Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets.

BackgroundBrain hypoxic-ischemic (HI) damage induces distant inflammatory lung damage in newborn pigs. We aimed to investigate the effects of cannabidiol (CBD) on lung damage in this scenario.MethodsNewborn piglets received intravenous vehicle, CBD, or CBD+WAY100635 (5-HT1A receptor antagonist) after HI brain damage (carotid flow interruption and FiO2 0.10 for 30 min). Total lung compliance (TLC), oxygenation index (OI), and extravascular lung water content (EVLW) were monitored for 6 h. Histological damage, interleukin (IL)-1ß concentration, and oxidative stress were assessed in brain and lung tissue. Total protein content was determined in bronchoalveolar lavage fluid (BALF).ResultsCBD prevented HI-induced deleterious effects on TLC and OI and reduced lung histological damage, modulating inflammation (decreased leukocyte infiltration and IL-1 concentration) and reducing protein content in BALF and EVLW. These effects were related to CBD-induced anti-inflammatory changes in the brain. HI did not increase oxidative stress in the lungs. In the lungs, WAY100635 blunted the beneficial effects of CBD on histological damage, IL-1 concentration, and EVLW.ConclusionsCBD reduced brain HI-induced distant lung damage, with 5-HT1A receptor involvement in these effects. Whether the effects of CBD on the lungs were due to the anti-inflammatory effects on the brain or due to the direct effects on the lungs remains to be elucidated.

Hypoxic-ischemic brain damage induces distant inflammatory lung injury in newborn piglets.

BACKGROUND: We aimed to investigate whether neonatal hypoxic-ischemic (HI) brain injury induces inflammatory lung damage. METHODS: Thus, hypoxic (HYP, FiO2 10% for 30 min), ischemic (ISC, bilateral carotid flow interruption for 30 min), or HI event was performed in 1-2-d-old piglets. Dynamic compliance (Cdyn), oxygenation index (OI), and extravascular lung water (EVLW) were monitored for 6 h. Then, histologic damage was assessed in brain and lung (lung injury severity score). Total protein content (TPC) was determined in broncoalveolar lavage fluid (BALF), and IL-1ß concentration was measured in lung and brain tissues and blood. RESULTS: Piglets without hypoxia or ischemia served as controls (SHM). HI-induced brain damage was associated with decreased Cdyn, increased OI and EVLW, and histologic lung damage (interstitial leukocyte infiltration, congestive hyperemia, and interstitial edema). BALF TPC was increased, suggesting inflammatory damage. In agreement, tissue IL-1ß concentration increased in the brain and lung, in correspondence with increased IL-1ß serum concentration. Neither HYP nor ISC alone led to brain or lung damage. CONCLUSION: HI brain damage in newborn piglets led to inflammatory lung damage, suggesting an additional mechanism accounting for the development of lung dysfunction after neonatal HI encephalopathy.

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.

Surfactant and perfluorocarbon aerosolization during different mechanical ventilation strategies by means of inhalation catheters: an in vitro study.

BACKGROUND: Aerosol delivery of surfactant and perfluorocarbon (PFC) is a desirable therapeutic approach for the treatment of various lung diseases in patients undergoing mechanical ventilation. However, the behavior of these substances during aerosolization differs significantly from that of aqueous solutions. In particular, the high vapor pressure of many PFCs tends to result in greater evaporation during mechanical ventilation. METHODS: Three PFCs and surfactant were aerosolized during mechanical ventilation by means of three intratracheal inhalation catheters (IC) with different air flow rates (IC-1.23, IC-1.1, and IC-1.4), with their aerosol generating tip placed at the distal end of the endotracheal tube (i.d. 4 mm). The influence of four different ventilation strategies on aerosol production rate and PFC and surfactant recovery was studied. The changes in intrapulmonary pressure produced by the air jets of each IC were measured. RESULTS: With IC-1.23 and IC-1.1, the highest rates of aerosol production were achieved using FC75 (2.27±0.18 and 0.76±0.01, respectively) followed by PFOB (1.74±0.06 and 0.56±0.04), PFD (0.82±0.01 and 0.21±0.01), and surfactant (0.42±0.05 and 0.092±0.01). With IC-1.4 modest aerosol production was obtained irrespective of the aerosolized compound. Mechanical ventilation influenced aerosol recovery, with the trend being toward recovering higher percentages of the compounds with lower peak inspiratory pressure (PIP) and lower respiratory rate (RR) settings. The highest percentages of the initial volume were recovered with IC-1.23 (between 65.43%±4.2 FC75 and 90.21%±4.71 surfactant) followed by IC-1.1 (between 46.48%±4.46 FC75 and 73.19%±2.82 PFOB) and IC-1.4 (between 4.65%±4.36 FC75 and 63.24%±9.71 surfactant). Each of three of the ICs were found to increase the intrapulmonary pressure by about 2-3 cmH2O during mechanical ventilation. CONCLUSIONS: Despite of mechanical ventilation, IC-1.23 and IC-1.1 were able to deliver significant amounts of surfactant and perfluorocarbon to the lung model. Changes in PIP and RR directly influence the percentage of surfactant and perfluorocarbon recovered.

Surfactant and perfluorocarbon aerosolization by means of inhalation catheters for the treatment of respiratory distress syndrome: an in vitro study.

BACKGROUND: The aerosolization of perfluorocarbons or surfactant has emerged as a feasible alternative to instillation, for the treatment of experimental respiratory distress syndrome. However, the biophysical properties that make these compounds useful in such therapies, significantly affect the performance of nebulizers. Therefore, in vitro studies are required to assess the suitability of new aerosolization technologies for use with these compounds. METHODS: The aim of the present in vitro study was to investigate the influence of the biophysical properties of perfluorocarbons (PFD, FC75, and PFOB) and a natural porcine surfactant, Curosurf®; on aerosolization and to assess the suitability of three intratracheal inhalation catheters (IC) with different air flow rates (IC-1.23, IC-1.1, IC-1.4) coupled to a jet nebulizer, for aerosol delivery of these compounds. RESULTS: With IC-1.23 significantly higher aerosol production rates were achieved (p < 0.0001), ranging between 6.05 ± 0.17 mL/min (FC75) and 1.94 ± 0.09 mL/min (Curosurf®), and lower percentage losses of the compound (5-21%), compared to IC-1.1 and IC-1.4 catheters. The lowest aerosolization rates were produced with IC-1.4 ranging from 0.58 ± 0.02 mL/min (FC75) to 0.14 ± 0.01 mL/min (Curosurf®), and this catheter also resulted in the highest percentage losses (25-60%). The mass median aerodynamic diameter (MMAD) ranged between 0.77 µm (PFD) and 8.29 µm (Curosurf®) with IC-1.1, whereas higher MMAD values, of between 4.84 µm (FC75) and 13.42 µm (PFOB), were observed with IC-1.23. Regardless of the catheter used during aerosolization, the perfluorocarbon with the highest kinematic viscosity showed the lowest aerosolization and emission rates and vice versa, which reveals the substantial contribution of this parameter that should accordingly be considered in the design of perfluorocarbon aerosol drug delivery systems. CONCLUSIONS: Jet aerosolization of perfluorocarbons or surfactant with the intratracheal inhalation catheters seems to be a suitable method for treating experimental respiratory distress syndrome, because it delivers relatively high doses of perfluorocarbons and surfactant to the lungs in a respirable size droplets.

Acute and sustained effects of lucinactant versus poractant-alpha 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-alpha). 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-alpha 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-alpha 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.