Effect of preoperative pulmonary hemodynamic and cardiopulmonary bypass on lung function in children with congenital heart disease.

In children with congenital heart disease (CHD), pulmonary blood flow (Qp) contributes to alterations of pulmonary mechanics and gas exchange, while cardiopulmonary bypass (CPB) induces lung edema. We aimed to determine the effect of hemodynamics on lung function and lung epithelial lining fluid (ELF) biomarkers in biventricular CHD children undergoing CPB. CHD children were classified as high Qp (n = 43) and low Qp (n = 17), according to preoperative cardiac morphology and arterial oxygen saturation. We measured ELF surfactant protein B (SP-B) and myeloperoxidase activity (MPO) as indexes of lung inflammation and ELF albumin as index of alveolar capillary leak in tracheal aspirate (TA) samples collected before surgery and in 6 hourly intervals within 24 h after surgery. At the same time points, we recorded dynamic compliance and oxygenation index (OI). The same biomarkers were measured in TA samples collected from 16 infants with no cardiorespiratory diseases at the time of endotracheal intubation for elective surgery. Preoperative ELF biomarkers in CHD children were significantly increased than those found in controls. In the high Qp, ELF MPO and SP-B peaked 6 h after surgery and tended to decrease afterward, while they tended to increase within the first 24 h in the low Qp. ELF albumin peaked 6 h after surgery and decreased afterwards in both CHD groups. Dynamic compliance/kg and OI significantly improved after surgery only in the High Qp.  Conclusion: In CHD children, lung mechanics, OI, and ELF biomarkers were significantly affected by CPB, according to the preoperative pulmonary hemodynamics. What is Known: • Congenital heart disease children, before cardiopulmonary run, exhibit changes in respiratory mechanics, gas exchange, and lung inflammatory biomarkers that are related to the preoperative pulmonary hemodynamics. • Cardiopulmonary bypass induces alteration of lung function and epithelial lining fluid biomarkers according to preoperative hemodynamics. What is New: • Our findings can help to identify children with congenital heart disease at high risk of postoperative lung injury who may benefit of tailored intensive care strategies, such as non-invasive ventilation techniques, fluid management, and anti-inflammatory drugs that can improve cardiopulmonary interaction in the perioperative period.

Early postnatal weight loss does not affect the 2-year neurodevelopment in preterm infants of less than 32 weeks.

AIM: It is still unclear if the magnitude of early postnatal weight loss (PWL) could be associated with neurodevelopmental outcomes in preterm infants. We studied the association between PWL and neurodevelopment at 2-year corrected age in preterm infants. METHODS: We retrospectively reviewed data of preterm infants with a gestational age between 24 + 0 and 31 + 6 weeks/days, admitted at the G.Salesi Children's Hospital, Ancona, Italy, between 1 January 2006 and 31 December 2019. Infants with PWL greater than or equal to 10% (PWL ≥ 10%) were compared with those with PWL of less than 10% (PWL < 10%). A matched cohort analysis was also performed using gestational age and birth weight as matching variables. RESULTS: We analysed 812 infants: 471 (58%) PWL ≥ 10% and 341 (42%) PWL < 10%. A subgroup of 247 PWL ≥ 10% was closely match-paired with 247 PWL < 10% infants. There were no differences in amino acid and energy intakes from birth to day 14 of life and from birth to 36 weeks. Although at 36 weeks, body weight and total length were lower in PWL ≥ 10% than PWL < 10%, anthropometry and neurodevelopment at 2 years were similar between groups. CONCLUSION: Given similar amino acid and energy intakes on PWL ≥ 10% and PWL < 10% preterm infants of less than 32 + 0 weeks/days, PWL does not affect 2-year neurodevelopment.

A novel deuterium-based model for measurement of exogenous surfactant using deuterium-depleted water.

Stable isotope tracers, like 13 C, can be used for the measurement of the partition between the endogenous and exogenous pulmonary disaturated-phosphatidylcholine (DSPC). Deuterium labeling methods are still not fully explored. Our aim was to investigate the feasibility of using deuterium-depleted water (DDW) and deuterium-enriched water (DEW) to measure endogenous and exogenous pulmonary DSPC in a rabbit model of surfactant depletion. Data obtained from the 13 C dilution method were used as a reference. We studied 9 adult rabbits: 4 drank DDW and 5 DEW for 5 days. Lung surfactant depletion was induced at Day 5 by repeated saline bronchoalveolar lavages (BAL), which were stored as a pool (BAL pool). After endogenous surfactant depletion, rabbits received exogenous surfactant followed by a second BAL depletion procedure (End-Experiment Pool). DSPC quantity, and palmitic acid (PA)-DSPC 2 H/1 H (δ2 H) and 13 C/12 C ratios (δ13 C) of exogenous surfactant batches and of BAL pools were measured by High-Resolution Mass Spectrometry. The amount of exogenous surfactant recovered from the lungs ranged from 45% to 81% and, it was highly correlated with those obtained with the use of the 13 C (r = 0.9844, p < 0.0001). We demonstrated that commercially available purified DDW and even low doses of DEW can be used to modify the deuterium background of endogenous surfactants with the purpose of measuring the contribution of exogenous surfactants to the endogenous alveolar surfactant pool.

DHA turnover in pregnant women using the natural abundance variation of 13C: a pilot study.

The importance of DHA intake to support fetal development and maternal health is well established. In this pilot study we applied the natural abundance approach to determine the contribution of 200 mg/day of DHA supplement to the plasma DHA pool in 19 healthy pregnant women on a free diet.Women received DHA, from pregnancy week 20 until delivery, from an algal source (N=13, Algae group) or from fish oil (N=6, Fish group) with slightly different content of 13C.We measured plasma phospholipids DHA 13C:12C ratio (reported as δ13C) prior to supplementation (T0), after 10 (T1) and 90 days (T2) and prior to delivery (T3).The δ13C of DHA in algae and fish supplements were -15.8±0.2 mUr and -25.3±0.2 mUr (p<0.001).DHA δ13C in the Algae group increased from -27.7±1.6 mUr (T0) to -21.9±2.2 mUr (T3) (p<0.001), whereas there were not significant changes in the Fish group (-27.8±0.9 mUr at T0 and -27.3±1.1 mUr at T3, p=0.09).In the Algae group 200 mg/day of DHA contributed to the plasma phospholipid pool by a median value of 53% (31-75% minimum and maximum). This estimation was not possible in the fish group.Our results demonstrate the feasibility of assessing the contribution of DHA from an algal source to the plasma DHA pool in pregnant women by the natural abundance approach. Plasma δ13C DHA did not change when consuming DHA of fish origin, with almost the same δ13C value of that of the pre-supplementation plasma δ13C DHA.

UBIAD1 and CoQ10 protect melanoma cells from lipid peroxidation-mediated cell death.

Cutaneous melanoma is the deadliest type of skin cancer, although it accounts for a minority of all skin cancers. Oxidative stress is involved in all stages of melanomagenesis and cutaneous melanoma can sustain a much higher load of Reactive Oxygen Species (ROS) than normal tissues. Melanoma cells exploit specific antioxidant machinery to support redox homeostasis. The enzyme UBIA prenyltransferase domain-containing protein 1 (UBIAD1) is responsible for the biosynthesis of non-mitochondrial CoQ10 and plays an important role as antioxidant enzyme. Whether UBIAD1 is involved in melanoma progression has not been addressed, yet. Here, we provide evidence that UBIAD1 expression is associated with poor overall survival (OS) in human melanoma patients. Furthermore, UBIAD1 and CoQ10 levels are upregulated in melanoma cells with respect to melanocytes. We show that UBIAD1 and plasma membrane CoQ10 sustain melanoma cell survival and proliferation by preventing lipid peroxidation and cell death. Additionally, we show that the NAD(P)H Quinone Dehydrogenase 1 (NQO1), responsible for the 2-electron reduction of CoQ10 on plasma membranes, acts downstream of UBIAD1 to support melanoma survival. By showing that the CoQ10-producing enzyme UBIAD1 counteracts oxidative stress and lipid peroxidation events in cutaneous melanoma, this work may open to new therapeutic investigations based on UBIAD1/CoQ10 loss to cure melanoma.

Protective continuous ventilation strategy during cardiopulmonary bypass in children undergoing surgery for congenital heart disease: a prospective study.

OBJECTIVES: The aim of this study was to evaluate if a 'protective' (low-tidal/low-frequency) ventilation strategy can shorten the postoperative ventilation time and minimize acute lung injury in children with congenital heart disease (CHD) undergoing repair with cardiopulmonary bypass (CPB). METHODS: This is a single-centre prospective, interventional study, including children with CHD under the age of 5 years, undergoing open-heart surgery with a CPB >60 min, in hypothermia, haemodynamically stable, and without evident genetic abnormalities. Assist-control ventilation (tidal volume of 4 ml/kg, 10 breaths/min, positive end-expiratory pressure 5 cmH2O and FiO2 0.21) was applied in a cohort of patients during CPB. We compared clinical outcomes and in fully ventilated versus non-ventilated (control) patients. Propensity score was used to weigh ventilated and control groups to correct for the effect of other confounding clinical variables. Clinical and ventilation parameters and lung inflammatory biomarkers in tracheal aspirates were measured. The primary outcome was the postoperative intubation time of more or less than 48 h. RESULTS: We included 140 children (53 ventilated, 87 non-ventilated) with different CHD. There were no deaths or adverse events in ventilated patients. Using a weighted generalized linear model, we found no sufficient evidence for an effect of intraoperative ventilation on postoperative intubation time [estimate 0.13 (95% confidence interval, -0.08; 0.35), P = 0.22]. CONCLUSIONS: Continuous low-tidal/low-frequency mechanical ventilation during CPB is safe and harmless. However, no significant advantages were found when compared to non-ventilated patients in terms of postoperative ventilation time.

Deuterium-depleted water: A new tracer to label pulmonary surfactant lipids in adult rabbits.

Stable isotope tracing can be safely used for metabolic studies in animals and humans. The endogenous biosynthesis of lipids (lipogenesis) is a key process throughout the entire life but especially during brain and lung growth. Adequate synthesis of pulmonary surfactant lipids is indispensable for life. With this study, we report the use of deuterium-depleted water (DDW), suitable for human consumption, as metabolic precursor for lipogenesis. We studied 13 adult rabbits for 5 days. Four rabbits drank tap water (TW) and served as controls; in four animals, DDW was substituted to drinking water, whereas five drank deuterium-enriched water (DEW). After 5 days, a blood sample and a bronchoalveolar lavage (BAL) sample were collected. The 2 H/1 H (δ2 H) of BAL palmitic acid (PA) desaturated phosphatidylcholine (DSPC), the major phospholipid of pulmonary surfactant, and of plasma water was determined by high-resolution mass spectrometry. We found that the δ2 H values of DDW, DEW and TW were -984 ± 2‰, +757 ± 2‰ and -58 ± 1‰, respectively. After 5 days, plasma water values were -467 ± 87‰, +377 ± 56‰ and -53 ± 6‰, and BAL DSPC-PA was -401 ± 27‰, -96 ± 38‰ and -249 ± 9‰ in the DDW, DEW and TW, respectively. With this preliminary study, we demonstrated the feasibility of using DDW to label pulmonary surfactant lipids. This novel approach can be used in animals and in humans, and we speculate that it could be associated with more favourable study compliance than DEW in human studies.

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

Perioperative Glial Fibrillary Acidic Protein Is Associated with Long-Term Neurodevelopment Outcome of Infants with Congenital Heart Disease.

BACKGROUND: Brain injury, impaired brain maturation, and long-term neurodevelopmental disorders are common in infants with congenital heart diseases (CHD). We aimed to assess whether plasma glial fibrillary acidic protein (GFAP) can predict neurodevelopmental anomalies in CHD infants operated on cardiopulmonary bypass (CPB). METHODS: We measured plasma GFAP in 38 infants at multiple CPB phases. Cognitive, neuropsychological, and psychopathological functioning were assessed 5.7 ± 2.2 years after surgery. We identified an impaired global neurodevelopmental index (NDI) when at least two domains were abnormal. The relationships between NDI, GFAP, and clinical variables were explored with non-supervised feature selection methods and modeled with a nested non-linear logistic regression. RESULTS: Intelligence quotient scores were within the normal range in 84% of children, whereas 58% showed an abnormal NDI, with the greatest impairments in the psychopathological area. The plasma GFAP peak was 0.95 (0.44-1.57) ng/mL, and it was correlated with age, weight, duration of surgery phases, and CPB minimum temperature. In the regression model, the GFAP peak was associated with an impaired NDI with a possible flexible point toward NDI impairment at 0.49 ng/mL, keeping constant ICU stay, CPB duration, CHD anatomy, weight, and CPB minimum temperature. CONCLUSION: GFAP is a promising early marker of abnormal long-term neuropsychological development.

Chorioamnionitis alters lung surfactant lipidome in newborns with respiratory distress syndrome.

BACKGROUND: Chorioamnionitis is associated with preterm delivery and morbidities; its role in lung disease is controversial. The aim of this study is to assess the effect of chorioamnionitis on metabolite and lipid profiles of epithelial lining fluid in preterm newborns with respiratory distress syndrome (RDS). METHODS: The study involved 30 newborns with RDS, born from mothers with or without histological chorioamnionitis (HCA): HCA+, N = 10; HCA-, N = 20. Patients had a gestational age ≤30 weeks; the groups were matched for age and birth weights. Tracheal aspirates were collected within 24 h after birth and analyzed using liquid chromatography/mass spectrometry-based untargeted lipidomics. RESULTS: According to Mann-Whitney U tests, 570 metabolite features had statistically significantly higher or lower concentrations (p < 0.05) in tracheal aspirates of HCA+ compared to HCA-, and 241 metabolite features were putatively annotated and classified. The most relevant changes involved higher levels of glycerophospholipids (fold change 2.42-17.69) and sphingolipids, with lower concentration of all annotated sphingomyelins in HCA+ (fold change 0.01-0.50). CONCLUSIONS: Untargeted lipidomics of tracheal aspirates suggested the production of lipid mediators in the context of an ongoing inflammatory status in HCA+ babies. However, the effect of chorioamnionitis on epithelial lining fluid composition deserves further investigations on a larger group of infants. IMPACT: Our lipidomics investigation on tracheal aspirates of preterm newborns at birth suggested that exposure to maternal histological chorioamnionitis may cause changes in epithelial lining fluid composition. This is the first description of epithelial lining fluid lipidomic profiles in preterm infants with and without exposition to chorioamnionitis. These results could provide novel link between placental membrane inflammation and newborns' respiratory outcome.

Surfactant lung delivery with LISA and InSurE in adult rabbits with respiratory distress.

BACKGROUND: In preterm infants, InSurE (Intubation-Surfactant-Extubation) and LISA (less invasive surfactant administration) techniques allow for exogenous surfactant administration while reducing lung injury associated with mechanical ventilation. We compared the acute pulmonary response and lung deposition of surfactant by LISA and InSurE in surfactant-depleted adult rabbits. METHODS: Twenty-six spontaneously breathing surfactant-depleted adult rabbits (6-7 weeks old) with moderate RDS and managed with nasal continuous positive airway pressure were randomized to 3 groups: (1) 200 mg/kg of surfactant by InSurE; (2) 200 mg/kg of surfactant by LISA; (3) no surfactant treatment (Control). Gas exchange and lung mechanics were monitored for 180 min. After that, surfactant lung deposition and distribution were evaluated monitoring disaturated-phosphatidylcholine (DSPC) and surfactant protein C (SP-C), respectively. RESULTS: No signs of recovery were found in the untreated animals. After InSurE, oxygenation improved more rapidly compared to LISA. However, at 180' LISA and InSurE showed comparable outcomes in terms of gas exchange, ventilation parameters, and lung mechanics. Neither DSPC in the alveolar pool nor SP-C signal distributions in a frontal lung section were significantly different between InSurE and LISA groups. CONCLUSIONS: In an acute setting, LISA demonstrated efficacy and surfactant lung delivery similar to that of InSurE in surfactant-depleted adult rabbits. IMPACT: Although LISA technique is gaining popularity, there are still several questions to address. This is the first study comparing LISA and InSurE in terms of gas exchange, ventilation parameters, and lung mechanics as well as surfactant deposition and distribution. In our animal study, three hours post-treatment, LISA method seems to be as effective as InSurE and showed similar surfactant lung delivery. Our findings provide some clarifications on a fair comparison between LISA and InSurE techniques, particularly in terms of surfactant delivery. They should reassure some of the concerns raised by the clinical community on LISA adoption in neonatal units.

Detecting neurodevelopmental trajectories in congenital heart diseases with a machine-learning approach.

We aimed to delineate the neuropsychological and psychopathological profiles of children with congenital heart disease (CHD) and look for associations with clinical parameters. We conducted a prospective observational study in children with CHD who underwent cardiac surgery within five years of age. At least 18 months after cardiac surgery, we performed an extensive neuropsychological (intelligence, language, attention, executive function, memory, social skills) and psychopathological assessment, implementing a machine-learning approach for clustering and influencing variable classification. We examined 74 children (37 with CHD and 37 age-matched controls). Group comparisons have shown differences in many domains: intelligence, language, executive skills, and memory. From CHD questionnaires, we identified two clinical subtypes of psychopathological profiles: a small subgroup with high symptoms of psychopathology and a wider subgroup of patients with ADHD-like profiles. No associations with the considered clinical parameters were found. CHD patients are prone to high interindividual variability in neuropsychological and psychological outcomes, depending on many factors that are difficult to control and study. Unfortunately, these dysfunctions are under-recognized by clinicians. Given that brain maturation continues through childhood, providing a significant window for recovery, there is a need for a lifespan approach to optimize the outcome trajectory for patients with CHD.

Thioridazine requires calcium influx to induce MLL-AF6-rearranged AML cell death.

In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate. TDZ induced cell death and irreversible progress toward the loss of leukemia cell clonogenic capacity in vitro. Thus, we explored its mechanism of action and found a profound cytoskeletal remodeling of blast cells that led to Ca2+ influx, triggering apoptosis through mitochondrial depolarization, confirming that this latter phenomenon occurs selectively in t(6;11)AML, for which AF6 does not work as a cytoskeletal regulator, because it is sequestered into the nucleus by the fusion gene. We confirmed TDZ-mediated t(6;11)AML toxicity in vivo and enhanced the drug's safety by developing novel TDZ analogues that exerted the same effect on leukemia reduction, but with lowered neuroleptic effects in vivo. Overall, these results refine the MLL-AF6 AML leukemogenic mechanism and suggest that the benefits of targeting it be corroborated in further clinical trials.

Oxygen saturation to fraction of inspired oxygen ratio in preterm infants on routine parenteral nutrition with conventional or fish oil containing lipid emulsions.

INTRODUCTION: The benefits of intravenous (IV) fish oil (FO), as a source of n-3 long-chain polyunsaturated fatty acids, on lung growth in preterm infants, remain controversial. AIM: To evaluate if IV FO improves lung growth in small preterm infants on routine parenteral nutrition (PN). MATERIALS AND METHODS: We retrospectively reviewed prospectively collected data of preterm infants with a birth weight <1250 g who received routine PN from birth. We compared patients who received FO containing IV lipid emulsions with infants who received conventional emulsions (CNTR). The oxygen saturation (SpO2 ) to a fraction of inspired oxygen (FiO2 ) ratio (SFR) at 36 weeks (W) of gestation was chosen as the primary outcome variable to assess lung growth. RESULTS: Four hundred and seventy-seven infants were studied: 240 received IV FO and 237 CNTR. While exposure to antenatal glucocorticoids was higher in IV FO group than in CNTR (95 vs 90%, P = .04), there were no differences in birth data, enteral and parenteral nutrition intakes, ventilator supports and drug therapies. The incidence of the most common complications of prematurity at 36 W was not different (bronchopulmonary dysplasia was 27 vs 21% in IV FO vs CNTR infants, P = .1). Weight gain from birth to 36 W was marginally, but significantly, higher (+0.5 g/kg/d, P = .03) in IV FO group vs CNTR. SFR increased from 32 W to 36 W in all study patients (P < .001). IV FO infants had significantly lower SpO2 from 33 W to 35 W (P < .001) and lower (worse) SFR at 36 W (432 ± 57 vs 444 ± 51, P = .026) compared to CNTR. CONCLUSION: Contrary to our hypothesis, the use of FO containing IV lipid emulsions for the routine PN of the preterm infant did not improve lung growth compared to the infants who received conventional IV lipid emulsions.

Pre-surgery urine metabolomics may predict late neurodevelopmental outcome in children with congenital heart disease.

BACKGROUND: From fetal life until cardiac surgery, complex congenital heart diseases (CHD) exhibit different hemodynamic and oxygenation patterns that can lead to alteration of the metabolic profile. We used a metabolomic approach to identify urine metabolic markers before cardiac surgery, aiming to define the physiology of patients with complex CHD and to contribute to predict their neurodevelopmental outcome. METHODS: In a prospective, observational, single-center study we enrolled 28 patients with complex biventricular and univentricular CHD aged less than 5 years, on stable hemodynamic conditions, and with no genetic anomalies. We analyzed urine samples, collected at the induction of anesthesia, by 1H NMR spectroscopy. Profiles of 1H NMR spectra were submitted to unsupervised (principal component) and supervised (partial least squares-discriminant) multivariate analysis. Neurodevelopment was assessed by neuropsychological and adaptive functioning testing. RESULTS: Principal components analysis divided CHD patients metabolic profiles in two distinct clusters (RED and BLACK). Metabolic profiles belonging to the RED cluster showed higher levels of accumulation of citric acid cycle intermediates and glucose compared to the profiles in the BLACK cluster, indicating a possible switching to anaerobic metabolism. Patients belonging to the RED cluster were significantly more prone to show an adverse neurodevelopment pattern (p = 0.01). CONCLUSIONS: The application of metabolomic analysis to CHD children permitted a deeper insight on their metabolic status that could help to obtain a better understanding of the physiological implications and to predict long-term neurodevelopmental outcome.

Urinary metabolomics reveals kynurenine pathway perturbation in newborns with transposition of great arteries after surgical repair.

INTRODUCTION: Transposition of the great arteries (TGA) is a cyanotic congenital heart defect that requires surgical correction, with the use of cardiopulmonary-bypass (CPB), usually within 3 weeks of life. The use of CPB in open heart surgery results in brain hypoperfusion and in a powerful systemic inflammatory response and oxidative stress. OBJECTIVE: We aimed to develop a novel untargeted metabolomics approach to detect early postoperative changes in metabolic profile following neonatal cardiac surgery. METHODS: We studied 14 TGA newborns with intact ventricular septum undergoing arterial switch operation with the use of CPB. Urine samples were collected preoperatively and at the end of the surgery and were analyzed using an untargeted metabolomics approach based on UHPLC-high resolution mass spectrometry. RESULTS: Since post surgery metabolic spectra were heavily contaminated by metabolites derived from administered drugs, we constructed a list of drugs used during surgery and their related metabolites retrieved from urine samples. This library was applied to our samples and 1255 drugs and drug metabolites were excluded from the analysis. Afterward, we detected over 39,000 unique compounds and 371 putatively annotated metabolites were different between pre and post-surgery samples. Among these metabolites, 13 were correctly annotated or identified. Metabolites linked to kynurenine pathway of tryptophan degradation displayed the highest fold change. CONCLUSIONS: This is the first report on metabolic response to cardiac surgery in TGA newborns. We developed an experimental design that allowed the identification of perturbed metabolic pathways and potential biomarkers of brain damage, limiting drugs interference in the analysis.

Tracing exogenous surfactant in vivo in rabbits by the natural variation of 13C.

BACKGROUND: Respiratory Distress Syndrome (RDS) is a prematurity-related breathing disorder caused by a quantitative deficiency of pulmonary surfactant. Surfactant replacement therapy is effective for RDS newborns, although treatment failure has been reported. The aim of this study is to trace exogenous surfactant by 13C variation and estimate the amount reaching the lungs at different doses of the drug. METHODS: Forty-four surfactant-depleted rabbits were obtained by serial bronchoalveolar lavages (BALs), that were merged into a pool (BAL pool) for each animal. Rabbits were in nasal continuous positive airway pressure and treated with 0, 25, 50, 100 or 200 mg/kg of poractant alfa by InSurE. After 90 min, rabbits were depleted again and a new pool (BAL end experiment) was collected. Disaturated-phosphatidylcholine (DSPC) was measured by gas chromatography. DSPC-Palmitic acid (PA) 13C/12C was analyzed by isotope ratio mass spectrometry. One-way non-parametric ANOVA and post-hoc Dunn's multiple comparison were used to assess differences among experimental groups. RESULTS: Based on DSPC-PA 13C/12C in BAL pool and BAL end experiment, the estimated amount of exogenous surfactant ranged from 61 to 87% in dose-dependent way (p < 0.0001) in animals treated with 25 up to 200 mg/kg. Surfactant administration stimulated endogenous surfactant secretion. The percentage of drug recovered from lungs did not depend on the administered dose and accounted for 31% [24-40] of dose. CONCLUSIONS: We reported a risk-free method to trace exogenous surfactant in vivo. It could be a valuable tool for assessing, alongside the physiological response, the delivery efficiency of surfactant administration techniques.

Effects of Arachidonic and Docosohexahenoic Acid Supplementation during Gestation in Rats. Implication of Placental Oxidative Stress.

Arachidonic and docosahexaenoic acids (ARA and DHA) are important during pregnancy. However, the effects of dietary supplementation on fetal growth and oxidative stress are inconclusive. We aimed to assess the effect of high ARA and DHA diet during rat gestation on: (1) ARA and DHA availability in plasma and placenta, (2) fetal growth, and (3) placental oxidative stress, analyzing the influence of sex. Experimental diet (ED) was prepared by substituting soybean oil in the control diet (CD) by a fungi/algae-based oil containing ARA and DHA (2:1). Rats were fed with CD or ED during gestation; plasma, placenta, and fetuses were obtained at gestational day 20. DHA, ARA, and their precursors were analyzed in maternal plasma and placenta by gas chromatography/mass spectrophotometry. Fetuses and placentas were weighed, the proportion of fetuses with intrauterine growth restriction (IUGR) determined, and placental lipid and protein oxidation analyzed. ED fetuses exhibited lower body weight compared to CD, being >40% IUGR; fetal weight negatively correlated with maternal plasma ARA, but not DHA. Only ED female placenta exhibited higher lipid and protein oxidation compared to its CD counterparts; lipid peroxidation is negatively associated with fetal weight. In conclusion, high ARA during gestation associates with IUGR, through placental oxidative stress, with females being more susceptible.

Surfactant Components and Tracheal Aspirate Inflammatory Markers in Preterm Infants with Respiratory Distress Syndrome.

In 93 preterm infants ≤32 weeks of gestational age and 12 control infants, epithelial lining fluid disaturated-phosphatidylcholine, surfactant protein A and B, albumin, and myeloperoxidase activity were assessed after intubation and before exogenous surfactant administration. We found that disaturated-phosphatidylcholine, surfactant protein B, and myeloperoxidase were significantly higher in preterms with chorioamnionitis.

Cardiopulmonary-Bypass Glial Fibrillary Acidic Protein Correlates With Neurocognitive Skills.

BACKGROUND: Neurocognitive deficits at school starting age may affect as many as 50% of children who underwent cardiac surgery for complex congenital heart disease (CHD). The aim of this study was to identify which phases of cardiopulmonary bypass (CPB) are associated with an increased risk of impaired neurodevelopmental skills in children with complex CHD. This was assessed by means of glial fibrillary acidic protein (GFAP) plasma levels during CPB for CHD surgery, as a marker of neurologic insult. We correlated GFAP levels with clinical parameters and neurodevelopmental outcome. METHODS: We studied 45 children undergoing surgery for complex CHD. We measured plasma GFAP levels by enzyme-linked immunosorbent assay at the following steps: anesthesia induction, CPB start, end of hypothermia, end of rewarming, and end of CPB. Neurologic assessment and Vineland Adaptive Behavior Scales (VABS-I) were administered to patients at least 18 months after surgery. RESULTS: GFAP was undetectable before surgery and it peaked at the end of hypothermia or rewarming. Multiple regression analyses showed that GFAP peak level and preoperative neurologic comorbidity were significant independent predictors of neurologic impairment, as showed by VABS-I communication domain intelligence quotient (IQ). Receiver operating characteristic curve showed that the model was highly significant. CONCLUSIONS: Impaired neurodevelopment was associated with increase of GFAP plasma levels during cardiac surgery in infants. The identification of the neurologic high-risk phases of CPB run could support the application of new neuroprotective strategies for CHD repair.