hospital mortality, with secondary outcomes being length of hospital stay and duration of oxygen support. RESULTS: Nine RCTs (758 neonates) were included. Overall, steroids did not decrease in-hospital mortality (RR: 0.59; 95% CI 0.28 to 1.23; I2 = 0%; GRADE: low) nor had any effect on the secondary outcomes. CONCLUSIONS: There is low quality of evidence that the administration of steroids is not associated with a reduction in mortality in infants with MAS. Further well-designed studies with low bias are needed to draw conclusions.

Severe neonatal pulmonary artery hypertension rescued with vasopressin.

An inborn term neonate weighing 2600 g developed meconium aspiration syndrome at birth. Baby had respiratory failure requiring high-frequency oscillatory ventilation support at 15 hours of life. He additionally developed hypotension with left ventricular dysfunction noted on point-of-care echocardiography (POCE), which required dopamine and epinephrine infusions. At 28 hours of life, he was started on inhaled nitric oxide (iNO), followed by milrinone due to hypoxaemic respiratory failure and the POCE revealed severe pulmonary artery hypertension (PAH). As PAH was refractory to iNO and milrinone, vasopressin was added which resulted in rapid improvement in oxygenation and normalisation of pulmonary artery pressures. Baby was weaned off from vasoactive support in the next 120 hours. Vasopressin proved to be the rescue agent in this case of iNO refractory PAH without any side effects during therapy. Baby was successfully extubated on day 18 and was discharged with a normal neurological examination finding.

Clinical and echocardiography predictors of response to inhaled nitric oxide in hypoxemic term and near-term neonates.

Approximately 40% of hypoxemic term/near-term neonates are nonresponders to inhaled nitric oxide (iNO). Phenotypic characterization of patients less likely to respond may improve diagnostic precision and therapeutic decisions. We conducted a retrospective cohort study of neonates born ≥35 weeks gestation with hypoxemia who received iNO in the first 72 h of life and classified them into responders and nonresponders according to changes in the fraction of inspired oxygen, saturations and/or arterial partial pressure of oxygen after 1 h of administration. Comprehensive targeted neonatal echocardiography (TnECHO) data were collected when performed up to 6 h prior or 24 h after iNO initiation. Descriptive statistics, univariate analysis, and binary logistic regression were used to compare the groups. There were 183 patients included (63% responders) and TnECHO was performed in 54 infants. The presence of lung disease, and particularly meconium aspiration syndrome (p = .004), was associated with nonresponse to iNO. Nonresponders were characterized by a higher need for rescue high-frequency ventilation (p < .001), longer duration of mechanical ventilation (p < .001), and need for oxygen support (p = .003). Pulmonary hypertension documented on TnECHO was present in 96.3% of the patients but there was no difference in frequency or severity of pulmonary hypertension, or rates of low cardiac output between the groups. Moderate-to-severe right ventricular systolic dysfunction (p > .05) and lower left ventricular strain (p < .05) were more likely in the nonresponder group. In summary, response to iNO is influenced by lung disease, choice of ventilation strategy, and perhaps underlying cardiovascular physiology. Prospective pre- and post-iNO echocardiography data may provide novel physiologic insights.

Surfactant lavage for neonatal meconium aspiration syndrome-An updated meta-analysis.

BACKGROUND: Surfactant lavage seems to have a good application prospect both in experimental models and patients with meconium aspiration syndrome (MAS). Data regarding the effect of surfactant lavage on pulmonary complications of MAS are conflicting. In view of these uncertainties, an updated meta-analysis including the latest literatures is performed. METHODS: A search was conducted by two investigators involved in this research in PubMed, Embase, and Cochrane databases for studies in English and other languages, in Wanfang, VIP, and Cnki databases for Chinese studies (all last launched on December 18, 2018). Ultimately, we identified 11 original studies, including the surfactant lavage group (n = 189) and the control group (n = 204). Odds ratio and weighted mean difference were calculated using a random effects or fixed effects model, depending on the data type and heterogeneity of the included studies. RESULTS: The comparison of effectiveness on MAS: (1) With respect to oxygen index at 48 hours stage and 72 hours stage, data showed significant difference between surfactant lavage/control groups (we/ighted mean difference [WMD] = -3.37, 95% confidence interval [CI], -5.68 ~ -1.06; p = 0.004 and 95% CI, -5.03 ~ -2.37; p < 0.00001). (2) With respect to days on mechanical ventilation, the analysis showed that there was significant difference between surfactant lavage group and control group (WMD = -1.12, 95% CI, -1.40 ~ -0.84; p < 0.00001). (3) Regarding the need for extracorporeal membrane oxygenation, days of oxygen therapy, and hospital stay, no significant differences were found. The comparison of possible complications of MAS: (1) Regarding pneumothorax, the analysis showed there was significant difference between surfactant lavage and control groups (odds ratio [OR] = 0.46, 95% CI, 0.24 ~ 0.85; p = 0.01). (2) With respect to mortality, persist pulmonary hypertension and pulmonary hemorrhage, the results showed no difference between the two groups. CONCLUSION: With respect to oxygen index and days on mechanical ventilation, surfactant lavage is significantly effective compared with control group, though didn't eventually shorten days of oxygen therapy and hospital stay. In addition, our meta-analysis showed that surfactant lavage does not increase the risk of complications.

Optimal Oxygen Targets in Term Lambs with Meconium Aspiration Syndrome and Pulmonary Hypertension.

Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (FiO2) = 1.0 irrespective of SpO2, and three groups had FiO2 titrated to keep preductal SpO2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% SpO2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO2 but were exposed to higher FiO2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO2 through the first 6 hours are higher with target SpO2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower FiO2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% SpO2 target range in term infants with PPHN are warranted.

Surfactant therapy for meconium aspiration syndrome in neonates: a systematic overview of systematic reviews and recent clinical trials.

Aim: To conduct a systematic overview of systematic reviews (SRs) and randomized clinical trials (RCTs) on surfactant therapy in neonatal meconium aspiration syndrome. Methods: We searched EMBASE, PROQUEST and PubMed to summarize the different effects of surfactant lung lavage and bolus surfactant therapies in neonates with meconium aspiration syndrome. Results: With a total of 1377 patients, three SRs and two RCTs were included in analysis. Surfactant effectiveness was concluded by low-quality SRs, with high risk of bias, which was contradicted by high-quality SRs, with low risk of bias. In SRs, the surfactant lung lavage reduced mortality, need for extracorporeal membrane oxygenation and hospitalization, while the bolus surfactant did not. In recent high-quality RCTs, however, the two modalities did not significantly differ. Conclusion: The evidence on surfactant effectiveness and its method of administration is sparse and inconsistent.

Surfactant Injury in the Early Phase of Severe Meconium Aspiration Syndrome.

No in vivo data are available regarding the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). In the present study, we sought to characterize the changes in surfactant composition, function, and structure during the early phase of meconium injury. We designed a translational prospective cohort study of nonbronchoscopic BAL of neonates with severe MAS (n = 14) or no lung disease (n = 18). Surfactant lipids were analyzed by liquid chromatography-high-resolution mass spectrometry. Secretory phospholipase A2 subtypes IB, V, and X and SP-A (surfactant protein A) were assayed by ELISA. SP-B and SP-C were analyzed by Western blotting under both nonreducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, and lung aeration was evaluated by semiquantitative lung ultrasound. Surfactant nanostructure was studied using cryo-EM and atomic force microscopy. Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by phospholipase A2 hydrolysis were increased. SP-B and SP-C were significantly increased together with some shorter immature forms of SP-B. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicle size, tridimensional complexity, and compactness. Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration and were due to hydrolysis and inflammation and a defensive response. This impairs both surfactant structure and function, finally resulting in reduced lung aeration. These findings support the development of new surfactant protection and antiinflammatory strategies for severe MAS.

Effects of intravenous phosphodiesterase inhibitors and corticosteroids on severe meconium aspiration syndrome.

BACKGROUND: Meconium aspiration syndrome (MAS) is a major cause of severe respiratory failure in near- and full-term neonates. Alleviating inflammation is key to successfully treating severe MAS. Phosphodiesterase (PDE) inhibitors are known to play a role in airway smooth muscle relaxation and alveolar inflammation inhibition. This study aimed to investigate the effects of various intravenous (IV) PDE inhibitors and corticosteroids on MAS. METHODS: MAS was induced in newborn piglets by instilling human meconium in them. The piglets were randomly divided into five groups (n = 5 in each group): (1) control (sham treatment); (2) dexamethasone (Dex) (IV 0.6 mg/kg of dexamethasone); (3) aminophylline (Ami) (IV 6 mg/kg of aminophylline, followed by continuous infusion of 0.5 mg/kg/h of aminophylline; (4) milrinone (Mil) (IV 50 µg/kg of milrinone, followed by continuous infusion of 0.75 µg/kg/h of milrinone); and (5) rolipram (Rol) (IV 0.8 mg/kg of rolipram). The duration of the experimental period was 4 hours. RESULTS: Compared to the control group, all the four treatment groups revealed better oxygenation 3 hours and more after the start of treatment. The Rol group had a significantly elevated heart beat (p < 0.05) and relatively lower blood pressure compared to the other groups during the first 2 hours of the experiment. The Dex group had significantly lower interleukin (IL)-1ß levels in the lung tissue compared to the other groups (p < 0.05) and significantly lower IL-6 levels compared to the Ami and Mil groups (p < 0.05). Lung histology showed slightly less inflammation and atelectasis in the Dex group compared to the other groups, but lung injury scores showed no significant between-group differences. CONCLUSION: Using IV corticosteroids or any type of PDE inhibitors has some beneficial effects in improving oxygenation in MAS. PDE inhibitors are not superior to IV corticosteroids; in fact, adverse cardiovascular effects occur with the phosphodiesterase type 4 (PDE4) inhibitor. Further investigations are required before using IV corticosteroids and PDE inhibitors in future clinical application.

Recombinant Human Superoxide Dismutase and N-Acetylcysteine Addition to Exogenous Surfactant in the Treatment of Meconium Aspiration Syndrome.

This study aimed to evaluate the molecular background of N-acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO2/FiO2 and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A2) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.

Effects of intratracheal captopril on severely meconium-injured piglet lungs.

BACKGROUND: Severe meconium aspiration syndrome (MAS) may cause intractable respiratory failure in neonates. Targeting the renin-angiotensin system may be an effective way to treat such pulmonary dysfunction. Captopril has the potential to mitigate the severity of lung injury by inhibiting angiotensin-converting enzyme. METHODS: Twelve newborn piglets were intratracheally instilled with human meconium to induce severe MAS and were randomly treated with IT administration of captopril (0.5 mg/kg) (IT-Cap group, n = 6), or sham air instillation (Control group, n = 6). Cardiopulmonary profiles were monitored for a total of 5 hours. Pulmonary history was examined to compare lung injury severity between groups. RESULTS: There were no significant differences between the two study groups in gas exchange and lung compliance, peak inspiratory pressure, heart rate, and mean arterial blood pressure over the 5-h experimental period, but there were trends toward lower blood pressure and pH in the IT-Cap group. Histopathological examinations revealed significantly higher lung injury scores in the dependent site of the control group than in the nondependent site of the control group and both sites of the IT-Cap group. CONCLUSION: Intratracheal captopril did not present significant beneficial effects on severe meconium-injured lungs within 5 hours after injury. Further studies with different disease severities and dosing strategies are required.

Lung Lavage with Dilute Surfactant vs. Bolus Surfactant for Meconium Aspiration Syndrome.

OBJECTIVE: To compare the effectiveness of lung lavage with surfactant vs. bolus surfactant treatment in meconium aspiration syndrome (MAS). PATIENTS AND METHODS: This randomized controlled trial included newborns ventilated with MAS. In lavage group (n = 17) 30 ml/kg of diluted porcine surfactant was instilled into the lung. In bolus group (n = 16) porcine surfactant (100 mg/kg) was administered as bolus. Respiratory outcomes and mortality were compared between groups. RESULTS: Duration of respiratory support was found to be similar between lavage and bolus groups (3 vs. 3.5 days, p = 0.36). Death or requirement for extracorporeal membrane oxygenation (ECMO) was 12% vs. 6%; respectively (RR: 2, 95% CI 0.16-24.48; p = 1.0). Duration of oxygen therapy, high-frequency ventilation or inhaled nitric oxide requirement did not differ among the groups. CONCLUSION: Lung lavage did not show any advantage over bolus therapy on duration of respiratory support. The incidence of pneumothorax and surfactant re-administration decreased nonsignificantly in lavage group. CLINICAL TRIAL REGISTRATION: We registered the trial to ClinicalTrials.gov (http://clinicaltrials.gov) under identifier NCT02041546. REGISTRY NAME: Lung Lavage With Dilute Poractant Alfa for Meconium Aspiration Syndrome.

Phosphodiesterase inhibitors: Potential role in the respiratory distress of neonates.

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the hydrolysis of phosphodiester bonds of 3',5' cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDEs control hydrolysis of cyclic nucleotides in many cells and tissues. Inhibition of PDEs by selective or nonselective PDE inhibitors represents an effective targeted strategy for the treatment of various diseases including respiratory disorders. Recent data have demonstrated that PDE inhibitors can also be of benefit in respiratory distress in neonates. This article outlines the pharmacological properties of nonselective and selective PDE inhibitors and provides up-to-date information regarding their use in experimental models of neonatal respiratory distress as well as in clinical studies.

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.

BACKGROUND: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. OBJECTIVES: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. METHODS: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. RESULTS: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1ß and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. CONCLUSION: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

Anti-IL-8 antibody potentiates the effect of exogenous surfactant in respiratory failure caused by meconium aspiration.

AIM: Meconium aspiration syndrome (MAS) is life-threatening respiratory failure of newborns which can be treated by exogenous surfactant. In response to meconium, increased levels of chemokine IL-8 (CXCL8) stimulate massive neutrophil infiltration of the lungs. Local accumulation and activation of neutrophils, on-going inflammation, lung edema, and oxidative damage contribute to inactivation of endogenous and therapeutically given surfactants. Therefore, we have hypothesized that addition of monoclonal anti-IL-8 antibody into exogenous surfactant can mitigate the neutrophil-induced local injury and the secondary surfactant inactivation and may finally result in improvement of respiratory functions. METHODS: New Zealand rabbits with intratracheal meconium-induced respiratory failure (meconium 25 mg/ml, 4 ml/kg) were divided into three groups: untreated (M), surfactant-treated (M + S), and treated with combination of surfactant and anti-IL-8 antibody (M + S + anti-IL-8). Surfactant therapy consisted of two lung lavages with diluted porcine surfactant Curosurf (10 ml/kg, 5 mg phospholipids (PL)/ml) followed by undiluted Curosurf (100 mg PL/kg) delivered by means of asymmetric high-frequency jet ventilation (f. 300/min, Ti 20%). In M + S + anti-IL-8 group, anti-IL-8 antibody (100 µg/kg) was added directly to Curosurf dose. Animals were oxygen-ventilated for additional 5 h, respiratory parameters were measured regularly. Subsequently, cell counts in bronchoalveolar lavage fluid (BAL), lung edema formation, oxidative damage, levels of interleukins (IL)-1ß and IL-6 in the lung homogenate were evaluated. RESULTS: Surfactant instillation significantly improved lung function. Addition of anti-IL-8 to surfactant further improved gas exchange and ventilation efficiency and had longer-lasting effect than surfactant-only therapy. Combined treatment showed the trend to reduce neutrophil count in BAL fluid, local oxidative damage, and levels of IL-1ß and IL-6 more effectively than surfactant-alone, however, these differences were not significant. CONCLUSION: Addition of anti-IL-8 antibody to surfactant could potentiate the efficacy of Curosurf on the gas exchange in experimental model of MAS.

Comparison of different dosing strategies of intratracheally instilled budesonide on meconium injured piglet lungs.

BACKGROUND: Severe inflammation plays a vital role in the pathogenesis of meconium aspiration syndrome (MAS). Intratracheal (IT) instillation of corticosteroids may be beneficial for MAS in optimizing local effect and reducing systemic adverse effects, but the optimum dosing course remains open to question. METHODS: Thirty meconium-injured newborn piglets were enrolled into six study groups. The first four groups consisted of the IT instillation of 0.25/0.5 mg/kg using either one (IT-B251/IT-B501) or two (IT-B252/IT-B502) doses of budesonide, while the other two groups were the intravenous (IV) dexamethasone (0.5 mg/kg) (IV-Dex) group and the control group (Ctrl). Vital signs and cardiopulmonary functions were monitored throughout the experiments. Pulmonary histology was examined after completing the experiments. RESULTS: Both the IV-Dex and IT-B501 groups got significant improvement in oxygenation (P < 0.05). Lung compliance became worse after one dose of 0.25 mg/kg of IT budesonide. Pulmonary histology revealed that there were significantly lower lung injury scores for all treatment groups compared to control group, especially at the non-dependent sites of both the IT-B501 and IT-B502 groups. There was no significant difference between double- and single-dose groups, no matter whether 0.25 or 0.5 mg/kg of budesonide was used. CONCLUSIONS: IT instillation of one dose of 0.5 mg/kg budesonide is beneficial in treating meconium-injured piglet lungs during the first 8 h of injury, but a second dose at an interval of 4 h does not have a superior beneficial effect compared to one dose.