Bundle formation of sperm: Influence of environmental factors.

Cooperative behaviour of sperm is one of the mechanisms that plays a role in sperm competition. It has been observed in several species that spermatozoa interact with each other to form agglomerates or bundles. In this study, we investigate the effect of physical and biochemical factors that will most likely promote bundle formation in bull sperm. These factors include fluid viscosity, swim-up process, post-thaw incubation time and media additives which promote capacitation. While viscosity does not seem to influence the degree of sperm bundling, swim-up, post-thaw migration time and suppressed capacitation increase the occurrence of sperm bundles. This leads to the conclusion that sperm bundling is a result of hydrodynamic and adhesive interactions between the cells which occurs frequently during prolonged incubation times.

Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1.

Chiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.

Hemodynamic and metabolic effects of a new pediatric dobutamine formulation in hypoxic newborn pigs.

BACKGROUND: The aim of our study was to measure drug-related changes in hemodynamics and oxygen metabolism in response to different doses of an age-appropriate dobutamine formulation in hypoxic pigs. A secondary aim was to validate superior vena cava flow (SVCF) as a marker of cardiac index (CI) for subsequent clinical trials of this formulation in humans. METHODS: Newborn pigs (n = 18) were exposed to 2-h hypoxia (10-15% oxygen) followed by reoxygenation (21-30% oxygen 4 h). After 1-h reoxygenation, pigs were randomized to: control group (no treatment), dobutamine infusion at a rate of 10-15 or 15-20 µg/kg/min. Dobutamine groups received two dobutamine doses during 30 min with a 60 min washout period between doses. Cardiovascular profile and oxygen metabolism were monitored. In four animals, an ultrasonic perivascular flow probe was placed around superior vena cava to measure SVCF. RESULTS: Hypoxia significantly decreased CI, systemic vascular resistance and mean arterial blood pressure (MABP). Dobutamine doses significantly increased heart-rate, CI, and oxygen-delivery without changes in stroke-volume and MABP. Only 10-15 µg/kg/min increased oxygen consumption and peripheral tissue oxygenation measured by Near-infrared spectroscopy. A positive correlation was observed between SVCF and CI. CONCLUSION: The new pediatric dobutamine formulation improved hemodynamic status, with dose-specific differences in metabolic response. SVCF may be a useful surrogate for CI in subsequent clinical trials.

Cerebral Effect of Intratracheal Aerosolized Surfactant Versus Bolus Therapy in Preterm Lambs.

OBJECTIVE: Aerosolization has been proposed as a useful alternative to rapid intratracheal instillation for the delivery of exogenous surfactant in neonatal respiratory distress syndrome. However, there is a lack of information regarding the likely safety of this new therapeutic approach for the neonatal brain. We aimed to compare the cerebral effects of aerosolized versus bolus surfactant administration in premature lambs with respiratory distress syndrome. DESIGN: Prospective randomized study. SETTING: BioCruces Institute Animal Research Facility. SUBJECTS: Fourteen intensively monitored and mechanically ventilated preterm lambs. INTERVENTIONS: Preterm lambs were randomly assigned to receive intratracheal aerosolized surfactant or bolus surfactant. Brain hemodynamics (cerebral and regional cerebral blood flow) and cerebral oxygen metabolism (cerebral oxygen delivery, cerebral metabolic rate of oxygen, and oxygen extraction fraction) were measured every 30 minutes for 6 hours. We also performed cerebral biochemical and histological analysis. MEASUREMENTS AND MAIN RESULTS: In preterm lambs with respiratory distress syndrome, cerebral blood flow, regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate of oxygen increased significantly in the bolus surfactant group during the first 5 minutes, without changes in cerebral oxygen extraction fraction. By 60 minutes, all parameters had decreased in both groups, cerebral blood flow and regional cerebral blood flow (in inner and cerebellum brainstem regions) remaining higher in the bolus surfactant than in the aerosolized surfactant group. Overall, the impact of aerosol surfactant was not significantly different to that of bolus surfactant in terms of cerebral necrosis, edema, inflammation, hemorrhage, infarct, apoptosis, or oxidative stress. CONCLUSIONS: In preterm lambs with severe respiratory distress syndrome, aerosol surfactant administration seems to be as safe as bolus administration, showing more stable cerebral hemodynamics and cerebral oxygen metabolism to the same dose of surfactant administered as a standard bolus.

Eficacia de la cafeína en la extubación de recién nacidos de menos de 32 semanas. Revisión sistemática y estudio observacional / Efficacy of caffeine in extubation of newborns under 32 weeks of age. Systematic revision and observational study

Introducción. En neonatos inmaduros que precisan intubación traqueal para recibir asistencia respiratoria o surfactante exógeno, la extubación puede no ser bien tolerada, siendo preciso reintubar. Objetivo. Evaluar la evidencia científica sobre 1) prevención y tratamiento de la apnea de la prematuridad, 2) prevención del fracaso de la extubación, y 3) registrar y valorar el uso del citrato de cafeína en una UCIN. Métodos. Se realizó una revisión sistemática de la literatura referente al uso del citrato de cafeína en la apnea de la prematuridad. Se realizó un registro de uso de la cafeína y su indicación específica, en la unidad neonatal de nuestro hospital. Resultados. El citrato de cafeína es eficaz y seguro tanto en la profilaxis y tratamiento de la apnea de la prematuridad, como para prevenir el fracaso de la extubación, reduciendo la necesidad de reintubación en un 50%, especialmente con dosis altas (15-20 mg/kg/día). En nuestra unidad, el 85% de los neonatos de menos de 32 sem recibieron tratamiento con cafeína, y en la mitad de casos fue para prevenir el fracaso de la extubación. Conclusiones. En todos los neonatos < 30 sem, y de forma individualizada entre las 30 y 32 sem, se recomienda el uso de citrato de cafeína desde 24 horas antes y durante los 6 días siguientes a la extubación; no siendo preciso determinar de modo sistemático sus niveles sanguíneos. Se recomienda también su uso tras la intubación precoz para administrar surfactante exógeno y extubar. Es aconsejable usar simultáneamente CPAP-n (AU)

Background. Immature neonates requiring tracheal intubation for ventilator support or to receive exogenous surfactant therapy, extubation may not be we1ltolerated been reintubation often required. Methods. A systematic literature review was performed concerning the use of caffeine citrate for prematurity apnea, and more specifically,for the prevention of extubation failure. Moreover, the use of caffeine in infants of less than 32 weeks and its specific indications in our hospital neonatal unit was registered. Results. The use of caffeine is safe and effective in the prophylaxis and treatment of apnea of prematurity, as well as to prevent the extubation failure, (50% reduction), especially if high doses are used (15-20 mg/kg/d). In addition, it is not necessary to routinely measure the blood levels. The simultaneous use of continuous positive airway pressure (CPAP-n) is also recommended. In our unit, 85% of all infants of less than 32 weeks were treated with caffeine citrate, half of them to prevent extubation failure. Conclusions. In all premature infants below 30 week of gestation, and in some between 30 and 32 weeks, the use of caffeine citrate from 24 hours before and for the 6 days following extubation is recommended. The systematic measurement of its blood levels is not required. It is also recommended the simultaneous use of CPAP-n in these infants and in those requiring surfactant to facility their early extubation (AU)

A Delphi process to optimize quality and performance of drug evaluation in neonates.

BACKGROUND: Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. METHODOLOGY AND MAIN FINDINGS: This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: "NICUs description-Level of care" (21), "Ability to perform drug trials: NICU organization and processes (15), "Research Experience" (12), "Scientific competencies and area of expertise" (8), "Quality Management" (16), "Training and educational capacity" (8) and "Public involvement" (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. CONCLUSION: A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. SUMMARY POINTS: 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings--"NICUs description-Level of care" (21), "Ability to perform drug trials: NICU organization and processes (15), "Research Experience" (12), "Scientific competencies and area of expertise" (8), "Quality Management" (16), "Training and educational capacity" (8) and "Public involvement" (6)--47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network.

In vitro surfactant and perfluorocarbon aerosol deposition in a neonatal physical model of the upper conducting airways.

OBJECTIVE: Aerosol delivery holds potential to release surfactant or perfluorocarbon (PFC) to the lungs of neonates with respiratory distress syndrome with minimal airway manipulation. Nevertheless, lung deposition in neonates tends to be very low due to extremely low lung volumes, narrow airways and high respiratory rates. In the present study, the feasibility of enhancing lung deposition by intracorporeal delivery of aerosols was investigated using a physical model of neonatal conducting airways. METHODS: The main characteristics of the surfactant and PFC aerosols produced by a nebulization system, including the distal air pressure and air flow rate, liquid flow rate and mass median aerodynamic diameter (MMAD), were measured at different driving pressures (4-7 bar). Then, a three-dimensional model of the upper conducting airways of a neonate was manufactured by rapid prototyping and a deposition study was conducted. RESULTS: The nebulization system produced relatively large amounts of aerosol ranging between 0.3±0.0 ml/min for surfactant at a driving pressure of 4 bar, and 2.0±0.1 ml/min for distilled water (H2Od) at 6 bar, with MMADs between 2.61±0.1 µm for PFD at 7 bar and 10.18±0.4 µm for FC-75 at 6 bar. The deposition study showed that for surfactant and H2Od aerosols, the highest percentage of the aerosolized mass (∼65%) was collected beyond the third generation of branching in the airway model. The use of this delivery system in combination with continuous positive airway pressure set at 5 cmH2O only increased total airway pressure by 1.59 cmH2O at the highest driving pressure (7 bar). CONCLUSION: This aerosol generating system has the potential to deliver relatively large amounts of surfactant and PFC beyond the third generation of branching in a neonatal airway model with minimal alteration of pre-set respiratory support.

Dobutamine in paediatric population: a systematic review in juvenile animal models.

OBJECTIVE: Although dobutamine is widely used in neonatal clinical practice, the evidence for its use in this specific population is not clear. We conducted a systematic review of the use of dobutamine in juvenile animals to determine whether the evidence from juvenile animal experiments with dobutamine supported the design of clinical trials in neonatal/paediatric population. METHODS: Studies were identified by searching MEDLINE (1946-2012) and EMBASE (1974-2012). Articles retrieved were independently reviewed by three authors and only those concerning efficacy and safety of the drug in juvenile animals were included. Only original articles published in English and Spanish were included. RESULTS: Following our literature search, 265 articles were retrieved and 24 studies were included in the review: 17 focused on neonatal models and 7 on young animal models. Although the aims and design of these studies, as well as the doses and ages analysed, were quite heterogeneous, the majority of authors agree that dobutamine infusion improves cardiac output in a dose dependent manner. Moreover, the cardiovascular effects of dobutamine are influenced by postnatal age, as well as by the dose used and the duration of the therapy. There is inadequate information about the effects of dobutamine on cerebral perfusion to draw conclusions. CONCLUSION: There is enough preclinical evidence to ensure that dobutamine improves cardiac output, however to better understand its effects in peripheral organs, such as the brain, more specific and well designed studies are required to provide additional data to support the design of clinical trials in a paediatric population.

Evaluation of fentanyl disposition and effects in newborn piglets as an experimental model for human neonates.

BACKGROUND: Fentanyl is widely used off-label in NICU. Our aim was to investigate its cerebral, cardiovascular and pulmonary effects as well as pharmacokinetics in an experimental model for neonates. METHODS: Fentanyl (5 µg/kg bolus immediately followed by a 90 minute infusion of 3 µg/kg/h) was administered to six mechanically ventilated newborn piglets. Cardiovascular, ventilation, pulmonary and oxygenation indexes as well as brain activity were monitored from T = 0 up to the end of experiments (T = 225-300 min). Also plasma samples for quantification of fentanyl were drawn. RESULTS: A "reliable degree of sedation" was observed up to T = 210-240 min, consistent with the selected dosing regimen and the observed fentanyl plasma levels. Unlike cardiovascular parameters, which were unmodified except for an increasing trend in heart rate, some of the ventilation and oxygenation indexes as well as brain activity were significantly altered. The pulmonary and brain effects of fentanyl were mostly recovered from T = 210 min to the end of experiment. CONCLUSION: The newborn piglet was shown to be a suitable experimental model for studying fentanyl disposition as well as respiratory and cardiovascular effects in human neonates. Therefore, it could be extremely useful for further investigating the drug behaviour under pathophysiological conditions.

The role of coagulase-negative staphylococci in early onset sepsis in a large European cohort of very low birth weight infants.

BACKGROUND: Early Onset Sepsis (EOS) is associated with increased major morbidity and mortality rates among very low birth weight (VLBW) infants. The epidemiology is changing in response to evolving medical practice. The objective of the study was to evaluate EOS epidemiology, risk factors, mortality and major morbidity rates among VLBW infants within a European cohort. METHODS: Data from VLBW infants born from 2006 through 2009 was collected by neonatal units participating in the EuroNeoNet initiative. Univariate and multivariate analyses were performed to assess the independent association of EOS with VLBW infant's perinatal characteristics, morbidity and mortality rates. RESULTS: The cohort included 14,719 infants, 391 developed EOS (2.7%). The most common pathogen responsible for EOS was Gram-positive bacteria (53.9%). Coagulase-negative staphylococci (CoNS) were isolated in 22.5% of episodes. Antenatal steroids exposure, single gestation, very low gestational age and birth weight, low 5 minute Apgar score and delivery room resuscitation were independently associated with EOS. EOS was also associated with a longer hospital stay, increased risk of mortality [adjusted odd ratio (aOR): 2.4; 95% Confidence Interval (CI): 1.9-3.1], respiratory distress syndrome (OR: 1.4; 95% CI: 1.1-1.9), severe intraventricular haemorrhage (aOR: 2.1; 95%CI: 1.6-2.8) and severe retinopathy of prematurity (aOR: 5; 95% CI: 1.9-13.3). Morbidity and mortality rates of infants with EOS caused by CoNS were similar to those of infants with EOS caused by other pathogens. CONCLUSIONS: VLBW infants with EOS are at an increased risk of mortality and major morbidities. CoNS was a significant cause of sepsis, infants with CoNS were at a similarly high risk of complication of prematurity and mortality as those with EOS caused by other organisms.

Errores en la preparación de fármacos intravenosos en una Unidad de Cuidados Intensivos Neonatal. Una potencial fuente de eventos adversos / Intravenous drug preparation errors in a Neonatal Intensive Care Unit. A potential source of adverse events

Introducción: El objetivo del estudio fue determinar la tasa de errores en la preparación de fármacos de administración intravenosa en una Unidad de Cuidados Intensivos Neonatal (UCIN). Pacientes y métodos: Se realizó un estudio prospectivo observacional, durante 24 días elegidos al azar. Se determinaron las concentraciones de vancomicina y tobramicina preparadas para uso intravenoso. Se definieron 2 tipos de errores: 1) error de cálculo, cuando la desviación entre la dosis prescrita por el médico y la dosis teórica administrada, según los cálculos realizados por la enfermera, era superior a un ±10%, y 2) error de precisión, cuando la desviación entre la concentración teórica y la determinada por el laboratorio era superior a un ±10%. Resultados: Se recogieron un total de 91 muestras, 52 de vancomicina y 39 de tobramicina. En un 4,6% de las muestras se detectaron errores de cálculo. La tasa de errores de precisión fue del 37,9%. Conclusiones: Aunque los errores registrados no produjeron consecuencias clínicas negativas evidentes, nuestros resultados señalan una fuente potencial de complicaciones severas. Por ello, deben mejorarse los métodos usados para la preparación de medicamentos de uso intravenoso a pie de cama (AU)

Introduction: To determine the rate of errors during preparation of intravenous drugs in a regional Neonatal Intensive Care Unit (NICU). Methods: A prospective observational study was performed on 24 non-consecutive working days. The vancomycin and tobramycin solutions administered were analysed to determine drug concentrations. We defined 2 types of error: 1) calculation error, when the deviation between the dose prescribed by the physician and theoretical dose administered, according to calculations performed by the nurse, was greater than ±10%, and 2) precision error, when the deviation between the theoretical concentration and that determined by the laboratory was greater than ±10%. Results: A total of 91 samples were collected, 52 of vancomycin and 39 of tobramycin. Calculation errors were detected in 4.6% of samples. Precision errors were identified in 37.9% of the total sample. Conclusions: Although the errors reported did not produce adverse clinical consequences, our findings point out a potential source of severe complications. Better methods in the preparation of intravenous medications in NICU are needed (AU)

Acute and sustained effects of aerosolized vs. bolus surfactant therapy in premature lambs with respiratory distress syndrome.

BACKGROUND: Surfactant (SF) instillation may produce acute deleterious effects on gas exchange and both systemic and cerebral hemodynamics. Our aim was to compare the effects of aerosolized SF (SF-aero) with those of bolus SF (SF-bolus) administration on gas exchange, lung mechanics, and cardiovascular function in premature lambs with respiratory distress syndrome (RDS). METHODS: Fourteen preterm lambs (85% gestation) were randomly assigned to receive SF-aero or SF-bolus. Oxygenation index (OI), PaCO2, cardiovascular parameters, carotid blood flow (CBF), lung compliance (mean dynamic compliance), and tidal volume (VT) were measured every 30 min for 6 h. Biochemical and histological analyses were performed. RESULTS: After delivery, lambs developed severe RDS (inspiratory fraction of oxygen: 1; pH < 7.15; PaCO2 > 80 mm Hg; PaO2 < 30 mm Hg, mean dynamic compliance < 0.08 ml/cm H2O/kg). By 60 min after treatment, both groups showed an improvement in OI, PaCO2, mean dynamic compliance, and VT that was maintained until the end of the experiment. PaCO2 and CBF increased significantly in the SF-bolus group during the first 15-30 min, without concomitant changes in cardiovascular parameters, whereas in the SF-aero group, PaCO2 and CBF decreased gradually. SF-aero induced less alveolar hemorrhage and inflammation. CONCLUSION: SF-aero produced improvements in gas exchange and lung mechanics similar to those produced by bolus administration but with less lung injury and fewer cerebral hemodynamic changes.

Effect of surfactant and partial liquid ventilation treatment on gas exchange and lung mechanics in immature lambs: influence of gestational age.

OBJECTIVES: Surfactant (SF) and partial liquid ventilation (PLV) improve gas exchange and lung mechanics in neonatal RDS. However, variations in the effects of SF and PLV with degree of lung immaturity have not been thoroughly explored. SETTING: Experimental Neonatal Respiratory Physiology Research Unit, Cruces University Hospital. DESIGN: Prospective, randomized study using sealed envelopes. SUBJECTS: 36 preterm lambs were exposed (at 125 or 133-days of gestational age) by laparotomy and intubated. Catheters were placed in the jugular vein and carotid artery. INTERVENTIONS: All the lambs were assigned to one of three subgroups given: 20 mL/Kg perfluorocarbon and managed with partial liquid ventilation (PLV), surfactant (Curosurf®, 200 mg/kg) or (3) no pulmonary treatment (Controls) for 3 h. MEASUREMENTS AND MAIN RESULTS: Cardiovascular parameters, blood gases and pulmonary mechanics were measured. In 125-day gestation lambs, SF treatment partially improved gas exchange and lung mechanics, while PLV produced significant rapid improvements in these parameters. In 133-day lambs, treatments with SF or PLV achieved similarly good responses. Neither surfactant nor PLV significantly affected the cardiovascular parameters. CONCLUSION: SF therapy response was more effective in the older gestational age group whereas the effectiveness of PLV therapy was not gestational age dependent.

[Intravenous drug preparation errors in a Neonatal Intensive Care Unit. A potential source of adverse events]. / Errores en la preparación de fármacos intravenosos en una Unidad de Cuidados Intensivos Neonatal. Una potencial fuente de eventos adversos.

INTRODUCTION: To determine the rate of errors during preparation of intravenous drugs in a regional Neonatal Intensive Care Unit (NICU). METHODS: A prospective observational study was performed on 24 non-consecutive working days. The vancomycin and tobramycin solutions administered were analysed to determine drug concentrations. We defined 2 types of error: 1) calculation error, when the deviation between the dose prescribed by the physician and theoretical dose administered, according to calculations performed by the nurse, was greater than ±10%, and 2) precision error, when the deviation between the theoretical concentration and that determined by the laboratory was greater than ±10%. RESULTS: A total of 91 samples were collected, 52 of vancomycin and 39 of tobramycin. Calculation errors were detected in 4.6% of samples. Precision errors were identified in 37.9% of the total sample. CONCLUSIONS: Although the errors reported did not produce adverse clinical consequences, our findings point out a potential source of severe complications. Better methods in the preparation of intravenous medications in NICU are needed.

Valoración del daño cerebral tras la administración de surfactante / Brain damage assesment after surfactant administration

Objetivo: La terapia de reemplazo de surfactante se asocia frecuentemente a fluctuaciones del flujo sanguíneo cerebral (FSC). Presentamos la administración de surfactante nebulizado para evitar las fluctuaciones del FSC. Métodos: El estudio se llevó a cabo en muestras cerebrales (congeladas y fijadas) de corderos prematuros que recibieron surfactante instilado (SFinstil, administración clásica) o surfactante nebulizado (SFneb). Se analizaron el FSC regional, la actividad de las enzimas antioxidantes, el Factor de Necrosis Tumoral (TNFα) y el número de células apoptóticas (TUNEL). También se realizó una valoración semi-cuantitativa del daño cerebral por un anátomo- patólogo. Se analizaron zonas corticales (corteza frontal y occipital), zonas internas (tálamo, estriado e hipocampo), el cerebelo y el bulbo cefalorraquídeo. Resultados: La administración de surfactante nebulizado produjo una respuesta hemodinámica cerebral diferente a la instilación intratraqueal, especialmente en las zonas internas donde a los cinco minutos el FSC registrado resultó ser significativamente superior en el grupo SFinstil. No se registraron diferencias significativas en la actividad de las enzimas antioxidantes. El porcentaje de células positivas para TNFα y el número de células TUNEL positivas en las zonas internas fue significativamente superior en el grupo SFinstil (p<0.05). La valoración histológica determinó un mayor grado de necrosis neuronal (p<0.05) en el tálamo en el grupo SFinstil. Conclusión: La administración de surfactante en forma de aerosol debería tenerse en cuenta como una alternativa menos agresiva a la instilación intratraqueal (AU)

Objective: Surfactant replacement therapy has been associated with cerebral blood flow (CBF) fluctuations. We propose the administration of aerosolized surfactant to prevent those fluctuations. Methods: Brain samples (frozen and paraffin-fixed) of preterm lambs received instilled surfactant (SFinstil, common administration) or aerosolized surfactant (SFneb). Regional CBF, the activity of antioxidant enzymes, the number of TNFα positive cells and the number of apoptotic cells (TUNEL) were determined. In addition, a semi-quantitative histological evaluation was performed by an expert pathologist. Cortical zones (frontal and occipital), inner zones (thalamus, striatum and hippocampus), cerebellum and the brain stem were analyzed. Results: Surfactant delivered as an aerosol produced a different cerebral hemodynamic response than surfactant instillation, especially towards the inner zones, where already five minutes after the start of the therapy the regional CBF was significantly higher in the SFinstil group. There were no differences between groups in the activity of antioxidant enzymes. The percentage of TNFα positive cells and the number of TUNEL positive cells in the inner zones was significantly higher in the SFinstil group. The histological score also showed a significantly higher necrosis in the SFinstil group compared to the SFneb group. Conclusion: Surfactant delivered as an aerosol should be considered as a less harmful method of surfactant administration (AU)

Mortalidad y morbilidad de neonatos de muy bajo peso asistidos en el País Vasco y Navarra (2001-2006): estudio de base poblacional / Mortality and morbidity in very low birth weight infants in the Basque Country and Navarra (2001-2006): population-based study

Introducción: Este estudio describe la morbilidad y mortalidad de los recién nacidos de muy bajo peso (RNMBP) asistidos en las unidades neonatales del País Vasco y Navarra entre los años 2001-2006, y evalúa los factores que afectan a la mortalidad. Pacientes y métodos: Estudio descriptivo observacional de una cohorte de 1.318 RNMBP asistidos entre el año 2001 y 2006 en cinco hospitales del País Vasco y Navarra. Se recogieron un total de 37 variables incluidas en la base de datos de EuroNeoNet, que se refieren a factores perinatales de riesgo y protectores, características demográficas, días de ingreso, intervenciones, morbilidades y mortalidad. Resultados: Un 94% de las mujeres embarazadas recibieron cuidados prenatales y un 78,7% administración de esteroides prenatales, en ambos casos hubo un aumento significativo durante el periodo estudiado. El 42% de los embarazos fueron múltiples y en un 63% el parto fue por cesárea. La displasia broncopulmonar disminuyó de manera estadísticamente significativa de un 20 a un 15%. La incidencia de hemorragia intraventricular de grado III o IV fue de 7,5% y de leucomalacia periventricular de un 3,1%. Se diagnosticó infección vertical en un 4% de niños y sepsis o meningitis tardía en 25%, enterocolitis necrotizante en 9% y persistencia del conducto arterioso en el 14% de los niños. El tratamiento con indometacina o ibuprofeno disminuyó significativamente durante el estudio. La tasa bruta de mortalidad neonatal total, tardía y precoz se ha mantenido constante en este periodo de tiempo. La mortalidad neonatal inmediata mostró una tendencia descendente y una diferencia significativa por sexo, siendo esta mayor en los varones. Conclusión: Este estudio de base poblacional aporta información valiosa sobre variables resultado en UCIN y puede ayudar en el planteamiento de intervenciones que mejoren la calidad asistencial y disminuyan la morbilidad y mortalidad en estos neonatos de alto riesgo(AU)

Introduction: This study describes very low birth weight (VLBW) infant morbidity and mortality in Basque Country and Navarra neonatal units between the years 2001-2006, and evaluates the factors that affect the mortality. Patients and methods: A descriptive observational study of a cohort of 1,318 VLBW infants in neonatal units in five Basque Country and Navarra hospitals between 2001 and 2006. A total of 37 variables included in EuroNeoNet database were collected as regards, perinatal risk and protective factors, demographic characteristics, length of stay, interventions, morbidity and mortality. Results: A total of 94% of pregnant women received prenatal care and 78.7% antenatal steroids. In both cases there was a significant increase during the period studied. A total of 42% of pregnancies were multiple and in 63% delivery was by Caesarean section. Bronchopulmonary dysplasia statistically significantly decreased from 20% to 15%. The incidence of intraventricular haemorrhage grade III or IV was 7.5% and for periventricular leukomalacia it was 3.1%. Vertical infection was diagnosed in 4% of infants and sepsis or late meningitis in 25%, necrotizing enterocolitis in 9% and patent ductus arteriosus in 14% of the infants. The prophylactic or therapeutic treatment with indometacin or ibuprofen decreased significantly during the study. The overall rate of total, late and first day neonatal mortality was almost constant during this period of time. Nevertheless, the early neonatal mortality showed a decreasing trend and with a significant difference between sexes, being higher in males. Conclusion: This population-based study provides valuable information on clinical outcomes in NICUs, and may help in planning strategies to improve health care quality, and to reduce the morbidity and mortality in these neonates at high risk(AU)

Aerosolized perfluorocarbon improves gas exchange and pulmonary mechanics in preterm lambs with severe respiratory distress syndrome.

BACKGROUND: Aerosolized perfluorocarbon (PFC) has been proposed as an alternative method of PFC administration; however, the efficacy of aerosolized PFC in a preterm animal model has not yet been demonstrated. METHODS: Twelve preterm lambs were randomized to two groups: a perfluorodecalin (PFD) aerosol group (n = 6) receiving 10 ml/kg/h of PFD delivered by an intratracheal inhalation catheter followed by 4 h of mechanical ventilation (MV) or the control group, in which animals (n = 6) were managed for 6 h with MV. Gas exchange, pulmonary mechanics, cardiovascular parameters, and cerebral blood flow (CBF) were measured. RESULTS: Both groups developed hypoxia, hypercarbia, and acidosis at baseline. Aerosolized PFD improved oxygenation (P < 0.0001) and pulmonary mechanics (P < 0.0001) and changed carbon dioxide values to normal physiological levels, unlike the treatment given to the controls (P < 0.0003). The time course of mean arterial blood pressure and CBF were significantly affected by PFD aerosolization, especially during the first hour of life. CBF gradually decreased during the first hour in the PFD aerosol group and remained stable until the end of the follow-up, whereas CBF remained higher in the control group (P < 0.0028). CONCLUSION: Aerosolized PFD improves pulmonary function in preterm lambs and should be further investigated as an alternative mode of PFC administration.

[Mortality and morbidity in very low birth weight infants in the Basque Country and Navarra (2001-2006): population-based study]. / Mortalidad y morbilidad de neonatos de muy bajo peso asistidos en el País Vasco y Navarra (2001-2006): estudio de base poblacional.

INTRODUCTION: This study describes very low birth weight (VLBW) infant morbidity and mortality in Basque Country and Navarra neonatal units between the years 2001-2006, and evaluates the factors that affect the mortality. PATIENTS AND METHODS: A descriptive observational study of a cohort of 1,318 VLBW infants in neonatal units in five Basque Country and Navarra hospitals between 2001 and 2006. A total of 37 variables included in EuroNeoNet database were collected as regards, perinatal risk and protective factors, demographic characteristics, length of stay, interventions, morbidity and mortality. RESULTS: A total of 94% of pregnant women received prenatal care and 78.7% antenatal steroids. In both cases there was a significant increase during the period studied. A total of 42% of pregnancies were multiple and in 63% delivery was by Caesarean section. Bronchopulmonary dysplasia statistically significantly decreased from 20% to 15%. The incidence of intraventricular haemorrhage grade III or IV was 7.5% and for periventricular leukomalacia it was 3.1%. Vertical infection was diagnosed in 4% of infants and sepsis or late meningitis in 25%, necrotizing enterocolitis in 9% and patent ductus arteriosus in 14% of the infants. The prophylactic or therapeutic treatment with indometacin or ibuprofen decreased significantly during the study. The overall rate of total, late and first day neonatal mortality was almost constant during this period of time. Nevertheless, the early neonatal mortality showed a decreasing trend and with a significant difference between sexes, being higher in males. CONCLUSION: This population-based study provides valuable information on clinical outcomes in NICUs, and may help in planning strategies to improve health care quality, and to reduce the morbidity and mortality in these neonates at high risk.

Comparative effects of bronchoalveolar lavage with saline, surfactant, or perfluorocarbon in experimental meconium aspiration syndrome.

OBJECTIVE: Today, in meconium aspiration syndrome, treatment focuses on bronchoalveolar lavage, because it removes meconium and proinflammatory factors from airways. This technique might be more effective if different solutions were used such as saline solution, a protein-free surfactant, or a perfluorocarbon, because these would be less inhibited by meconium proteins. SETTING: Pulmonary physiology research unit, Cruces Hospital. DESIGN: Prospective, randomized study. SUBJECTS: We studied 24 lambs (<6 days) on mechanical ventilation for 180 mins. Catheters were placed and femoral and pulmonary arteries pressures registered (systemic and pulmonary arterial pressures). INTERVENTIONS: Lambs were instilled with 20% meconium (3-5 mL/Kg) and were randomly assigned to one of the following groups (n = 6): control: only continuous mechanical ventilation; saline bronchoalveolar lavage: bronchoalveolar lavage with 30 mL/kg of saline solution; dilute surfactant bronchoalveolar lavage: bronchoalveolar lavage with 32 mL/kg of diluted surfactant (lucinactant, 10 mg/mL); or perfluorocarbon bronchoalveolar lavage: bronchoalveolar lavage with 30 mL/kg of perfluorocarbon. MEASUREMENTS AND MAIN RESULTS: Blood gases, cardiovascular parameters, and pulmonary mechanics were assessed. Meconium instillation produced severe hypoxia, hypercapnia, acidosis, and pulmonary hypertension with impairment of pulmonary mechanics (p < .05). Lung lavage with dilute surfactant resulted in the resolution of pulmonary hypertension as well as better gas exchange and pulmonary mechanics than the control group (p < .05). Bronchoalveolar lavage with perfluorocarbon produced a transient improvement in gas exchange and ventilatory indices in comparison with control and saline bronchoalveolar lavage groups. CONCLUSIONS: In lambs with meconium aspiration syndrome, bronchoalveolar lavage with diluted lucinactant is an effective therapy producing significant improvements in gas exchange, pulmonary hypertension, and pulmonary mechanics. In addition, bronchoalveolar lavage with perfluorocarbon appears to confer some advantages over lavage with equal volumes of saline or no lavage.