Intratracheal Instillation Of Surfactant Research Articles

Aerosol Delivery of Lung Surfactant and Nasal CPAP in the Treatment of Neonatal Respiratory Distress Syndrome.

After shifting away from invasive mechanical ventilation and intratracheal instillation of surfactant toward non-invasive ventilation with nasal CPAP and less invasive surfactant administration in order to prevent bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome, fully non-invasive surfactant nebulization is the next Holy Grail in neonatology. Here we review the characteristics of animal-derived (clinical) and new advanced synthetic lung surfactants and improvements in nebulization technology required to secure optimal lung deposition and effectivity of non-invasive lung surfactant administration. Studies in surfactant-deficient animals and preterm infants have demonstrated the safety and potential of non-invasive surfactant administration, but also provide new directions for the development of synthetic lung surfactant destined for aerosol delivery, implementation of breath-actuated nebulization and optimization of nasal CPAP, nebulizer circuit and nasal interface. Surfactant nebulization may offer a truly non-invasive option for surfactant delivery to preterm infants in the near future.

Preclinical Assessment of Nebulized Surfactant Delivered through Neonatal High Flow Nasal Cannula Respiratory Support.

High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, the delivery efficiency of nebulized surfactant during HFNC has not been evaluated in vitro or in animal models of respiratory distress. We, therefore, performed first a benchmark study to compare the surfactant lung dose delivered by commercially available neonatal nasal cannulas (NCs) and HFNC circuits commonly used in neonatal intensive care units. Then, the pulmonary effect of nebulized surfactant delivered via HFNC was investigated in spontaneously breathing rabbits with induced respiratory distress. The benchmark study revealed the surfactant lung dose to be relatively low for both types of NCs tested (Westmed NCs 0.5 ± 0.45%; Fisher & Paykel NCs 1.8 ± 1.9% of a nominal dose of 200 mg/kg of Poractant alfa). The modest lung doses achieved in the benchmark study are compatible with the lack of the effect of nebulized surfactant in vivo (400 mg/kg), where arterial oxygenation and lung mechanics did not improve and were significantly worse than the intratracheal instillation of surfactant. The results from the present study indicate a relatively low lung surfactant dose and negligible effect on pulmonary function in terms of arterial oxygenation and lung mechanics. This negligible effect can, for the greater part, be explained by the high impaction of aerosol particles in the ventilation circuit and upper airways due to the high air flows used during HFNC.

SAVING AND EARLY DICHARGE OF A NEONATE WITH SEVERE MECONIUM ASPIRATION SYNDROME

Animal experiments have shown the resolution of radiological infiltrates of meconium aspiration syndrome (MAS) after using surfactant lavage. Intra-tracheal instillation of surfactant, as well as surfactant lavage, is studied in MAS. However, INSURE (INtubation, administration of SURfactant, Extubation) is never reported to have been used for meconium aspiration syndrome although it is used as the standard method of delivery of surfactant for respiratory distress syndrome. This is a case report of the use of INSURE technique for severe Meconium Aspiration syndrome. The baby was born at term gestational age to a primigravida mother by C-section for fetal distress. The baby was vigorous with chest retractions. Hence baby was supported with delivery room Continuous positive airway pressure (CPAP) and shifted to Neonatal Intensive Care Unit (NICU). In NICU, the baby was stabilized and given surfactant using the INSURE technique. Subsequently, a Chest X-ray showed clearing of lung infiltrates and drastically reduced oxygen requirement of the baby and the baby was discharged early to home.

A single-center observational study on clinical features and outcomes of 21 SARS-CoV-2-infected neonates from India.

Coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing pandemic with significant morbidity and mortality. Neonates represent a vulnerable population, in which we have limited knowledge of its natural history, optimal management, and outcomes. In this retrospective observational study from a low-middle-income setting, clinical characteristics and outcomes of neonatal SARS-CoV-2 infection were evaluated. We report an incidence of 10.6% of SARS-CoV-2 infection (21 neonates), among a group of 198 neonates with suspected infection. Most of the SARS-CoV-2-infected neonates were term (80.9%) and none required any resuscitation. The infection was detected by a positive nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2. Neonatal COVID-19 manifestations developed in one-third (33.3%) of the infected neonates. Most of them demonstrated the involvement of respiratory (33.3%) and gastrointestinal systems (4.8%). Laboratory parameters suggested multi-systemic involvement, with elevated creatine kinase (CK) (76.2%), creatine kinase-myocardial band (CK-MB) (76.2%), and lactate dehydrogenase (LDH) (71.4%) levels. Supportive treatment was given to infected neonates with intensive care required in six neonates (28.6%). This included four preterm and two term neonates, of which two received non-invasive and one received invasive ventilation with intra-tracheal surfactant instillation. IgM antibodies against COVID-19 were detected in one neonate. All neonates with COVID-19 improved and were successfully discharged.Conclusion: SARS-CoV-2 in neonates has a wide clinical spectrum. Further studies are needed which are adequately powered to completely understand the course of this infection in neonates, its implications not only in the neonatal period but also on long-term follow-up.What is Known:• SARS-CoV-2 infection has a predilection for all age groups but with limited literature on clinical profile, outcomes, and long-term follow-up in neonates.What is New:• SARS-CoV-2 infection in neonates has a wide clinical spectrum and displays a significant overlap with common neonatal conditions.• Most neonates with COVID-19 improved with supportive care, though a subset required intensive care, emphasizing the need for cautious monitoring and management.

Surfactant for pulmonary haemorrhage in neonates.

In the 1960s and 1970s, pulmonary haemorrhage (PH) occurred mainly in full-term infants with pre-existing illness with an incidence of 1.3 per 1000 live births. Risk factors for PH included severity of illness, intrauterine growth restriction, patent ductus arteriosus (PDA), coagulopathy and the need for assisted ventilation. Presently, PH occurs in 3% to 5% of preterm ventilated infants with severe respiratory distress syndrome (RDS) who often have a PDA and have received surfactant. The cause of PH is thought to be due to rapid lowering of intrapulmonary pressure, which facilitates left to right shunting across a PDA and an increase in pulmonary blood flow. Retrospective case reports and one prospective uncontrolled study have shown promising results for surfactant in treating PH. To evaluate the effect of surfactant treatment compared to placebo or no intervention on mortality and morbidities in neonates with PH. For this update The Cochrane Library, Issue 2, 2012; MEDLINE; EMBASE; CINAHL; Clinicaltrials.gov; Controlled-trials.com; proceedings (2000 to 2011) of the Annual Meetings of the Pediatric Academic Societies (Abstracts2View) and Web of Science were searched on 8 February 2012. Randomised or quasi-randomised controlled trials that evaluated the effect of surfactant in the treatment of PH in intubated term or preterm (< 37 weeks) neonates with PH. Infants were included up to 44 weeks' postmenstrual age. The interventions studied were intratracheal instillation of surfactant (natural or synthetic, regardless of dose) versus placebo or no intervention. If studies were identified by the literature search, the planned analyses included risk ratio, risk difference, number needed to treat to benefit or to harm for dichotomous outcomes, and mean difference for continuous outcomes, with their 95% confidence intervals. A fixed-effect model would be used for meta-analyses. The risk of bias for included trials would be assessed. Heterogeneity tests, including the I2 statistic, would be performed to assess the appropriateness of pooling the data and the results would be reported. No trials were identified. No randomised or quasi-randomised trials that evaluated the effect of surfactant in PH were identified. Therefore, no conclusions from such trials can be drawn. In view of the promising results from studies with less strict study designs than a randomised controlled trial, there is reason to conduct further trials of surfactant for the treatment of PH in neonates.

Nebulised surfactant in preterm infants with or at risk of respiratory distress syndrome

Nebulised surfactant has the potential to deliver surfactant to the infant lung with the goal of avoiding endotracheal intubation and ventilation, ventilator-induced lung injury and bronchopulmonary dysplasia (BPD). To determine the effect of nebulised surfactant administration either as prophylaxis or treatment compared to placebo, no treatment or intratracheal surfactant administration on morbidity and mortality in preterm infants with, or at risk of, respiratory distress syndrome (RDS). Searches were performed of CENTRAL (The Cochrane Library, January 2012), MEDLINE and PREMEDLINE (1950 to January 2012), EMBASE (1980 to January 2012) and CINAHL (1982 to January 2012), as well as proceedings of scientific meetings, clinical trial registries, Google Scholar and reference lists of identified studies. Expert informants and surfactant manufacturers were contacted. Randomised, cluster-randomised or quasi-randomised controlled trials of nebulised surfactant administration compared to placebo, no treatment, or other routes of administration (laryngeal, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials. Two review authors independently assessed studies for eligibility and quality, and extracted data. No studies of prophylactic or early nebulised surfactant administration were found. A single small study of late rescue nebulised surfactant was included. The study is of moderate risk of bias. The study enrolled 32 preterm infants born < 36 weeks' gestation with RDS on nasal continuous positive airway pressure (nCPAP). The study reported no significant difference between nebulised surfactant administration compared to no treatment groups in chronic lung disease (risk ratio (RR) 5.00; 95% confidence interval (CI) 0.26 to96.59) or other outcomes (oxygenation 1 to 12 hours after randomisation, need for mechanical ventilation, days of mechanical ventilation or continuous positive airways pressure (CPAP) or days of supplemental oxygen). No side effects of the nebulised surfactant therapy or aerosol inhalation were reported. There are insufficient data to support or refute the use of nebulised surfactant in clinical practice. Adequately powered trials are required to determine the effect of nebulised surfactant administration for prevention or early treatment of RDS in preterm infants. Nebulised surfactant administration should be limited to clinical trials.

411 Comparison of Regional Cerebral Blood Flow Distribution after Aerosolized Versus Instilled Surfactant in Preterm Lambs

BackgroundRapid Intratracheal instillation of surfactant (SF) in preterm neonates with respiratory distress syndrome (RDS) has been associated with cerebral haemodynamic disturbances. Aerosolized surfactant might potentially avoid these disturbances through a...

Surfactant for pulmonary haemorrhage in neonates

In the 1960s and 1970s, pulmonary haemorrhage (PH) occurred mainly in full-term infants with pre-existing illness with an incidence of 1.3 per 1000 live births. Risk factors for PH included severity of illness, intrauterine growth restriction, patent ductus arteriosus (PDA), coagulopathy and the need for assisted ventilation. Presently, PH occurs in 3% to 5% of preterm ventilated infants with severe respiratory distress syndrome (RDS) who often have a PDA and have received surfactant. The cause of PH is thought to be due to rapid lowering of intrapulmonary pressure, which facilitates left to right shunting across a PDA and an increase in pulmonary blood flow. Retrospective case reports and one prospective uncontrolled study have shown promising results for surfactant in treating PH. To evaluate the effect of surfactant treatment compared to placebo or no intervention on mortality and morbidities in neonates with PH. For this update The Cochrane Library, Issue 2, 2012; MEDLINE; EMBASE; CINAHL; Clinicaltrials.gov; Controlled-trials.com; proceedings (2000 to 2011) of the Annual Meetings of the Pediatric Academic Societies (Abstracts2View) and Web of Science were searched on 8 February 2012. Randomised or quasi-randomised controlled trials that evaluated the effect of surfactant in the treatment of PH in intubated term or preterm (< 37 weeks) neonates with PH. Infants were included up to 44 weeks' postmenstrual age. The interventions studied were intratracheal instillation of surfactant (natural or synthetic, regardless of dose) versus placebo or no intervention. If studies were identified by the literature search, the planned analyses included risk ratio, risk difference, number needed to treat to benefit or to harm for dichotomous outcomes, and mean difference for continuous outcomes, with their 95% confidence intervals. A fixed-effect model would be used for meta-analyses. The risk of bias for included trials would be assessed. Heterogeneity tests, including the I(2) statistic, would be performed to assess the appropriateness of pooling the data and the results would be reported. No trials were identified. No randomised or quasi-randomised trials that evaluated the effect of surfactant in PH were identified. Therefore, no conclusions from such trials can be drawn. In view of the promising results from studies with less strict study designs than a randomised controlled trial, there is reason to conduct further trials of surfactant for the treatment of PH in neonates.

Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome

Laryngeal mask airway (LMA) administration is one way of delivering surfactant to the infant lung, with the potential benefit of avoiding endotracheal intubation and ventilation, ventilator induced lung injury and bronchopulmonary dysplasia (BPD). To determine the effect of LMA surfactant administration either as prophylaxis or treatment compared to placebo, no treatment, or intratracheal surfactant administration on morbidity and mortality in preterm infants with, or at risk of, respiratory distress syndrome (RDS). We searched CENTRAL (The Cochrane Library, October 2010), MEDLINE and PREMEDLINE (1950 to October 2010), EMBASE (1980 to October 2010) and CINAHL (1982 to October 2010). We also searched proceedings of scientific meetings, clinical trial registries, Google Scholar and reference lists of identified studies, as well as contacting expert informants and surfactant manufacturers. Randomised, cluster-randomised or quasi-randomised controlled trials of laryngeal mask surfactant administration compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials. Two review authors independently assessed studies for eligibility and quality, and extracted data. We found no studies of prophylactic or early LMA surfactant administration. A single small study of late rescue LMA surfactant was identified as eligible for inclusion. The study enrolled 26 preterm infants born ≥ 1200 g with RDS on continuous positive airway pressure (nCPAP). LMA surfactant administration compared to no treatment resulted in a reduction in mean FiO(2) required to maintain oxygen saturation between 88% and 92% for 12 hours after the intervention. No significant difference was reported in subsequent mechanical ventilation and endotracheal surfactant, pneumothorax, days on intermittent positive airway pressure (IPPV), and days on IPPV or oxygen. There is evidence from a single small trial that LMA surfactant administration in preterm infants ≥ 1200 g with established RDS may have a short term effect in reducing oxygen requirements although the study is underpowered to detect important clinical effects. Adequately powered trials are required to determine the effect of LMA surfactant administration for prevention or treatment of RDS in preterm infants. LMA surfactant administration should be limited to clinical trials.

Variable ventilation improves ventilation and lung compliance in preterm lambs

In adult animals, ventilation with variable tidal volume and rate improves lung mechanics, arterial oxygenation and ventilation compared to a monotonously controlled ventilation pattern. We assessed the physiological consequences of variable ventilation in the immature lung. Lambs delivered at 129 days (term = 150 days) were euthanised (n = 9) or anaesthetised, tracheostomised and suctioned prior to prophylactic intra-tracheal surfactant instillation (Curosurf(®), 100 mg/kg) and commencement of controlled ventilation (50 breaths/min, tidal volume 7.7 ± 0.8 mL/kg). Volume history was standardised at 20 min with two sustained (3 s) inflations to 30 cmH(2)O followed immediately by measurement of baseline dynamic lung mechanics (FlexiVent, Scireq, Canada). Ventilation was continued according to prior randomisation (variable or conventional ventilation). For variable ventilation (n = 9), breath-to-breath tidal volume and respiratory rate varied but intra-breath minute volume (MV) and average tidal volume were equivalent to the conventional ventilation group with fixed tidal volume and rate (n = 7). Lung mechanics and gas exchange were measured at intervals. Lambs were euthanised at 2 h. Inflammatory cell counts and protein from bronchoalveolar lavage fluid and lung tissue cytokine mRNA were quantified. At study completion, PaCO(2) (p = 0.026) and mean airway pressure (p = 0.002) were lower and pH (p = 0.047), ventilation efficiency index (p = 0.021) and dynamic compliance were higher (p = 0.003) in lambs on variable rather than conventional ventilation. However, oxygenation indices and post-mortem static compliances were not different between groups. Variable ventilation improves ventilation efficiency and in vivo lung compliance in the preterm lung, but unlike adult models, had no effect on arterial oxygenation.

Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome

Intrapartum pharyngeal instillation of surfactant before the first breath may result in surfactant administration to the infant lung, with the potential benefit of avoiding endotracheal intubation and ventilation, ventilator induced lung injury and bronchopulmonary dysplasia. To determine the effect of pharyngeal instillation of surfactant before the first breath compared to placebo, no treatment or intratracheal surfactant administration followed by intermittent positive pressure ventilation (IPPV) on morbidity and mortality in preterm infants at risk of respiratory distress syndrome (RDS). Searches were made of CENTRAL (The Cochrane Library, to September 2010), MEDLINE and PREMEDLINE (1950 to September 2010), EMBASE (1980 to 2010) and CINAHL (1982 to 2010). This strategy was supplemented by searches of proceedings of scientific meetings, Google Scholar and reference lists of identified studies, as well as contact with expert informants and surfactant manufacturers. Published, unpublished and ongoing randomised controlled or quasi-randomised trials (using individual or cluster allocation) of pharyngeal instillation of surfactant before the first breath compared to placebo or no treatment, or intratracheal surfactant instillation followed by IPPV, on morbidity and mortality in preterm infants at risk of RDS. Two authors independently assessed study eligibility and quality. No published, unpublished or ongoing trials that met the inclusion criteria for this review were found. There were no data from randomised controlled or quasi-randomised trials that evaluated the effect of intrapartum instillation of pharyngeal surfactant before the first breath. Evidence from animal and observational human studies suggest that pharyngeal instillation of surfactant before the first breath is potentially safe, feasible and may be effective. Well designed trials are needed.

Acute Pathophysiological Effects of Intratracheal Instillation of Budesonide and Exogenous Surfactant in a Neonatal Surfactant-depleted Piglet Model

Chronic lung disease continues to be a major complication in premature infants with severe respiratory distress syndrome (RDS). This is despite having advanced ventilatory care, prenatal corticosteroids, and postnatal surfactant therapies. The combined use of intratracheal corticosteroids and surfactant may not only recruit the lungs, but also alleviate pulmonary inflammation in severe RDS. Fifteen newborn piglets received repeated pulmonary saline lavage to induce surfactant-depleted lungs, mimicking neonatal RDS. They were randomly divided into three groups: control group receiving no treatment; surfactant (Surf) group, treated with standard intratracheally instilled surfactant (100 mg/kg); and Budesonide plus surfactant (Bude + Surf) group, treated with intratracheally administered mixed suspension of budesonide (0.5 mg/kg) and surfactant (100 mg/kg). Blood samples were taken every 30 minutes for 4 hours. Lung tissue was examined after the experiment. Significantly better oxygenation with higher PaO(2) and alveolar-arterial oxygen difference was noted in the Surf and Bude + Surf groups, compared with the control group (p < 0.05), but there were no significant differences between the Surf and Bude + Surf groups. Pulmonary histologic damage was also markedly alleviated in both the Surf and Bude + Surf groups, compared with the control group, and lung injury scores were significantly decreased in the Surf and Bude + Surf groups, compared with the control group (p < 0.05). Intratracheal instillation of surfactant or surfactant plus budesonide can improve oxygenation and pulmonary histologic outcome in neonatal surfactant-depleted lungs. The additional use of budesonide does not disturb the function of the exogenous surfactant. Intratracheal administration of a corticosteroid combined with surfactant may be an effective method for alleviating local pulmonary inflammation in severe RDS.

Inflammatory Response of Lung Derived Cells in Rat Pups Following Intratracheal Surfactant Instillation

Background: Neonatal respiratory-distress syndrome (nRDS) is a disease that affects the lung functions in premature infants who are born before their surfactant biosynthetic system has matured. Several surfactant-replacement therapies have been developed and are efficacious in treating the RDS. Objective: The study investigates the inflammatory response of the lung derived cells in rat pups with intratracheal instillation of surfactant (SF), isolated from porcine and the synthetic surfactant. Methods: Rat pups were divided into three groups: Controls were instilled with buffer, similarly P-SF and S-SF group of animals were instilled with porcine and synthetic surfactant, respectively. Bronchoalveolar fluid (BALF) was isolated and the different cytokines and reactive oxygen-nitrogen species (RONS) were measured using quantitative ELISA and fluorescence spectroscopic methods, respectively. Results: After 24 hrs, cytokines secretions were found to be elevated in the BALF with porcine and synthetic surfactant. Further, nitric oxide (NO) and citrulline levels as well as the reactive oxygen species (ROS) generation were also found to be increased with surfactant administration. Conclusion: In the treatment of respiratory distress syndrome, the anti-inflammatory response of surfactant may thus depend upon the specific preparation of the surfactant and its administration.

Intratracheal Instillation of Surfactant Inhibits Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats

To determine the possible contribution of apoptosis in the pathogenesis of ARDS, we investigated the role of exogenous surfactant in a rodent model of ARDS after intratracheal instillation of lipopolysaccharide. Adult male Sprague Dawley rats were divided into four groups: buffer controls; rats challenged with LPS (055:B5 E.coli); challenged with LPS and treated with porcine surfactant (P-SF); and challenged with LPS and treated with synthetic surfactant (S-SF). Parameters of lung injury and inflammation were assessed 72h after treatment. We demonstrated that intratracheal administration of LPS could provoke significant lung injury, which was characterized by increase of MPO activity, wet/dry lung weight ratio, cytokine levels in bronchoalveolar lavage fluid (BALF), apoptosis of BALF cells and caspase-3 activity in lung tissue. Intratracheally delivered surfactant significantly reduced the parameters of LPS-induced inflammation: infiltration of inflammatory cells into lung tissue and BALF, pulmonary edema, lung myeloperoxidase activity, lipid peroxidation, caspase-3 activity, number of apoptotic BALF cells, lactate dehydrogenase level & pro-inflammatory cytokines levels. Taken together, the present data demonstrate that exogenous surfactant systemically attenuates lipopolysaccharide-induced inflammation.

Immunomodulatory properties of exogenous surfactant in adult rat alveolar macrophages

Background and aim: The study investigates the immune response of the lung alveolar macrophages in adult rats with intratracheal instillation of surfactant, isolated from porcine, rabbit and rat lung as well as the synthetic surfactant.Material and methods: Adult male rats were divided into five groups: Controls were instilled with buffer, similarly P-SF, R-SF, r-SF, and S-SF group of animals were instilled with porcine, rabbit, rat and synthetic surfactant, respectively.Results: After one month, IL-1β secretions were found to be elevated in the supernatant of alveolar macrophages. Further, nitric oxide (NO) level was elevated with porcine and synthetic surfactant, while reactive oxygen species (ROS) generation was found to be inhibited significantly in all the treatment groups. Apoptoses were studied by using fluorescence dyes acridine orange/ethidium bromide, where percent of the apoptotic cells were found to be decreased in all the treated groups.Conclusions: Exogenous surfactant elevates secretion of pro-inflammatory cytokine IL-1β and also the NO as signaling molecule. The inhibitory effects of surfactants on ROS generation and on apoptosis may result from the interruption in the cell signaling pathway. In the treatment of respiratory distress syndrome, the anti-inflammatory response of surfactant may thus depend upon the specific preparation of the surfactant.

Improvement in respiratory compliance after surfactant therapy evaluated by a new method.

Descriptions of the effects of intratracheally applied surfactant on respiratory system compliance (C(rs)) have been somewhat controversial because the commonly used methods for assessing pulmonary function were designed for a linear pressure/volume (P/V) relation of the respiratory system. In infants with lung disease a linear P/V relation cannot be expected. Therefore, a new method (APVNL) was employed which enabled us to calculate respiratory system compliance (C(rs)) and resistance (R(rs)) based on changes in volume (V). This method is independent of the P/V relation, and was used to assess the effects of intratracheal instillation of surfactant. Fourteen infants (gestational age, 24 to 30 weeks) with respiratory distress syndrome were treated with bovine surfactant intratracheally while the fractional inspired oxygen concentration (FiO(2)) exceeded 50%. C(rs) was evaluated for the infants using the APVNL method and the method of linear regression (LR) based on the equation of motion designed for linear P/V relationships. Two hours after surfactant treatment, the median reduction of FiO(2) was 33% (95% CI: 20-50%; P < 0.01). There was no correlation between the change in FiO(2) and the change in C(rs), using either the APVNL method or the LR method. Two hours after surfactant treatment, the median improvement in C(rs) was 0.37 mL/cmH(2)O/kg (95% CI: 0.07-1. 16 mL/cmH(2)O) at a change in V of 1 mL/kg (P < 0.02) and 0.23 mL/cmH(2)O/kg (95% CI: 0-0.57 mL/cmH(2)O) at a change in V of 2 mL/kg (P < 0.05) when the APVNL method was used. The LR method could not show a significant change in C(rs) after surfactant treatment. Further, R(rs) did not show significant changes 2 hr after surfactant administration. We conclude that the APVNL method is more appropriate for evaluating changes of C(rs) elicited by surfactant treatment than the LR method. The APVNL method demonstrated significant initial improvements in compliance as lung volumes were increased; there were no significant further decreases in C(rs) as peak inspiratory pressures and the upper limits of tidal volume were approached.

The effect of surfactant therapy for acute lung injury induced by intratracheal endotoxin instillation in rats examination of the lung

Background : Acute lung injury is an hypoxic respiratory failure resulting from damage to the alveolar-capillary membrane, which can be developed by a variety of systemic inflammatory diseases. In this study the therapeutic effects of intra-tracheal pulmonary surfactant instillation was evaluated in the intratracheal endotoxin induced acute lung injury model of a rat. Methods : Twenty Sprague-Dawley rats were divided into 4 groups, and normal saline (2 ml/kg, for group 1) or LPS (5 mg/kg, for group 2, 3, and 4) was instilled into the trachea respectively. Either normal saline (2 ml/kg, for group 1 & 2, 30 min later) or bovine surfactant (15 mg/kg, 30 min later for group 3, 5 hr later for group 5) was instilled into the trachea. The therapeutic effect of intratracheal surfactant therapy was evaluated with one chamber body plethysmography (respiratory frequency, tidal volume and enhanced pause), ABGA, BAL fluid analysis (cell count with differential, protein concentration) and pathologic examination of the lung. Results : Intratracheal endotoxin instillation increased the respiration rate decreased the tidal volume and int creased the Penh in all group of rats. Intratracheal instillation of surfactant decreased Penh, increased arterial oxygen tension, decreased protein concentration of BAL fluid and decreased lung inflammation at both times of administration (30 minute and 5 hour after endotoxin instillation). Conclusion : Intratracheal instillation of surfactant can be a beneficial therapeutic modality as discovered in the acute lung injury model of rats induced by intratracheal LPS intillation. It deserves to be evaluated for treatment of human acute lung injury.

Influence of a Pulmonary Surfactant on the In Vitro Activity of Tobramycin against Pseudomonas aeruginosa

Delivery of therapeutic concentrations of drugs to the lung periphery is crucial in treatment of many infectious and inflammatory diseases of the lung. Conventional drug treatment for serious pulmonary infections consists of systemic administration of drug in order to achieve concentrations in the bloodstream that will reach therapeutic results. Advantages to topical drug administration to the lungs via aerosol are well known (3). However, the amount of drug that can be inhaled as aerosol is frequently small, thereby limiting the amount of drug delivered to the distal portion of the lung (1). Intratracheal instillation of surfactant, in the animal model, increased the fractional area of lung exposed and improved the uniformity of spread of radioactive label in the lung compared to the saline control (2). We examined the effect of physical perturbation with the mixture, antibiotic, and surfactant, via heat and sonication and stability over time as a function of the MIC for Pseudomonas. Tobramycin and surfactant (Exosurf suspension) were combined in cationic adjusted Mueller-Hinton broth (CAMHB) to create mixtures containing 8, 16, 32, or 64 μg of surfactant per ml, all with 4 μg of tobramycin per ml (4). One aliquot of each mixture was heated at 80°C for 30 min, one was sonicated at room temperature for 30 min, and a third was held at room temperature for 30 min without additional treatment. Serial twofold dilutions of each aliquot were prepared in CAMHB in microdilution trays (final volume, 100 μl/well) and inoculated with approximately 5 × 105 CFU of Pseudomonas aeruginosa ATCC 27853. Serial dilutions of tobramycin in CAMHB and separate serial dilutions of surfactant in CAMHB were inoculated with the same organism to serve as controls. All trays were incubated for 18 h at 35°C, and the MIC was determined visually. When tobramycin and surfactant were mixed, sonicated, and heated to 80°C for 30 min, there was no in vitro reduction in MIC for P. aeruginosa. To assess the stability of mixtures of tobramycin and surfactant, we prepared a stock mixture containing 27 mg each of tobramycin and surfactant per ml. Dilutions of this mixture were prepared immediately to give final concentrations of tobramycin ranging from 0.06 to 8 μg/ml in CAMHB. Controls, inoculation, incubation, and examination were identical to those described above. The remaining stock mixture was stored at 4°C for 3 weeks, and the MIC was determined at 1 week and again at 3 weeks. No decline in the MIC of the mixture was found when it was stored in a refrigerated environment for up to 3 weeks. van’t Veen and coworkers (5) found a reduction in bactericidal activity of tobramycin when tobramycin was mixed with surfactant which could be compensated for by increasing the tobramycin concentration. A possible explanation of the difference from our study may be the difference in the surfactants. Exosurf, a synthetic compound, does not contain protein, whereas van’t Veen et al. used a surfactant obtained from the bovine lung containing a protein component.

Effects of exogenous surfactant on acute lung injury induced by intratracheal instillation of infant formula or human breast milk in rabbits.

An animal experimental model of acute lung injury after intratracheal instillation of acidified milk products has been recently demonstrated. Exogenous administration of surfactant has proved to be successful treatment for acute lung injury induced by many causes including acid aspiration. The authors conducted this study to investigate whether exogenous surfactant can reduce the magnitude of lung damage induced in rabbits by acidified milk products. The lung injury was induced by intratracheal instillation of acidified human breast milk or acidified infant formula (0.8 ml/kg, pH 1.8). Thirty minutes after the insult, some animals were treated with intratracheal surfactant 100 or 200 mg/kg. Lung compliance and alveolar-to-arterial oxygen gradient were recorded during ventilation. After 4 or 12 h, the lungs were excised to determine physiologic and histologic lung damage. Albumin, interleukin-8, and eicosanoids in bronchoalveolar lavage fluid and superoxide production by neutrophils were measured. The acidified milk products increased A-aD(O2)(550+/-52 and 156+/-28 mmHg; mean+/-SD at 4 h in saline solution and infant formula groups, respectively), lung wet-to-dry weight ratio (6.6+/-0.5 and 5.6 +/- 0.2), %neutrophils in bronchoalveolar lavage fluid (84+/-4% and 8+/-20%), and decreased compliance (0.76+/-0.09 and 1.90+/-0.11 ml/cm H2O). Surfactant improved these variables in a dose-dependent manner (A-aDO2 = 363+/-50 and 237+/-55 mmHg in 100-mg/kg and 200-mg/kg surfactant groups). Surfactant attenuated extensive histologic changes caused by the milk products. Superoxide production was less in rabbits receiving surfactant than in those not receiving it. Exogenous surfactant improved physiologic, histologic, and biochemical lung injury induced by acidified milk products in a dose-dependent manner. The effectiveness of surfactant may be caused, in part, by inhibition of neutrophils' sequestration and activation. These data indicate that intratracheal instillation of surfactant may be a promising therapeutic modality in acute lung injury resulting from aspiration of acidified milk products.

Recent advances in the treatment of ARDS

Despite more than 25 years of extensive research the mortality of ARDS patients remains high. Besides the often deleterious course of the underlying disease, another reason for this high mortality lies in the aggressive ventilatory regimen which is required to maintain arterial blood gases in a more or less normal range. Therapeutic methods which are used to reduce iatrogenic damage to the lungs are pressure controlled ventilation with permissive hypercapnia, differential lung ventilation, positioning therapy, dehydration, and extracorporeal gas exchange with membrane lungs. Nevertheless, many of these patients still die following hypoxaemia or multiple organ failure. Therefore, the need remains to develop new therapeutic strategies and to investigate their influence on the morbidity and mortality of this life-threatening disease. First experiences with nitric oxide (NO) inhalation, intravenous application of antioxidants, intratracheal instillation of surfactant, tracheal gas insufflation and combined fluid/gas ventilation with perfluorocarbon are presented. All these new methods have proved their efficacy, at least in animal studies, however, they should still be regarded as experimental.