Adolf Valls-i-Soler

European consensus guidelines on the management of neonatal respiratory distress syndrome

Abstract Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the recommendations of a European panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is not clear if repeated courses are safe. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be life saving but can cause lung injury, and protocols should be directed to avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure. For babies with RDS to have the best outcome, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate blood pressure.

Hypoxic-ischemic injury in the immature brain--key vascular and cellular players.

Over the past decade, much has been learned about the cellular and molecular mechanisms underlying hypoxic-ischemic (H-I) injury in the preterm human brain. The pathogenesis of H-I brain injury is now understood to be multifactorial and quite complex, depending on (i) the severity, intensity and timing of asphyxia, (ii) selective ischemic vulnerability, (iii) the degree of maturity of the brain, and (iv) the characteristics of the ensuing reoxygenation/reperfusion phase. Each of these factors has differential effects on the distinct cell populations in the brain, with certain specific cell types being particularly vulnerable in the developing brain. In this review, we discuss the role of the blood vessels and the distinct cell populations, which are the mayor constitutive elements of the immature brain, in the pathophysiology of H-I lesion. The presence of fragile and poorly anastomosed blood vessels and the existence of disturbances in the blood-brain barrier alter blood flow, vascular tone and nutrient delivery. Brain cells are sensitive to the overstimulation of neurotransmitter receptors, particularly glutamate receptors, which can provoke excitotoxicity leading to the death of neurons and other cells such as astrocytes and oligodendrocyte progenitors. Microglial activation by means of excitatory amino acids and by leukocyte migration initiates the inflammatory response giving rise to an increase in regional cerebral blood flow and promoting astrocyte and oligodendrocyte injuries. A better understanding of these aspects of H-I injury will contribute to more efficient strategies for the management of the associated damage.

Educational strategy to reduce medication errors in a neonatal intensive care unit

Objective: We aimed to evaluate the effect of a comprehensive preventive educational strategy on the number and type of drug errors in the prescription process in a regional neonatal intensive care unit (NICU).

A European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)

Conducting clinical trials in the paediatric population is difficult for a host of reasons that include logistical, methodological, financial and ethical problems. Indeed for many paediatric conditions, their low prevalence means that multicentre studies performed on an international scale often represent the only possibility to gather a sufficient number of patients (ie, to obtain clinically and statistically valid results) over a reasonable period of time, especially for drug trials. However, such studies are difficult to conduct for several reasons including ethical issues such as assignment to placebo, lack of adequate paediatric methods to assess response to therapy, lack of adequate paediatric formulations, the need for specific study designs, inadequate funding as the consequence of the small potential market and limited funding for investigator led academic studies. In addition, there are several bureaucratic constraints related to ethics approval and clinical trial authorisation that often hinder investigator led academic sponsored clinical trials, which do not have the extensive logistical support normally provided by pharmaceutical companies.1 The overall result is that, until recently, evidence regarding the safety and effectiveness of available treatment regimens tended to be from small, open, uncontrolled trials or from anecdotal reports and non-randomised case series. From a logical and scientific point of view, one of the key issues to overcome these problems is to work with established clinical trials networks that have a wide international representation and a good scientific reputation. In this regard, the adoption of legislations to encourage paediatric clinical trials both in Europe and in the USA has opened a new era in the …

Acute and Sustained Effects of Lucinactant Versus Poractant-α on Pulmonary Gas Exchange and Mechanics in Premature Lambs With Respiratory Distress Syndrome

BACKGROUND. Animal-derived, protein-containing surfactants seem to be superior to protein-free surfactants. Lucinactant, a synthetic surfactant containing a surfactant protein-B peptide analog, has been shown to be effective in animal models and phase II clinical trials. To date, lucinactant has not been compared with an animal-derived surfactant in a premature animal model. OBJECTIVE. The objective was to compare the acute and sustained effects of lucinactant among premature lambs with respiratory distress syndrome (RDS) with the effects of a natural porcine surfactant (poractant-α). METHODS. After 5 minutes of mechanical ventilation twin premature lambs were assigned randomly to the lucinactant group (30 mg/mL, 5.8 mL/kg) or the poractant-α group (80 mg/mL, 2.2 mL/kg). Heart rate, systemic arterial pressure, arterial pH, blood gas values, and lung mechanics were recorded for 12 hours. RESULTS. Baseline fetal pH values were similar for the 2 groups (pH 7.27). After 5 minutes of mechanical ventilation, severe RDS developed (pH: <7.08; Paco2: >80 mm Hg; Pao2: <40 mm Hg; dynamic compliance: <0.08 mL/cm H2O per kg). After surfactant instillation, similar improvements in gas exchange and lung mechanics were observed for the lucinactant and poractant-α groups at 1 hour (pH: 7.3 ± 0.1 vs 7.4 ± 0.1; Paco2: 8 ± 18 mm Hg vs 40 ± 8 mm Hg; Pao2: 167 ± 52 mm Hg vs 259 ± 51 mm Hg; dynamic compliance: 0.3 ± 0.1 mL/cm H2O per kg vs 0.3 ± 0.1 mL/cm H2O per kg). The improvements in lung function were sustained, with no differences between groups. Cardiovascular profiles remained stable in both groups. CONCLUSIONS. Among preterm lambs with severe RDS, lucinactant produced improvements in gas exchange and lung mechanics similar to those observed with a porcine-derived surfactant.

Early cell death in the brain of fetal preterm lambs after hypoxic-ischemic injury.

The objective of the present study was to evaluate using premature fetal lambs the effect of cerebral hypoxia-ischemia induced by partial occlusion of the umbilical cord on the type of cell death which occurs in different brain regions and to ascertain some of the neural pathways which may underlie the associated pathologies. Lambs were sacrificed either immediately after a 1 h hypoxic-ischemic insult or 3 h later. Brains were fixed by perfusion and blocks of the different brain territories were processed for light microscopy (hematoxylin-eosin, Nissl staining), electron transmission microscopy and quantification of apoptosis by the TUNEL method. Other fixed brains were dissociated and labeled by nonyl acridine orange to determine mitochondrial integrity. Non-fixed brains were also used for membrane asymmetry studies, in which cell suspensions were analyzed by flow cytometry to quantify apoptosis. In both hypoxic-ischemic groups, necrotic-like neurons were observed mainly in the mesencephalon, pons, deep cerebellar nuclei and basal nuclei, whereas apoptotic cells were extensively found both in white and gray matter and were not limited to regions where necrotic neurons were present. The 3 h post-partial cord occlusion group, but not the 0 h group, showed a generalized alteration of cell membrane asymmetry and mitochondrial integrity as revealed by Annexin V/PI flow cytometry and nonyl acridine orange studies, respectively. Our results show that the apoptotic/necrotic patterns of cell death occurring early after hypoxic-ischemic injury are brain-region-specific and have distinct dynamics and suggest that therapeutic strategies aimed at rescuing cells from the effects of hypoxia/ischemia should be aimed at blocking the apoptotic components of brain damage.

A Randomized Comparison of Surfactant Dosing via a Dual-lumen Endotracheal Tube in Respiratory Distress Syndrome

Aim. To determine if 1-minute instillation of Curosurf via a dual-lumen endotracheal tube without interruption of mechanical ventilation could decrease the incidence of hypoxia (drop in oxygen saturation [Sao 2] to <80%, or of transcutaneous partial pressure of oxygen [Ptco 2] to <50 mm Hg [6.6 kPa]) and bradycardia (heart rate below 80 beats/minute) at dosing, without affecting the efficacy of the standard bolus delivery. Design. Prospective, multicenter, randomized, nonblinded clinical trial. Setting. Neonatal intensive care units of the Spanish Surfactant Collaborative Group. Patients and Methods. One hundred ninety-eight infants (birth weight 600–2000 g) with respiratory distress syndrome needing mechanical ventilation with a fraction of inspired oxygen [Fio 2] ≥0.40 were randomized before 24 hours to receive 200 mg/kg of Curosurf, either by bolus instillation (n = 99) or by a simplified dosing technique (n = 99), giving the full dose in 1 minute via a dual-lumen endotracheal tube without positioning, interruption of mechanical ventilation, or bagging. Two additional doses (100 mg/kg) were given within 12 and 24 hours of first dose, by the same method, if the infant still needed mechanical ventilation and had a Fio 2 ≥0.30. The effects of both procedures on the incidence of acute adverse events at dosing, gas exchange, ventilator requirements, and outcome at 28 days were compared. Results. Fewer episodes of hypoxia (18 vs 40% of doses), and a smaller decrease in heart rate and Sao 2were observed in the dual-lumen group. Efficacy of surfactant, based on improvement of oxygenation, ventilator requirements, and number of doses required, was similar in both groups. Infants in the dual-lumen group had a lower total time exposure to supplemental oxygen (195 ± 199 vs 266 ± 221 hours). No differences in the incidence of air leaks, intraventricular hemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia, or survival were observed. Conclusion. A simplified 1-minute Curosurf dosing procedure via a dual-lumen endotracheal tube without fractional doses, ventilator disconnection, changes in the infants position, or manual bagging was found to reduce the number of dosing-related adverse transient episodes of hypoxia. Although the simplified method appeared to be as effective as bolus delivery, this should be confirmed in a larger trial.

Medication errors in a neonatal intensive care unit. Influence of observation on the error rate

Aim: To study if medication error rate decreased as a consequence of a simple observation process of registering its occurrence.

A simplified surfactant dosing procedure in respiratory distress syndrome: the “side-hole” randomized study

Abstract The aim of this study was to compare the incidence of acute adverse events and long‐term outcome of two different surfactant dosing procedures in respiratory distress syndrome (RDS). The effects of two surfactant dosing procedures on the incidence of transient hypoxia and bradycardia, gas exchange, ventilatory requirements and 28 d outcome were compared. The patients, comprising 102 infants (birthweight 600–2000 g) with RDS on mechanical ventilation with FiO2 0.4, were randomized at 2–24 h to receive 200 mg kg‐1 of Curosurf® in 56 it was given by bolus delivery, and in 55 by a simplified technique (dose given in 1 min via a catheter introduced through a side‐hole in the tracheal tube adaptor. The babys position was not changed and ventilation was not interrupted). Two additional surfactant doses (100 mg kg‐1) were also given, by the same method, if ventilation with FiO2 0.3 was needed 12 and 24 h after the initial dose. The number of episodes of hypoxia and/or bradycardia was similar in both groups. A slight and transient increase in Paco2 was observed in the side‐hole group. The efficacy of the surfactant, based on oxygenation improvement, ventilator requirements, number of doses required and incidence of air leaks, was similar. No differences were observed in the incidence of intraventricular haemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia or survival. In conclusion, a simplified surfactant dosing procedure not requiring fractional doses, ventilator disconnection, changes in the babys position or manual bagging was found to be as effective as bolus delivery. The number of dosing‐related transient episodes of hypoxia and bradycardia was not decreased by the slow, 1 min, side‐hole instillation procedure.

The cardiovascular effects of partial liquid ventilation in newborn lambs after experimental meconium aspiration.

Objective To study the effects of partial liquid ventilation with perfluorocarbon on cardiovascular function, pulmonary gas exchange, and lung mechanics in term newborn lambs with pulmonary hypertension induced by tracheal instillation of human meconium. Design Prospective, randomized study. Setting Research Unit at a university-affiliated hospital. Subjects Twelve term newborn lambs (<6 days old). Interventions Lambs were studied in two groups (n = 6): meconium aspiration (3–5 ml/kg 20% meconium solution) managed on pressure-limited conventional mechanical ventilation with or without partial liquid ventilation with perfluorocarbon. Measurements and Main Results Heart rate, systemic and pulmonary arterial pressures, arterial pH and blood gases, cardiac output, and pulmonary mechanics were measured. Partial liquid ventilation in term newborn lambs with experimental meconium aspiration did not alter cardiovascular profile: heart rate, systemic arterial pressure, and cardiac output maintained initial values throughout the experiment. There was a significant improvement in gas exchange (oxygenation increased from values of <100 torr to 338 torr, and ventilation reached normal values in 15 mins). Dynamic compliance increased in 30 mins, reaching basal values (1.1 ± 0.3 ml/cm H2O per kg). Despite the good response (blood gases and cardiovascular profile) to partial liquid ventilation in meconium aspiration syndrome, pulmonary hypertension did not decrease. Conclusions Partial liquid ventilation with perfluorocarbon could be a good noninvasive alternative technique that improves gas exchange and pulmonary mechanics in meconium aspiration syndrome without impairing cardiovascular function.