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.

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.

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.

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.

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.

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.

Cerebral blood flow and morphological changes after hypoxic-ischaemic injury in preterm lambs.

AIM: To evaluate the effect of cerebral hypoxia-ischaemia induced by partial occlusion of the umbilical cord on the relationship of the regional cerebral blood flow and the cerebral cell death in near-term fetal lambs. METHODS: Fifteen near-term lambs were assigned to two hypoxic-ischaemic groups with or without life support (3 h), and a healthy one. Hypoxia-ischaemia was induced by partial occlusion of the umbilical cord (60 min). Routine light and electron microscopy, and the TUNEL method for apoptosis were performed. Regional cerebral blood flow was measured by coloured microspheres. Cardiovascular, gas exchange and pH parameters were also evaluated. RESULTS: Both hypoxic-ischaemic groups produced a transient acidosis and a decrease of base excess in comparison to the healthy group. Cortical and cerebellar zones, where the regional cerebral blood flow values were similar to baseline, showed an increased number of oligodendrocyte-like apoptotic cells. In contrast, in the inner zones, where regional cerebral blood flow was increased, the number of apoptotic cells did not increase. Necrotic neurons were observed in the basal nuclei, mesencephalon, pons and deep cerebellar nuclei. CONCLUSION: Our results suggest that regional cerebral blood flow and the presence of apoptotic cells, 3 h after hypoxic-ischemic injury, are correlated.