Artificial Surfactant Research Articles

Surfactant naturel ou artificiel? Les arguments en faveur des surfactants naturels

The use of exogenous surfactant (ES) is an essential component for prevention and treatment of hyaline membrane disease (HMD). The ES available for clinical use are of two therapeutic classes: natural surfactants prepared from mammalian lung and artificial surfactants. The choice between these two classes of ES is controversial. In this overview, we present the arguments in favour of the preferential use of natural ES. The presence of hydrophobic specific proteins (SP-B and SP-C) provides to natural ES better surface tension properties than artificial ES. The in vitro greater efficacy of natural ES has been confirmed in vivo in experimental models of surfactant deficiency, human pharmacodynamic studies, and comparative clinical trials. Furthermore, the excellent clinical tolerance and harmlessness of natural ES has been firmly established. A meta-analysis of the comparative clinical trials between natural ES and one artificial ES (enrolling as many as 4400 babies treated for HMD) suggests that the use of natural ES compared to this artificial ES significantly reduces the neonatal mortality by 20%. In conclusion, all these arguments are in favor of the preferential use of natural ES for prevention and treatment of HMD.

Exogenous surfactants in a piglet model of acute respiratory distress syndrome.

Evidence for surfactant dysfunction in acute respiratory distress syndrome (ARDS) suggests a role for exogenous surfactant which contains apoprotein for resistance to protein inhibition. We compared the effects of KL-4-Surfactant, an artificial preparation containing a synthetic 21 amino acid peptide with SP-B-like activity, with Exosurf, an artificial protein-free surfactant, and Survanta, a bovine protein-containing surfactant, in a saline lung lavage model of ARDS in neonatal piglets. Two sequential series of lung lavages were performed to lower PaO2 < 100 mm Hg, each followed by administration of surfactant or air and a 90-min observation period. Progressive lung injury was demonstrated by deterioration in pulmonary function, increasing bronchoalveolar lavage protein, and changes in histopathology. All surfactants improved oxygenation, although oxygenation was generally better with Survanta and KL-4-Surfactant. Further, Survanta and KL-4-Surfactant groups showed improvement in ventilation, with decreases in PaCO2 and increases in FRC. Only KL-4-Surfactant demonstrated greater pressure-volume characteristics and lower bronchoalveolar protein than those of Controls. We conclude that the physiologic effects of KL-4-Surfactant are more like Survanta in this model. We speculate that KL-4-Surfactant may improve pulmonary function, reduce alveolar protein leak, and thus be efficacious in the treatment of ARDS.

Alveolar macrophage uptake of the environmental particulate titanium dioxide: role of surfactant components.

Pulmonary surfactant components can modulate uptake of microorganisms and viruses by alveolar macrophages (AMs), but little is known about their role in the uptake and clearance of inert environmental particulates. We tested the hypotheses that surfactant components [e.g., surfactant protein A (SpA) and the artificial bovine surfactant Survanta] modulate phagocytosis of inert environmental particulates by acting as particle opsonins, or by direct activation of AMs. AM uptake of a model inert particulate [titanium dioxide (TiO2)] was measured using flow cytometry to quantitate increased right angle scatter caused by particle uptake (e.g., fold increase in right angle scatter versus control: 2.6 +/- 0.3; and 5.0 +/- 0.2 for AMs plus TiO2, 20 and 80 micrograms/ml TiO2, respectively). Opsonization of TiO2 with surfactant components resulted in a modest increase in AM uptake compared with that of unopsonized TiO2 [e.g., fold increase, uptake of TiO2 (50 micrograms/ml), opsonized with SpA, Survanta, and rat immunoglobulin G, respectively: 1.6 +/- 0.1; 1.3 +/- 0.01; 1.5 + 0.02, n = 3-4]. Uptake of inert latex beads was similarly enhanced after opsonizing with SpA and Survanta (beads per cell: unopsonized, 3.2 +/- 0.40; SpA, 5.0 +/- 0.55; Survanta, 6.0 +/- 0.12; n = 3-6). Pretreating AMs with surfactant components and measuring the subsequent uptake of unopsonized TiO2 resulted in approximately the same magnitude of enhancement. The data indicate that surfactant components can increase AM phagocytosis of environmental particulates in vitro, but only slightly relative to the already avid AM uptake of unopsonized particles.

Artificial Surfactant Administration in an Animal Model of Hydrocarbon Induced Pulmonary Toxicity

Artificial Surfactant Administration in an Animal Model of Hydrocarbon Induced Pulmonary Toxicity

A radiologic update on medical diseases of the newborn chest.

This paper reviews the common spectrum of medical diseases of the neonatal chest. Emphasis is on radiographic changes that have been produced by the introduction of new therapeutic maneuvers, particularly the use of artificial surfactant in treating hyaline membrane disease and the survival of profoundly premature newborns (less than 650 g). A discussion of meconium aspiration syndrome, neonatal pneumonia, transient tachypnea of the newborn, congenital lymphangiectasia, and congenital heart disease is also included. The effects on the neonatal chest radiograph of extracorporeal membrane oxygenation and high-frequency ventilation are also mentioned.

Adult respiratory distress syndrome and artificial surfactant replacement in the pediatric patient

Adult respiratory distress syndrome (ARDS) frequently develops after near-drowning, smoke inhalation, burns, blunt trauma to chest, and overwhelming sepsis. Surfactant depletion, inactivation or destruction by the accumulation of proteinaceous material in the alveoli, and changes in the relative composition of phospholipids or protein component have been associated with ARDS. Artificial surfactant reverses these changes in experimental animals. Seven cases of ARDS have been treated on an experimental basis with artificial surfactant after approval and in accordance with ethical standards of the institution's committee on human experimentation. Informed consent was obtained from parents prior to administering artificial surfactant. We identified five cases of ARDS in retrospective analysis and used them as historical controls. Mortality between these two groups was analyzed with Fisher's exact test. One of seven (14.2%) children treated with surfactant died of overwhelming infection, and 2/5 (40%) of the historical controls died of pulmonary causes (P = 0.523). Statistically, surfactant therapy did not improve survival in patients with ARDS; however, ARDS patients receiving surfactant improved in their pulmonary dynamic compliance and had a tendency to stabilize earlier in gas exchange, allowing us to decrease ventilatory support.

Hypocarbia before surfactant therapy appears to increase bronchopulmonary dysplasia risk in infants with respiratory distress syndrome.

To determine to what extent the risk of bronchopulmonary dysplasia is affected by ventilatory management before the first dose of rescue artificial surfactant. Retrospective cohort study. One hundred eighty-eight low-birth-weight infants (< or = 1700 g) who received artificial surfactant therapy for respiratory distress syndrome and who were alive at 36 weeks of gestational age. Bronchopulmonary dysplasia was defined by a need for supplemental oxygen to maintain an arterial saturation of 92% or more at 36 weeks of gestational age. Thirty-seven percent (70/188) of the cohort met study criteria for bronchopulmonary dysplasia. Early determinants significantly associated with bronchopulmonary dysplasia (given as odds ratio, 95% confidence interval) in the most parsimonious backward stepwise logistic regression model included the following: birth weight of 1000 g or less (5.1, 2.4 to 10.7), cesarean birth because of fetal distress (4.4, 1.7 to 11.4), ventilatory efficiency index of 0.15 or less before surfactant therapy (3.1, 1.4 to 6.8), arterial-alveolar oxygen ratio of 0.15 or less before surfactant therapy (2.2, 1.01 to 4.6), and a low arterial PCO2 (< or = 29 vs > or = 40 mm Hg, 5.6, 2.0 to 15.6; 30 to 39 vs > or = 40 mm Hg, 3.3, 1.3 to 8.3). The inverse relationship between hypocarbia and bronchopulmonary dysplasia persisted even in stratified analyses limited to infants with measures of cardiovascular or respiratory illness that suggested less severe manifestations of disease. Ventilatory management before rescue treatment with artificial surfactant therapy that result in hypocarbia may increase the risk of bronchopulmonary dysplasia. These findings suggest that early ventilatory management should not only provide adequate oxygenation but also limit hyperventilation.

Artificial surfactant attenuates hyperoxic lung injury in primates. I. Physiology and biochemistry

Prolonged exposure to O2 causes diffuse alveolar damage and surfactant dysfunction that contribute to the pathophysiology of hyperoxic lung injury. We hypothesized that exogenous surfactant would improve lung function during O2 exposure in primates. Sixteen healthy male baboons (10-15 kg) were anesthetized and mechanically ventilated for 96 h. The animals received either 100% O2 (n = 6) or 100% O2 plus aerosolized artificial surfactant (Exosurf; n = 5). A third group of animals (n = 5) was ventilated with an inspired fraction of O2 of 0.21 to control for the effects of sedation and mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion distribution (VA/Q) was measured daily using a multiple inert-gas elimination technique. Positive end-expiratory pressure was kept at 2.5 cmH2O and was intermittently raised to 10 cmH2O for 30 min to obtain additional measurements of VA/Q. After the experiments, lungs were obtained for biochemical and histological assessment of injury. O2 exposures altered hemodynamics, progressively worsened VA/Q, altered lung phospholipid composition, and produced severe lung edema. Artificial surfactant therapy significantly increased disaturated phosphatidylcholine in lavage fluid and improved intrapulmonary shunt, arterial PO2, and lung edema. Surfactant also enhanced the shunt-reducing effect of positive end-expiratory pressure. We conclude that an aerosolized protein-free surfactant decreased the progression of pulmonary O2 toxicity in baboons.

Artificial surfactant attenuates hyperoxic lung injury in primates. II. Morphometric analysis

Diffuse lung injury from hyperoxia is accompanied by low compliance and hypoxemia with disruption of endothelial and alveolar epithelial cell layers. Because both function and content of surfactant in diffuse lung injury decrease in animals and in humans, changes in the extent of injury during continuous hyperoxia were evaluated after treatments with a protein-free surfactant in primates. Ten baboons were ventilated with 100% O2 for 96 h and five were intermittently given an aerosol of an artificial surfactant (Exosurf). Physiological and biochemical measurements of the effects of the surfactant treatment are presented in a companion paper (Y.-C. T. Huang, A. C. Sane, S. G. Simonson, T. A. Fawcett, R. E. Moon, P. J. Fracica, M. G. Menache, C. A. Piantadosi, and S. L. Young. J. Appl. Physiol. 78: 1823-1829, 1995.) After O2 exposures, lungs were fixed and processed for electron microscopy. The cellular responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. Morphometry was used to quantitate changes in lungs of animals treated with the artificial surfactant during O2 exposure and to compare them with the untreated animals. The surfactant decreased neutrophil accumulation, increased fibroblast proliferation, and decreased changes in the volume of type I epithelial cells. Surfactant-treated animals also demonstrated better preservation of endothelial cell integrity. These responses indicate ameliorating effects of the surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction. Significant interstitial inflammation and fibroblast proliferation remained, however, in surfactant-treated lungs exposed to continuous hyperoxia.

Changes in pulmonary artery pressure in infants with respiratory distress syndrome following treatment with Exosurf.

The pulmonary artery pressure (PAP) changes were studied using Doppler echocardiography in preterm infants treated with an artificial surfactant (Exosurf) during the acute phase of respiratory distress syndrome (RDS). The ratio of pulmonary artery acceleration time to the right ventricular ejection time (AT:RVET), measured from the Doppler wave form, was determined in 38 infants before the first dose of Exosurf, at one and six hours after the first dose, immediately before the second dose of Exosurf, and at one, six, 12, 36, and 60 hours subsequently. The median AT:RVET ratio corrected for heart rate (AT:RVET(c)) increased significantly an hour after administration of the first dose of Exosurf from 0.330 (0.273-0.410) to 0.380 (0.303-0.445) and similarly an hour after the second dose from 0.426 (0.252-0.495) to 0.440 (0.373-0.500). These changes occurred against a steady increase in the median AT:RVET(c) over the first 72 hours. It is concluded that the reduction in PAP correlates well with clinical parameters of disease severity and raises questions regarding the mode of action of Exosurf.

Sensors and sample preparation in stripping voltammetry

The great choice of electrode reactions, electrode materials, electrode designs and registration modes is the basis for various sensors for stripping voltammetry (SV) development. The most important are mercury drop and carbon electrodes. The use of epoxy-impregnated graphite disk electrodes and thick-film graphite disposable electrodes in SV in comparison with glassy carbon electrodes was studied. Surface regeneration, the possibility of using electrodes as sensors in adsorptive stripping voltammetry (AdSV) and organic compounds (natural or pollutants) that affect the responses of elements were investigated. Two kinds of electrode reactions which are in use in SV were considered: discharge ionization of metals that are the basis of ASV and metal complex or special reagent sorption that are the basis of AdSV and modified electrodes. In the first case, a mercury preplated or in situ plated electrode is usually used. Low reproducibility in comparison with mercury electrodes is characteristic of such electrodes owing to non-uniformity and delay in mercury deposition on the electrode surface. It was shown that such difficulties can be eliminated by mercury deposition in the presence of metal ions with a small electronic work function, which are capable of forming adatoms on the electrode surface. Determination of Cr and W ions is considered as an example of the application of carbon electrodes in AdSV. Advantages of graphite electrodes over glassy carbon electrodes are better adsorbability of organic compounds, aromatics in particular, which makes it possible to use the electrodes in AdSV. Electrochemical sample preparation consists of two stages: organic compound oxidation and reduction of excess of oxidant without loss of the metals to be determined. Investigation of model solutions containing natural and artificial surfactants and complex-forming compounds and natural and waste waters showed the possibility of the use of graphite electrodes as sensors in the SV of the above-mentioned materials. The examples considered confirm the following advantages of thick film disposable electrodes: they are less sensitive to organic substance content than disc impregnated electrodes; and their properties are similar to those of microelectrode arrays.

Mechanisms of bilirubin toxicity.

Possible mechanisms of bilirubin toxicity on the brain and lung were studied in animal experiments and in vitro. The uptake of tyrosine as precursor of dopamine in rat synaptosomes was evaluated to study the role of different bilirubin concentrations on synaptic neurotransmission. The results of this study show a statistically significant correlation between bilirubin levels and tyrosine uptake, supporting the hypothesis that the effect of bilirubin on neuronal excitability is dose-dependent. Concerning bilirubin toxicity on the lung, we studied the effect of different bilirubin concentrations on surface activity of modified natural surfactant (Curosurf) and synthetic surfactant (Exosurf), both in current clinical use for treatment of neonatal respiratory distress syndrome. Surface activity of Curosurf and Exosurf was investigated with the captive bubble surfactometer. The results of this study show that bilirubin impairs, in vitro, the surface tension activity of natural surfactant in a dose dependent manner and has no effect on surface tension activity of artificial surfactant. These data suggest that bilirubin interferes with surfactant proteins SP-B and/or SP-C, thus impairing surfactant activity at the air-liquid interface. We conclude that bilirubin shows its toxic effect reacting with different biological systems in a dose-dependent fashion.

National institute of child health and human development (NICHD)-sponsored perinatal research networks

M ost rout ine practices used in perinatology today have not been subjected to rigorous investigation. Instead, they arose f rom the clinicians' let 's try it att i tude and the development of new technology. The most vivid example o f the price of such well meaning but untested t reatment is the story of administration of supplemental oxygen to low birthweight infants. In 1954, the results of the first neonatal, multicenter, randomized clinical trial repor ted that the previously accepted but untested practice of oxygen supplementation had been responsible for blindifig thousands of low birthweight infants.1 Despite the cont inuing tendency of clinicians to institute interventions without rigorous testing, t h e role of the randomized, controlled trial has increased markedly in the intervening four decades, as illustrated, for example, by the industrysponsored clinical trials of artificial surfactant replacement therapy, 2-4 and by the publication of systematic reviews of evidence from randomized trials in neonatology and perinatology. 57 Although the National Institutes of Health (NIH) typically funds individual investigator-initiated research grants, support for the multicenter, randomized, controlled trials has increased over the last decade. They are identified through a lengthy process that begins with a workshop addressing a current medical problem in which a specific population and treatment modality are defined and the need for a clinical trial articulated. The next step is usually the issuance of a Request for Application (RFA), soliciting applications for a clinical trial. A peer review group assesses the scientific merit of the proposals which are funded based on their quality and the funds available. In the best of circumstances, the time

Surfactant adjunctive therapy forPneumocystis carinii pneumonitis in an infant with acute lymphoblastic leukaemia

We report successful treatment of adult respiratory distress syndrome (ARDS) with artificial surfactant (40mg/kg, Colfosceril Palmitate, ‘Exosurf’, Wellcome) in an infant with severePneumocystis carinii pneumonitis.

Changes in oxygenation and heart rate after administration of artificial surfactant (ALEC) to preterm infants.

To determine if changes in oxygenation and heart rate occur after surfactant, changes in these variables were recorded continuously for 15 minutes before, during, and 15 minutes after the administration of the artificial surfactant ALEC to 21 preterm infants ventilated for respiratory distress syndrome. Median (range) birth weight and gestation were 1199 (561-2680) g and 28 (21-43) weeks, respectively. The mean (SD) time taken for administration was 17.6 (3.8) seconds. No clinically important changes resulted from the administration of ALEC in the mean (SD) values for oxygen saturation (before 91.3 (3.4)%, during 90.7 (3.2)%, after 90.4 (3.7)% and heart rate (before 143 (15), during 138 (17), after 142 (16)). The maximum change in mean arterial oxygen saturation (SaO2) was a fall of 4.8%.

Artificial surfactant administration in an animal model of near drowning.

To study the use of exogenous surfactant in a rabbit fresh-water near-drowning model. In a randomized, placebo-controlled experiment, 21 rabbits were anesthetized, paralyzed, and subjected to near drowning with 6 mL/kg of distilled water. Vital signs, arterial blood gases, and pulmonary compliance were measured at predetermined intervals. The animals were randomized into two groups: a normal O2 group that had their pO2 levels adjusted to 75-150 torr using supplemental O2 as needed, and a high O2 group ventilated with an FIO2 = 100%. Ventilator settings were further adjusted to normalize pH and pCO2 levels prior to instillation of distilled water. The two groups were further divided and 15 minutes after simulated near drowning, the animals were either treated with surfactant (5 mL/kg instilled endotracheally) or not treated. Data were analyzed by repeated-measures analysis of variance. Near drowning had no significant effect on heart rate or blood pressure. Acidosis was not changed by surfactant; hypoxia was worsened by surfactant: 158 +/- 54 torr before and 66 +/- 19 torr after administration (p < 0.01). Compliance did not change as a result of surfactant administration. Only the animals (n = 3) in the normal O2 plus surfactant group died during the 90-minute post-near-drowning period of the study. Surfactant administration (5 mL/kg) in this animal model of freshwater near drowning offers no benefit over simple ventilation. Assessment of the merit of smaller volumes of surfactant should be investigated because administration of this solution may represent a second pulmonary insult, given current volume recommendations.

Effect of maternal glucocorticoid exposure on risk of severe intraventricular hemorrhage in surfactant-treated preterm infants

Objective: To determine whether the reduced risk of severe intraventricular hemorrhage (SIVH) that follows antenatal maternal glucocorticoid (AMG) receipt is mediated by an AMG effect on blood pressure or improved respiratory function in infants who receive artificial surfactant as rescue therapy. Design: Retrospective cohort study. Setting: Two level III neonatal intensive care units, Boston, Mass. Participants: Two hundred twenty-five infants ≤32 weeks of gestational age and ≤1.7 kg birth weight, treated with surfactant. Main findings: SIVH occurred in 10% (10/102) of infants who were exposed to AMG, compared with 23% (25/111) of infants not exposed (odds ratio, 0.4; 95% confidence interval, 0.2 to 0.8). Hypotension and need for colloid or dopamine were associated with both SIVH and the absence of AMG exposure ( p ≤0.03). Logistic regression models of SIVH risk and AMG exposure, with adjustment for antenatal potential confounders, were altered by the addition of measures of hypotension. Most clinical measures of pulmonary function, both before and after surfactant receipt, were not associated with reduced risk of SIVH and did not appear to account for the increased risk of SIVH in babies not exposed to AMG. Conclusion: The reduced risk of SIVH in preterm newborn infants whose mothers received AMG was associated with normal blood pressures. The association between AMG and SIVH was not consistently enhanced by respiratory function improvement after surfactant therapy. (J P EDIATR 1995;126:272-9)

サーファクタント様物質と滲出性中耳炎(総説)

The cause of OME (otitis media with effusion) is not clearly known, but many studies indicate that dysfunction of the eustachian tube plays a role in its pathogenesis. The potential existence of a STLS (surface tension lowering substance) in the middle ear cavity which facilitates the opening of the eustachian tube was first postulated by Bauer in 1970.Appreciable phospholipids were shown to be present in eustachian tube lavage fluid by many investigators. The major components of pulmonary surfactant are phospholipids, especially DSPC (dipalmitoyl phosphatidylcholine). We also detected the existence of DSPC in middle ear effusions.Monoclonal antibodies against pulmonary surfactant protein were prepared by Kuroki et al. We found fine positive granules in the mucosal epithelial cells of the middle ear, while Lamellar bodies were found in the secretory cells of the middle ear by electromicroscopic examinations.Yamanaka et al reported that the positivity of SAP (surfactant apoprotein) in middle ear effusions showed a good correlation with the clinical course of OME, and the period of observation of SAP-positive cases being significantly shorter than that of SAP-negative cases.Some investigators have suggested the efficacy of treating OME with artificial pulmonary surfactant. Kobayashi et al reported that the use of artificial surfactant was effective for patients with OME.

Alternative treatment may lower the need for use of extracorporeal membrane oxygenation.

Access to artificial surfactant and high frequency oscillatory ventilation (HFO) in Japan seems to affect the actual indications for extracorporeal membrane oxygenation (ECMO). The relation between the methods of treatment and survival and/or neurological sequelae of 27 neonates with severe respiratory failure who would have met the US ECMO entry criteria in the Neonatal Intensive Care Unit of National Children's Hospital, Tokyo between January 1988 and May 1992 were retrospectively analyzed. Out of 27 neonates, conventional treatment including artificial surfactant was successful in 6 cases (22%). High frequency oscillatory ventilation was used for the 21 cases who did not respond to conventional treatment and it was effective in 5 cases (19% of total). Extracorporeal membrane oxygenation was used on 11 (40% of total) of 16 cases who did not respond to HFO. Eight (29% of total or 73% of ECMO cases) of these cases survived and 3 cases (11% of total) died. The remaining 5 cases (19% of total) who met the exclusion criteria of ECMO died. No patient with respiratory distress syndrome (RDS) became ill enough to meet the US ECMO entry criteria. Six out of 8 congenital diaphragmatic hernia cases were saved on a delayed surgery protocol with HFO. Only about 1% of the neonates who were admitted to our NICU during the last 4 years needed ECMO treatment. Forty-one per cent of the patients who would have met the US ECMO entry criteria were treated successfully without ECMO. The necessity for ECMO is less in Japan than in the US because other methods can often be used successfully to treat severe respiratory disorders.

Pulmonary Hemorrhage Risk in Infants With a Clinically Diagnosed Patent Ductus Arteriosus: A Retrospective Cohort Study

To determine if an early, clinically detectable patent ductus arteriosus (PDA) was associated with pulmonary hemorrhage (PH) in infants who received rescue artificial surfactant therapy. This retrospective cohort study of 233 low birth weight infants (< or = 1700 g) who received artificial surfactant therapy for respiratory distress syndrome compared antenatal and postnatal characteristics of infants with PH and without PH. Pulmonary hemorrhage was defined by an onset of bright red blood from the endotracheal tube in quantities that resulted in increased ventilatory support and a new infiltrate on a chest radiograph. Pulmonary hemorrhage occurred in 6% (15/233) of the infants. Thirty-three percent (5/15) of the infants with PH died within 14 days of the hemorrhage. Of the 15 PH, 73% occurred within 48 hours of the first surfactant dose. Pulmonary hemorrhage was more common in male infants and infants of mothers who received antibiotic therapy during labor (P < or = .04). Infants with PH received surfactant earlier than those without PH (P = .04). Nursery events or therapies occurring following surfactant therapy that were associated with PH included: little improvement in ventilatory efficiency index (P = .01), dopamine infusion (P = .04), and the presence of a clinically detectable PDA before, or at the time of, the PH [60% (9/15) vs 33% (71/217), P = .03]. After adjusting for severity of illness before surfactant therapy, risk of PH remained greater in infants who developed symptoms of a PDA. Dopamine support appeared to modify the association between PDA and PH. In this retrospective cohort study, pulmonary hemorrhage, was associated with the presence of a clinically detectable patent ductus arteriosus before, or at the time of, pulmonary hemorrhage.