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 2h-hypoxia (10-15% oxygen) followed by reoxygenation (21-30% oxygen 4h). After 1h-reoxygenation, pigs were randomized to: control group (no treatment), dobutamine infusion at a rate of 10-15μg/kg/min or 15-20μg/kg/min. Dobutamine groups received two dobutamine doses during 30min with a 60min 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-bloodpressure (MABP). Dobutamine doses significantly increased heart-rate, CI and oxygen-delivery without changes in stroke-volume and MABP. Only 10-15μg/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

Surfactant Nebulization Therapy During NIPPV Ventilation in Surfactant-Deficient Newborn Piglets

Background In recent years, nasal intermittent positive pressure ventilation (NIPPV) has been growing in popularity as a form of noninvasive ventilation for respiratory support in the initial treatment of neonates with surfactant (SF) deficiency. The combination of this type of ventilation with noninvasive SF administration (by nebulization) is an attractive treatment option for respiratory distress syndrome (RDS)-associated pathophysiology of the neonatal lungs. In this study, we aimed to test the tolerability and efficacy of SF nebulization during NIPPV for the treatment of neonatal RDS. Methods Spontaneously-breathing newborn piglets (n = 6/group) with bronchoalveolar lavage (BAL)-induced RDS were assigned to receive during NIPPV (180 min): poractant alfa (400 mg/kg) via an investigational customized vibrating-membrane nebulizer (eFlow-Neos) or poractant alfa (200 mg/kg) as a bolus using the Insure method or no surfactant (controls). Measurement and results We assessed pulmonary, hemodynamic and cerebral effects and performed histological analysis of lung and brain tissue. After repeated BAL, newborn piglets developed severe RDS (FiO2: 1, pH  70 mmHg, PaO2< 70 mmHg, Cdyn < 0.5 ml/cmH2O/kg). In both SF-treated groups, we observed rapid improvement in pulmonary status and also similar hemodynamic, cerebral behavior, and lung and brain injury scores. Conclusion Our results in newborn piglets with severe BAL-induced RDS show the administration of nebulized poractant alfa using the eFlow-Neos nebulizer during NIPPV to be well tolerated and efficacious, suggesting that this noninvasive SF administration option should be explored further.Drs. Rey-Santano, Mielgo, and Gomez-Solaetxe's institutions received funding from Chiesi Farmaceutici and Carlos III Health Institute (PI18/00166) (co-funded by ERDF/ESF, "Investing in your future") and GIU19/026 (University of the Basque Country Research Group

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

The most recent approaches to the initial treatment of respiratory distress syndrome (RDS)- involve non-invasive ventilation (NIV) and less-invasive surfactant (SF) administration (LISA). Combining these techniques has been proven a useful treatment option for SF-defi- cient neonates. The objective of this study was to explore the impact on the brain (using cerebral near infrared spectroscopy, NIRS) of different LISA methods during NIV, using nasal intermittent positive pressure ventilation (NIPPV) for treating neonatal RDS. For this, we used five groups of spontaneously breathing newborn piglets (n = 6/group) with bronch- oalveolar lavage (BAL)-induced respiratory distress which received NIPPV only (controls), poractant-alfa using the INSURE-like method (bolus delivery) followed by NIPPV, or porac- tant-alfa using one of three LISA devices, 1) a nasogastric tube (NT), 2) a vascular catheter (VC) or 3) the LISAcath® catheter. We assessed pulmonary, hemodynamic and cerebral effects, and performed histological analysis of lung and brain tissue. Following BALs, the piglets developed severe RDS (pH70 mmHg, PaO2<70 mmHg, dynamic com- pliance<0.5 ml/cmH2O/kg at FiO2 = 1). Poractant-alfa administration using different LISA techniques during NIPPV was well tolerated and efficacious in newborn piglets. In our study, although all groups showed normal physiological ranges of total lung injury score and bio- chemical lung analysis, VC and LISAcath® catheters were associated with better values of lung compliance and lower values of lung damage than NIPPV, NT or INSURE-like meth- ods. Moreover, neither of the SF administration methods used (LISA or INSURE-like) had a significant impact on the histological neonatal brain injury score. Of note, the LISAcath® has been recently withdrawn from the market.Drs. Rey-Santano, Mielgo, and Gomez- Solaetxe’s institutions received funding from Chiesi Farmaceutici (Number 10391902) and the Carlos III Health Institute (PI18/00166) (co-financed by the European Regional Development Fund “A way to make Europe”) and GIU19/026 (University of the Basque Country Research Group). Fabrizio Salomone and Francesca Ricci disclose that they are Chiesi employees. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Addition of terlipressin to initial volume resuscitation in a pediatric model of hemorrhagic shock improves hemodynamics and cerebral perfusion

Hemorrhagic shock is one of the leading causes of mortality and morbidity in pediatric trauma. Current treatment based on volume resuscitation is associated to adverse effects, and it has been proposed that vasopressors may be used in the pharmacological management of trauma. Terlipressin has demonstrated its usefulness in other pediatric critical care scenarios and its long half-life allows its use as a bolus in an outpatient critical settings. The aim of this study was to analyze whether the addition of a dose of terlipressin to the initial volume expansion produces an improvement in hemodynamic and cerebral perfusion at early stages of hemorrhagic shock in an infant animal model. We conducted an experimental randomized animal study with 1-month old pigs. After 30 minutes of hypotension (mean arterial blood pressure [MAP]<45 mmHg) induced by the withdrawal of blood over 30 min, animals were randomized to receive either normal saline (NS) 30 mL/kg (n = 8) or a bolus of 20 mcg/kg of terlipressin plus 30 mL/kg of normal saline (TP) (n = 8). Global hemodynamic and cerebral monitoring parameters, brain damage markers and histology samples were compared. After controlled bleeding, significant decreases were observed in MAP, cardiac index (CI), central venous pressure, global end-diastolic volume index (GEDI), left cardiac output index, SvO(2), intracranial pressure, carotid blood flow, bispectral index (BIS), cerebral perfusion pressure (CPP) and increases in systemic vascular resistance index, heart rate and lactate. After treatment, MAP, GEDI, CI, CPP and BIS remained significantly higher in the TP group. The addition of a dose of terlipressin to initial fluid resuscitation was associated with hemodynamic improvement, intracranial pressure maintenance and better cerebral perfusion, which would mean protection from ischemic injury. Brain monitoring through BIS was able to detect changes caused by hemorrhagic shock and treatment.This work was partially supported by Basque Government Grant (GIU19/026) to VEM and Spanish Society of pediatric critical care (Ruza Grant 2017) to JG

Early Cerebral Hemodynamic, Metabolic, and Histological Changes in Hypoxic–Ischemic Fetal Lambs during Postnatal Life

The hemodynamic, metabolic, and biochemical changes produced during the transition from fetal to neonatal life may be aggravated if an episode of asphyxia occurs during fetal life. The aim of the study was to examine regional cerebral blood flow (RCBF), histological changes, and cerebral brain metabolism in preterm lambs, and to analyze the role of oxidative stress in the first hours of postnatal life following severe fetal asphyxia. Eighteen chronically instrumented newborn lambs were randomly assigned to either a control group or the hypoxic–ischemic (HI) group, in which case fetal asphyxia was induced just before delivery. All the animals were maintained on intermittent positive pressure ventilation for 3 h after delivery. During the HI insult, the injured group developed acidosis, hypoxia, hypercapnia, lactic acidosis, and tachycardia (relative to the control group), without hypotension. The intermittent positive pressure ventilation transiently improved gas exchange and cardiovascular parameters. After HI injury and during ventilatory support, there continued to be an increased RCBF in inner regions among the HI group, but no significant differences were detected in cortical flow compared to the control group. Also, the magnitude of the increase in TUNEL positive cells (apoptosis) and antioxidant enzymes, and decrease of ATP reserves was significantly greater in the brain regions where the RCBF was not higher. In conclusion, our findings identify early metabolic, histological, and hemodynamic changes involved in brain damage in premature asphyxiated lambs. Such changes have been described in human neonates, so our model could be useful to test the safety and the effectiveness of different neuroprotective or ventilation strategies applied in the first hours after fetal HI injury

Experimental and Numerical Modeling of Aerosol Delivery for Preterm Infants

Respiratory distress syndrome (RDS) represents one of the major causes of mortality among preterm infants, and the best approach to treat it is an open research issue. The use of perfluorocarbons (PFC) along with non-invasive respiratory support techniques has proven the usefulness of PFC as a complementary substance to achieve a more homogeneous surfactant distribution. The aim of this work was to study the inhaled particles generated by means of an intracorporeal inhalation catheter, evaluating the size and mass distribution of different PFC aerosols. In this article, we discuss different experiments with the PFC perfluorodecalin (PFD) and FC75 with a driving pressure of 4-5 bar, evaluating properties such as the aerodynamic diameter (Da), since its value is directly linked to particle deposition in the lung. Furthermore, we develop a numerical model with computational fluid dynamics (CFD) techniques. The computational results showed an accurate prediction of the airflow axial velocity at different downstream positions when compared with the data gathered from the real experiments. The numerical validation of the cumulative mass distribution for PFD particles also confirmed a closer match with the experimental data measured at the optimal distance of 60 mm from the catheter tip. In the case of FC75, the cumulative mass fraction for particles above 10 mu m was considerable higher with a driving pressure of 5 bar. These numerical models could be a helpful tool to assist parametric studies of new non-invasive devices for the treatment of RDS in preterm infants.Consolidated Groups from the Basque Government supported this work. Technical and human support provided by IZO-SGI, SGIker (UPV/EHU) is gratefully acknowledged

Experimental Evaluation of Perfluorocarbon Aerosol Generation with Two Novel Nebulizer Prototypes

The potential of non-invasive ventilation procedures and new minimally invasive techniques has resulted in the research of alternative approaches as the aerosolization for the treatment of respiratory distress syndrome (RDS). The aim of this work was to design two nebulizer prototypes and to evaluate them studying the particle size distribution of the inhaled droplets generated with distilled water and two perfluorocarbons (PFCs). Different experiments were performed with driving pressures of 1⁻3 bar for each compound. An Aerodynamic Particle Sizer was used to measure the aerodynamic diameter (Da), the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD). The results showed that both prototypes produced heterodisperse aerosols with Da mean values in all cases below 5 m. The initial experiments with distilled water showed MMAD values lower than 9 m and up to 15 m with prototype 1 and prototype 2, respectively. Regarding the PFCs, relatively uniform MMAD values close to 12 m were achieved. The air delivery with outer lumens of prototype 1 presented more suitable mass distribution for the generation and delivery of a uniform aerosol than the two half-circular ring geometry proposed in the prototype 2.Funding: This work has been supported by Consolidated Groups from the Basque Government and Fundation VITAL Fundazioa

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.The research leading to these results received funding from the European Commission Seventh Framework Programme FP7 HEALTH-F5-2011 under grant agreement no 282533. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript