Long-Term Neurodevelopmental Outcomes after Moderate and Late Preterm Birth: A Systematic Review.

OBJECTIVE: To systematically review and perform meta-analyses on the long-term neurodevelopmental outcomes of adults born moderate and late preterm (MLPT) in relation to cognitive functioning and psychiatric disorders. STUDY DESIGN: A search was conducted to identify any studies that involved prematurity in adulthood. From these studies, reports that included a group of MLPT adults and included description of cognitive and/or mental health domains (including specific long-term outcomes) were selected. RESULTS: In total, 155 publications were identified, but only 16 papers met the inclusion criteria. A small effect size (g = 0.38) was found in MLPT to demonstrate poorer intellectual performance compared with those born at term. Moreover, MLPT adults exhibited greater odds for any psychiatric (OR 1.14), substance use (OR 1.16), mood (OR 1.06), and psychotic disorders (OR 1.40). CONCLUSIONS: Despite inconsistency due to the methodologic differences between the selected studies, MLPT showed minor long-term effects into adulthood. However, more studies are needed, because prematurity seems to confer some vulnerability to biological and environmental factors that enhance susceptibility to adverse neurodevelopment outcomes.

Environmental Exposure during Pregnancy: Influence on Prenatal Development and Early Life: A Comprehensive Review.

Preconception and prenatal exposure to environmental contaminants may affect future health. Pregnancy and early life are critical sensitive windows of susceptibility. The aim of this review was to summarize current evidence on the toxic effects of environment exposure during pregnancy, the neonatal period, and childhood. Alcohol use is related to foetal alcohol spectrum disorders, foetal alcohol syndrome being its most extreme form. Smoking is associated with placental abnormalities, preterm birth, stillbirth, or impaired growth and development, as well as with intellectual impairment, obesity, and cardiovascular diseases later in life. Negative birth outcomes have been linked to the use of drugs of abuse. Pregnant and lactating women are exposed to endocrine-disrupting chemicals and heavy metals present in foodstuffs, which may alter hormones in the body. Prenatal exposure to these compounds has been associated with pre-eclampsia and intrauterine growth restriction, preterm birth, and thyroid function. Metals can accumulate in the placenta, causing foetal growth restriction. Evidence on the effects of air pollutants on pregnancy is constantly growing, for example, preterm birth, foetal growth restriction, increased uterine vascular resistance, impaired placental vascularization, increased gestational diabetes, and reduced telomere length. The advantages of breastfeeding outweigh any risks from contaminants. However, it is important to assess health outcomes of toxic exposures via breastfeeding. Initial studies suggest an association between pre-eclampsia and environmental noise, particularly with early-onset pre-eclampsia. There is rising evidence of the negative effects of environmental contaminants following exposure during pregnancy and breastfeeding, which should be considered a major public health issue.

Nebulized Poractant Alfa Reduces the Risk of Respiratory Failure at 72 Hours in Spontaneously Breathing Surfactant-Deficient Newborn Piglets.

OBJECTIVES: We have setup for the first time a long-term (72 hr) respiratory distress syndrome model in spontaneously breathing surfactant-deficient newborn piglets to investigate the continuous positive airway pressure failure rate with nebulized poractant alfa compared with that with the intubation surfactant extubation technique or continuous positive airway pressure only. DESIGN: Prospective randomized animal study. SETTING: Biocruces-Bizkaia Health Research Institute Animal Facility. SUBJECTS-INTERVENTIONS: Eighteen newborn piglets (n = 6/group) with surfactant-deficient respiratory distress syndrome were randomized to three continuous positive airway pressure-ventilated groups: 1) nebulized surfactant (poractant alfa 400 mg/kg) via a customized investigational eFlow-Neos vibrating membrane nebulizer system, 2) bolus administration using the Intubation Surfactant Extubation method (200 mg/kg), or 3) continuous positive airway pressure alone. MEASUREMENTS AND MAIN RESULTS: Pulmonary and hemodynamic variables were assessed at 6-hour intervals for 72 hours. Lung and brain histological analyses were performed. After bronchoalveolar lavages, piglets developed respiratory distress syndrome. Over the follow-up, both surfactant-treated groups had significantly better pulmonary outcomes than the continuous positive airway pressure alone group. Furthermore, unlike in the continuous positive airway pressure group, there were no cases of respiratory failure in either of the surfactant-treated groups. CONCLUSIONS: In newborn piglets with respiratory distress syndrome, the nebulization of 400 mg/kg of poractant alfa using a customized investigational eFlow-Neos nebulizer was found to be safe and effective in reducing the risk of respiratory failure in the 72 hours after treatment.

Dose-Response Study on Surfactant Nebulization Therapy During Nasal Continuous Positive Airway Pressure Ventilation in Spontaneously Breathing Surfactant-Deficient Newborn Piglets.

OBJECTIVES: The current clinical treatment of neonates with respiratory distress syndrome includes endotracheal intubation and intratracheal instillation of exogenous surfactant. Nebulization of surfactant offers an attractive alternative. The aims of this study were to test nebulization as a noninvasive method of administering surfactant and determine the optimal dose for the treatment of respiratory distress syndrome-associated pathophysiology of the neonatal lungs. DESIGN: Prospective, randomized, animal model study. SETTING: An experimental laboratory. SUBJECTS: Thirty-six newborn piglets. INTERVENTIONS: Different doses (100, 200, 400, and 600 mg/kg) of poractant alfa were administered via a vibrating membrane nebulizer (eFlow-Neos; Pari Pharma GmbH, Starnberg, Germany) or a bolus administration using the intubation-surfactant-extubation (Insure) technique (200 mg/kg) to spontaneously breathing newborn piglets (n = 6/group) with bronchoalveolar lavage-induced respiratory distress syndrome during nasal continuous positive airway pressure (180 min). MEASUREMENTS AND MAIN RESULTS: Pulmonary, hemodynamic, and cerebral effects were assessed. Histologic analysis of lung and brain tissue was also performed. After repeated bronchoalveolar lavage, newborn piglets developed severe respiratory distress syndrome. Rapid improvement in pulmonary status was observed in the Insure group, whereas a dose-response effect was observed in nebulized surfactant groups. Nebulized poractant alfa was more effective at doses higher than 100 mg/kg and was associated with similar pulmonary, hemodynamic, and cerebral behavior to that in the Insure group, but improved lung injury scores. CONCLUSIONS: In newborn piglets with severe bronchoalveolar lavage-induced respiratory distress syndrome, our results demonstrate that the administration of nebulized poractant alfa using an investigational customized eFlow-Neos nebulizer is an effective and safe noninvasive surfactant administration technique.

Spanish survey on follow-up programmes for children born very preterm.

AIM: To describe variations in practice between follow-up programmes for very preterm children born at less than 32 weeks' gestation or with very low birth weight of less than 1,500 g. METHODS: A survey on follow-up practices was electronically distributed to level II and III units among hospitals of the Spanish National Health Service in 2016. The survey included 70 questions covering issues such as follow-up organisation and resources, routine assessments, relationships with other services and families, information management and training. RESULTS: The response rate was 91.5% (141/154). Among respondents, 70.9% (100/141) reported that they do provide follow-up and 42% do so up to six years of age. Routine neurological and ophthalmological follow-up is not performed in 60% and 37% of hospitals, respectively, and a second hearing assessment is not given in 62%. Just 38% of units have psychologist. In 41% of hospitals, training in follow-up skills is not included in Paediatric Residency training programme. CONCLUSION: Although Spain has a nationwide health system that provides universal health coverage, we found that follow-up care for children born very preterm/very low birth weight is not equitable. Nearly half of paediatric residents receive no training in follow-up for this high-risk population.

Non-invasive ventilation and surfactant treatment as the primary mode of respiratory support in surfactant-deficient newborn piglets.

BackgroundNasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV), forms of non-invasive ventilation (NIV) for respiratory support, are increasingly being chosen as the initial treatment for neonates with surfactant (SF) deficiency. Our objective was to compare NCPAP with NIPPV with or without SF administration as a primary mode of ventilation.MethodsTwenty-four newborn piglets with SF-deficient lung injury produced by repetitive bronchoalveolar lavages were randomly assigned to NCPAP or NIPPV, with or without SF administration (InSurE method). We evaluated pulmonary, systemic (hemodynamic and oxygen metabolism), and cerebral effects.ResultsSF-deficient piglets developed respiratory distress (FiO2:1, pH<7.2, PaCO2>70 mm Hg, PaO2<70 mm Hg, and Cdyn<0.5 ml/cmH2O/kg). Gradual improvements in pulmonary status were observed in both NIV groups, with NIPPV achieving lower lung inflammation markers and injury scores. Both SF-treated groups obtained significantly better respiratory outcomes than groups not treated with SF before NIV. All NIV-treated groups showed low brain injury scores.ConclusionIn spontaneously breathing SF-deficient newborn piglets, NIPPV is a suitable NIV strategy. SF administration in combination with NCPAP or NIPPV improves pulmonary status providing extra protection against pulmonary injury. No injury to the developing brain was observed to be associated with these NIV strategies, with or without SF therapy.

Structural and haemodynamic evaluation of less invasive surfactant administration during nasal intermittent positive pressure ventilation in surfactant-deficient newborn piglets.

The most recent approaches to the initial treatment of respiratory distress syndrome (RDS)- involve non-invasive ventilation (NIV) and less-invasive surfactant (SF) administration (LISA). Combining these techniques has been proven a useful treatment option for SF-deficient neonates. The objective of this study was to explore the impact on the brain (using cerebral near infrared spectroscopy, NIRS) of different LISA methods during NIV, using nasal intermittent positive pressure ventilation (NIPPV) for treating neonatal RDS. For this, we used five groups of spontaneously breathing newborn piglets (n = 6/group) with bronchoalveolar lavage (BAL)-induced respiratory distress which received NIPPV only (controls), poractant-alfa using the INSURE-like method (bolus delivery) followed by NIPPV, or poractant-alfa using one of three LISA devices, 1) a nasogastric tube (NT), 2) a vascular catheter (VC) or 3) the LISAcath® catheter. We assessed pulmonary, hemodynamic and cerebral effects, and performed histological analysis of lung and brain tissue. Following BALs, the piglets developed severe RDS (pH<7.2, PaCO2>70 mmHg, PaO2<70 mmHg, dynamic compliance<0.5 ml/cmH2O/kg at FiO2 = 1). Poractant-alfa administration using different LISA techniques during NIPPV was well tolerated and efficacious in newborn piglets. In our study, although all groups showed normal physiological ranges of total lung injury score and biochemical lung analysis, VC and LISAcath® catheters were associated with better values of lung compliance and lower values of lung damage than NIPPV, NT or INSURE-like methods. Moreover, neither of the SF administration methods used (LISA or INSURE-like) had a significant impact on the histological neonatal brain injury score. Of note, the LISAcath® has been recently withdrawn from the market.

Preterm birth and early life environmental factors: neuropsychological profiles at adolescence and young adulthood.

OBJECTIVES: To establish neuropsychological profiles after high- and low-risk preterm birth (i.e., with and without neonatal brain injury) during adolescence and young adulthood and to assess the potential role of early life environmental factors in cognition. STUDY DESIGN: Participants (N = 177; Mage = 20.11 years) of both sexes were evaluated when adolescent or in young adulthood. They were grouped according to their birth status: 30 high-risk preterm, 83 low-risk preterm and 64 born at full term. RESULTS: Significant differences were found in several cognitive domains between groups. Furthermore, familial socioeconomic status (SES) moderated the relation between the degree of maturity/immaturity at birth and cognition (F(5,171) = 11.94, p < 0.001, R2 = 0.26). DISCUSSION: The findings showed different neuropsychological profiles during adolescence and young adulthood, with the high-risk preterm sample evidencing lower cognitive values. In addition, higher scores in the familial SES score in this study seem to have a protective effect on cognition.

Analysis of standard concentrations of continuous infusions in nine Spanish neonatal intensive care units.

OBJECTIVES: The aim of this study was to describe the use of standard concentrations for continuous infusion drugs in Spanish neonatal intensive care units (NICUs). METHODS: We conducted an observational multicentre study based on a survey sent by email to 9 Spanish NICUs during January and February 2018. We collected data on intravenous drugs frequently used in neonates, and their preparation. Continuous infusion drugs with a standard concentration implemented in ≥2 NICUs were selected. An analysis of the concentrations reported was performed, and the rate of adherence to international recommendations of the Institute of Safe Medication Practice (ISMP) and Vermont Oxford Network (VON) was calculated. RESULTS: From 69 drugs mentioned in the survey, 14 were included in the study, with all but one (furosemide) being considered high-alert medications by the ISMP. From the 9 participating NICUs, 3 had no established standard concentrations for any of the 14 drugs selected. In the other participating NICUs, dexmedetomidine was used with a standard concentration in the 3 NICUs which used the drug, whereas furosemide showed the lowest implementation rate (a standard concentration was implemented in 2 of the 7 NICUs which used the drug). In regard to concentrations adopted in the different NICUs, 80 variations were identified for the 14 drugs. The mean number of different standard concentrations for each drug per NICU was 2 (range 1-5). Adherence to ISMP/VON recommendations varied considerably depending on the drugs, from high adherence for heparin (2/3) and fentanyl (2/3) to low adherence for norepinephrine (0/4). CONCLUSIONS: The establishment of standard concentrations is highly recommended for continuous infusion medications as an effective error-prevention strategy. Nevertheless, we detected a low implementation rate in our NICUs and a lack of consistency in the concentrations selected.

Intravenous drug use in neonatal intensive care units.

OBJECTIVES: Intravenous drug use in neonates is frequent and prone to medication errors. The aim of this study was to describe the intravenous drugs most frequently used in Spanish Neonatal Intensive Care Units (NICU), their preparation and the implementation rate of standardised concentration infusions. METHODS: We conducted an observational multicentre study based on a survey sent by email to nine Spanish NICUs during January and February 2018. We collected data describing the intravenous drugs frequently used in neonates and their preparation. A descriptive analysis of the medicines reported (and their preparation) was performed, to assess how frequently standard concentrations were used and how medications were prepared in central pharmacies. RESULTS: Overall, 69 different drugs were reported by participating NICUs. Of these, 33% (n=23) were not approved for use in neonates and 38% (n=26) corresponded to high-alert medications, according to the Institute for Safe Medication Practices. A mean of only 63.5% of intravenous medicines were standardised. The standard-concentration implementation rate was somewhat higher for intermittent (mean 74.1%) than continuous (mean 42.9%) infusions. Notably, infusions were more commonly prepared on wards than in hospital pharmacies. CONCLUSIONS: Intravenous drug use in NICUs has been identified as a high-risk process, and error-reduction strategies (such as concentration standardisation) have been recommended. Further data are necessary to design the most suitable intervention in our country (Spain), but institutional initiatives are needed to achieve this.

Importance of Timely Treatment Initiation in Infantile-Onset Pompe Disease, a Single-Centre Experience.

Classic infantile Pompe disease (IPD) is a rare lysosomal storage disorder characterized by severe hypertrophic cardiomyopathy and profound muscle weakness. Without treatment, death occurs within the first 2 years of life. Although enzyme replacement therapy (ERT) with alglucosidase alfa has improved survival, treatment outcome is not good in many cases and is largely dependent on age at initiation. The objective of the study was (a) to analyse the different stages in the diagnosis and specific treatment initiation procedure in IPD patients, and (b) to compare clinical and biochemical outcomes depending on age at ERT initiation (<1 month of age vs. <3 months of age). Here, we show satisfactory clinical and biochemical outcomes in two IPD patients after early treatment initiation before 3 months of life with immunomodulatory therapy in the ERT-naïve setting, with a high ERT dose from the beginning. Despite the overall good evolution, the patient who initiated treatment <1 month of life presented even better outcomes than the patient who started treatment <3 months of life, with an earlier normalization of hypertrophic cardiomyopathy, along with CK normalization, highlighting the importance of early treatment initiation in this progressive disease before irreversible muscle damage has occurred.

The Evolving Microbiome from Pregnancy to Early Infancy: A Comprehensive Review.

Pregnancy induces a number of immunological, hormonal, and metabolic changes that are necessary for the mother to adapt her body to this new physiological situation. The microbiome of the mother, the placenta and the fetus influence the fetus growth and undoubtedly plays a major role in the adequate development of the newborn infant. Hence, the microbiome modulates the inflammatory mechanisms related to physiological and pathological processes that are involved in the perinatal progress through different mechanisms. The present review summarizes the actual knowledge related to physiological changes in the microbiota occurring in the mother, the fetus, and the child, both during neonatal period and beyond. In addition, we approach some specific pathological situations during the perinatal periods, as well as the influence of the type of delivery and feeding.

The Role of Factor V Leiden, Prothrombin G20210A, and MTHFR C677T Mutations in Neonatal Cerebral Sinovenous Thrombosis.

Little is known about the pathogenesis of cerebral sinovenous thrombosis (CSVT) in the neonate. Although thrombophilia has been described as increasing the risk of CSVT in adults, it remains controversial in pediatric patients, and prospective case-control studies regarding neonatal CSVT are lacking. From 2008 to 2017, all 26 consecutive newborn infants ≥35 weeks of gestation diagnosed with neonatal CSVT, and their mothers, were tested for factor V Leiden (FV) G1691A, FII G20210A, and methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations. Eighty-five mother-infant pairs were recruited as controls. All infants except 1 with CSVT were suspected due to clinical symptoms, mainly seizures (22/25). Magnetic resonance imaging was performed in 24/26 infants. Heterozygous FV G1691A, FII G20210A, and homozygous MTHFR C677T mutations were present in 1/26, 3/26, and 3/20 infants with CSVT, respectively. FII (odds ratio: 10.96; 95% confidence interval [CI]: 1.09-110.35) and male sex (3.93; 95% CI: 1.43-10.76) were associated with CSVT. When FII G20210A analysis was adjusted for sex, the OR for FII G20210A was 6.70 (95% CI: 0.65-69.22). No differences were found for FV G1691A or homozygous MTHFR mutations between neonates with CSVT and their mothers, compared to controls.

Cerebral oxygenation associated with INSURE versus LISA procedures in surfactant-deficient newborn piglet RDS model.

BACKGROUND: Nasal continuous-positive airway pressure (nCPAP) with the INSURE (INtubation-SURfactant-Extubation) or LISA (Less-Invasive Surfactant Administration) procedures are increasingly being chosen as the initial treatment for neonates with surfactant deficiency. Our objective was to compare the effects on cerebral oxygenation of different methods for surfactant administration: INSURE and LISA, using a nasogastric tube (NT) or a LISAcath® catheter, in spontaneously breathing SF-deficient newborn piglets. METHODS: Eighteen newborn piglets with SF-deficient lung injury produced by repetitive bronchoalveolar lavages were randomly assigned to INSURE, LISA-NT, or LISAcath® groups. We assessed pulmonary (gas exchange, lung mechanics, lung histology) and hemodynamic (mean arterial blood pressure, heart rate) changes, cerebral oxygenation (cTOI) and cerebral fractional tissue extraction (cFTOE), with near-infrared spectroscopy, carotid blood flow and brain histology. RESULTS: SF-deficient piglets developed respiratory distress (FiO2 = 1, pH <7.2, PaCO2 >70 mmHg, PaO2 <70 mmHg, Cdyn <0.5 mL/cmH2 O/kg). Rapid improvements in pulmonary status were observed in all surfactant-treated groups without hemodynamic alterations. In the INSURE group, a transient decrease in cTOI occurred during and immediately after surfactant administration, while cTOI only decreased during surfactant administration in the LISA-NT group and did not change significantly in the LISAcath® group. Brain injury scores were low in all surfactant-treated groups. CONCLUSION: In spontaneously breathing SF-deficient newborn piglets, short-lasting decreases in cerebral oxygenation are associated with surfactant administration by the INSURE method or LISA using an NT, while no cerebral oxygenation changes occurred with LISA using a LISAcath®. Notably, none of treatments studied seems to have a negative impact on the neonatal brain.

Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial.

BACKGROUND AND OBJECTIVES: Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. STUDY DESIGN: Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs' cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. RESULTS: Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. CONCLUSIONS: Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.

[Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy]. / Estrés oxidativo en la asfixia perinatal y la encefalopatía hipóxico-isquémica.

Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis.

MRI Patterns of brain injury and neurodevelopmental outcomes in neonates with severe anaemia at birth.

AIMS: To define patterns of brain injury and associated neurodevelopmental outcomes in infants with severe neonatal anaemia. METHODS: We studied 20 infants with severe anaemia at birth (haemoglobin<7g/dL). Clinical details were analysed for causes of anaemia and co-morbidities. All had early brain magnetic resonance imaging (MRI) scans, which were reviewed for injury pattern. Neurodevelopmental outcomes were assessed at a median age of 24months. RESULTS: The aetiology of the anaemia was feto-maternal haemorrhage in 17 and antepartum haemorrhage in 3 infants. The predominant site of injury was the white matter, which was affected in all infants, with differing grades of severity and with cystic evolution in 45%. Only one infant showed an injury pattern typical of an acute severe hypoxic-ischaemic insult. Outcomes correlated closely to the severity of MRI findings. Cerebral palsy was seen only with the most severe neuroimaging patterns (n=6). Global developmental delay, learning or behavioural problems and seizures were common with moderate injury. Visual impairment occurred, particularly with posterior injury. Microcephaly developed in 45%. INTERPRETATION: Severe neonatal anaemia at birth was associated with a white matter predominant pattern of injury, the severity of which was related to neurodevelopmental outcomes. Early MRI and long-term follow-up are advisable following severe neonatal anaemia.

Cerebral and lung effects of a new generation synthetic surfactant with SP-B and SP-C analogs in preterm lambs.

BACKGROUND: Though natural surfactants (SF) are clinically superior to protein-free synthetic preparations, CHF-5633, a synthetic SF containing SP-B and SP-C analog peptides is a potential alternative to natural SF for treating neonatal respiratory distress syndrome (RDS). Nevertheless, information is lacking regarding the safety of this new treatment for the neonatal brain. We sought to compare the cerebral and pulmonary effects of this new synthetic surfactant (CHF5633) with those of natural porcine surfactant (Cursosurf) in premature lambs with RDS. METHODS: Twenty-one preterm lambs were randomly assigned to receive CHF5633, Curosurf, or no treatment (control). Pulmonary (gas exchange, lung mechanics) and cerebral (carotid artery blood flow, cerebral oxygen metabolism) effects were measured every 30 min for 6 h. Pulmonary and cerebral histological analysis were also performed. RESULTS: After delivery, lambs developed severe RDS (FIO2 :1, pH < 7.15, PaCO2 > 70 mmHg, PaO2 < 40 mmHg, Cdyn < 0.1 mL/cmH2 O/kg). By 30 min after treatment, animals in both SF-treated groups had consistently better gas exchange and lung mechanics than controls. After CHF5633 administration, PaCO2 , carotid artery blood flow, and cerebral oxygen delivery tended to slowly decrease compared to other groups. By 2 h, SF-treated groups had similar values of all parameters studied, these remaining steady for the rest of the experiment. Lambs administered CHF5633 obtained better lung and brain injury scores than controls. CONCLUSION: Intratracheal administration of a bolus of CHF5633 improves pulmonary status in preterm lambs with severe RDS, obtaining better lung and brain injury scores than controls and favorable cerebral hemodynamics, comparable to those with gold standard Curosurf treatment.

Evolution of Energy Related Metabolites in Plasma from Newborns with Hypoxic-Ischemic Encephalopathy during Hypothermia Treatment.

Therapeutic hypothermia (TH) initiated within 6 h from birth is the most effective therapeutic approach for moderate to severe hypoxic-ischemic encephalopathy (HIE). However, underlying mechanisms and effects on the human metabolism are not yet fully understood. This work aims at studying the evolution of several energy related key metabolites in newborns with HIE undergoing TH employing gas chromatography - mass spectrometry. The method was validated following stringent FDA requirements and applied to 194 samples from a subgroup of newborns with HIE (N = 61) enrolled in a multicenter clinical trial (HYPOTOP) for the determination of lactate, pyruvate, ketone bodies and several Krebs cycle metabolites at different sampling time points. The analysis of plasma samples from newborns with HIE revealed a decrease of lactate, pyruvate and ß-hydroxybutyrate concentrations, whereas rising malate concentrations were observed. In healthy control newborns (N = 19) significantly lower levels of pyruvate and lactate were found in comparison to age-matched newborns with HIE undergoing TH, whereas acetoacetate and ß-hydroxybutyrate levels were clearly increased. Access to a validated analytical method and a controlled cohort of newborns with HIE undergoing hypothermia treatment for the first time allowed the in-depth study of the evolution of key metabolites of metabolic junctions in this special population.