Exogenous Surfactant Replacement Therapy Research Articles

The Underlying Causes of Respiratory Distress in Late-Preterm and Full-Term Infants Are Different From Those of Early-Preterm Infants

Background: A diagnosis of neonatal respiratory distress syndrome (RDS) is common among newborns in China. Some late-preterm and full-term (LP/FT) infants with respiratory distress (RD) symptoms but not primary surfactant deficiency are also diagnosed with RDS and given exogenous surfactant replacement therapy (SRT). Objectives: An increasing number of neonatologists have proposed that RD etiologies should be specifically classified to guide clinical treatment. Methods: The therapeutic effects of SRT on infants of different gestational ages (GAs) were compared in a large retrospective multicenter cohort study performed at 26 Neonatal Intensive Care units in China. The cause of RD at different GAs was further analyzed by comparing the different risk factors closely related to RDS severity at different GAs. Results: Analysis of 1240 infants diagnosed with RDS showed that SRT was less effective in LP/FT infants than in early-preterm (EP) infants. GA < 30 weeks and no prenatal corticosteroid use were closely related to RDS severity in EP infants, whereas perinatal infection- and perinatal hypoxia-associated risk factors and a high cesarean rate were closely related to RDS severity in LP/FT infants. Conclusions: The causes of RD might differ between LP/FT and EP infants, and the diagnosis of RDS might be overused in LP/FT infants. RD in LP/FT infants is more likely related to perinatal infection, perinatal hypoxia, elective cesarean and hereditary factors, which are important causes of neonatal pulmonary edema. New strategies for the treatment of refractory RD in LP/FT infants should concentrate more on pulmonary edema and neonatal ARDS.

The Comparison of LISA and INSURE techniques in term of neonatal morbidities and mortality among premature infants.

Background and aim of the work:Respiratory distress syndrome (RDS) is the most common cause of respiratory failure among premature infants. The most important choice for the treatment of RDS is still exogenous surfactant replacement therapy and respiratory support. Today, there are some different surfactant applying techniques. In this study, we aimed to evaluate the effects of the surfactant administration techniques in premature infants less than 33 weeks of gestational age.Methods:The medical data were collected retrospectively from the medical records of Baskent University, Konya Training and Research Hospital between 2010 and 2016. The patient divided into two subgroups as Less Invasive Surfactant Administration (LISA) group (n: 35) and Intubation- Surfactant administration and rapid Extubation (INSURE) group (n: 30). Two surfactant administration techniques were evaluated on the neonatal morbidities and mortality among premature infants.Results:There were no significant differences in maternal and neonatal characteristics between the two groups. Duration on the nasal continues positive airway pressure (nCPAP) is significantly higher in the LISA group as compared with the INSURE group (p<0.001). And also between two groups, there were no significant differences in term of neonatal mortality and morbidities.Conclusion:The technique of the surfactant administration has no effect on the postnatal morbidities. LISA method is safe and effective as much as INSURE method, which is still a good alternative in centers with lack of experience about LISA. We need to perform studies that have larger sample size and prospective randomized controlled trials. (www.actabiomedica.it)

Estimating the contribution of surfactant replacement therapy to the alveolar pool: An in vivo study based on 13 C natural abundance in rabbits.

Variation of the isotopic abundance of selected nutrients and molecules has been used for pharmacological and kinetics studies under the premise that the administered molecule has a different isotopic enrichment from the isotopic background of the recipient subject. The aim of this study is to test the feasibility of assessing the contribution of exogenous surfactant phospholipids to the endogenous alveolar pool in vivo after exogenous surfactant replacement therapy in rabbits. The study consisted in measuring the consistency of 13 C/12 C ratio of disaturated-phosphatidylcholine palmitate (DSPC-PA) in 7 lots of poractant alfa, produced over a year, and among bronchoalveolar lavages of 20 rabbits fed with a standard chow. A pilot study was performed in a rabbit model of lavage-induced surfactant deficiency: 7 control rabbits and 4 treated with exogenous surfactant. The contribution of exogenous surfactant to the alveolar pool was assessed after intra-tracheal administration of 200mg/kg of poractant alfa. The 13 C content of DSPC-PA was measured by isotope ratio mass spectrometry. The mean DSPC-PA 13 C/12 C ratio of the 7 lots of poractant alfa was -18.8‰ with a SD of 0.1‰ (range: -18.9‰; -18.6‰). The mean 13 C/12 C ratio of surfactant DSPC recovered from the lung lavage of 20 rabbits was -28.8±1.2‰ (range: -31.7‰; -25.7‰). The contribution of exogenous surfactant to the total alveolar surfactant could be calculated in the treated rabbits, and it ranged from 83.9% to 89.6%. This pilot study describes a novel method to measure the contribution of the exogenous surfactant to the alveolar pool. This method is based on the natural variation of 13 C, and therefore it does not require the use of chemically synthetized tracers. This method could be useful in human research and especially in surfactant replacement studies in preterm infants.

Is Less Invasive Surfactant Administration Necessary or "Only" Helpful or Just a Fashion?

In the 1990s, the most relevant pillars in the treatment of neonatal respiratory distress syndrome (RDS) have been improvements in ventilation strategies, the introduction of exogenous surfactant replacement therapy, and the use of antenatal steroids. Lately, in addition to the standard INSURE (INtubation-SURfactant administration-Extubation) method to administer surfactant, a new technique has been gaining increasing popularity. It is the so-called less invasive surfactant administration (LISA) method, which has shown promising results in preventing bronchopulmonary dysplasia development and in reducing mortality in preterm neonates. The rationale behind this technique is to avoid positive pressure ventilation and the endotracheal tube, being surfactant delivered through a thin catheter while the neonate is maintained on continuous positive airway pressure. Given the paucity of large-scale randomized trials on LISA method to prove its effects on short- and long-term outcomes, some questions still remain unanswered. Then, uncertainty regarding the feasibility of this maneuver needs to be better clarified before gaining wide acceptance in routine clinical practice. In our report, we aim at hypothesizing the main mechanisms behind the efficacy of LISA, considering it as a single maneuver in a comprehensive approach for RDS management in the delivery room.

The Efficacy of Surfactant Replacement Therapy in the Growth-Restricted Preterm Infant: What is the Evidence?

Background: Surfactant replacement therapy (SRT) is an integral part of management of preterm surfactant deficiency respiratory distress syndrome (RDS). Its role in the management of RDS has been extensively studied. However, its efficacy in the management of lung disease in preterm infants born with intrauterine growth restriction (IUGR) has not been systematically studied.Objective: To evaluate the efficacy of exogenous SRT in the management of preterm IUGR lung disease.Methods: A systematic search of all available randomized clinical trials (RCT) of SRT in preterm IUGR infants was done according to the standard Cochrane collaboration search strategy. Neonatal respiratory outcomes were compared between the preterm IUGR and appropriately grown for gestational age (AGA) preterm infant populations in eligible studies.Results: No study was identified which evaluated the efficacy or responsiveness of exogenous SRT in preterm IUGR infants as compared to preterm AGA-infants. The only study identified through the search strategy used small for gestational age (SGA; defined as less than tenth centile for birth weight) as a proxy for IUGR. The RCT evaluated the efficacy or responsiveness of SRT in preterm SGA group as compared to AGA-infants. The rate of intubation, severity of RDS, rate of surfactant administration, pulmonary air leaks, and days on the ventilator did not differ between both groups. However, the requirement for prolonged nasal continuous positive airway pressure (p < 0.001), supplemental oxygen therapy (p < 0.01), and the incidence of bronchopulmonary dysplasia at 28 days and 36 weeks (both p < 0.01) was greater in SGA-infants.Discussion: There is currently insufficient data available to evaluate the efficacy of SRT in preterm IUGR lung disease. A variety of research strategies will be needed to enhance our understanding of the role and rationale for use of SRT in preterm IUGR lung disease.

ABSTRACT 439

Background and aims: to prove scientifically and introduce into clinical practice the method of exogenous surfactant replacement therapy at the time of “mobilization of alveoli” in neonates and infants with ALI / ARDS, operated on different CHD. Methods: Central hemodynamics, X-rays of the lungs, gas exchange, ventilator parameters and mechanical properties of the lungs have been analyzed in 6 hours since the syndrome manifestation and also after the recruitment maneuver and the administration of exogenous surfactant. We also analyzed the duration of mechanical ventilation and the ICU period in 25 children aged from 24 days to 16 months (5,7 ± 4,8 m.). Surfactant was administered after the procedure of lung recruitment without the decompression circuit. Results: There was an increase from 135 paO2/FiO2 ± 38,0 to 329,6 ± 33,2 (p <0.05) in patients after the recruitment maneuver and the subsequent introduction of exogenous surfactant at the peak of the disclosure of alveoli. This allowed to reduce the intensity of ventilation modes downward Pmean with 12,4 ± 1,65 to 10,77 ± 2,66 mbar and with FiO2 0,76 ± 0,2 to 0,45 ± 0,06. One (4.16%) of the 25 patients died from the critical respiratory failure. Conclusions: Securing of ALI /ARDS targeted delivery of exogenous surfactant to the damaged alveoli at the first 24 hours since the beginning of manifestation with the concept of “the open lung”, leads to significant improvement and stabilization of the mechanical properties of the lungs and gas exchange, which enables to reduce aggressive ventilator settings.

Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome--where do we go from here?

Acute lung injury and acute respiratory distress syndrome (ARDS) are characterised by severe hypoxemic respiratory failure and poor lung compliance. Despite advances in clinical management, morbidity and mortality remains high. Supportive measures including protective lung ventilation confer a survival advantage in patients with ARDS, but management is otherwise limited by the lack of effective pharmacological therapies. Surfactant dysfunction with quantitative and qualitative abnormalities of both phospholipids and proteins are characteristic of patients with ARDS. Exogenous surfactant replacement in animal models of ARDS and neonatal respiratory distress syndrome shows consistent improvements in gas exchange and survival. However, whilst some adult studies have shown improved oxygenation, no survival benefit has been demonstrated to date. This lack of clinical efficacy may be related to disease heterogeneity (where treatment responders may be obscured by nonresponders), limited understanding of surfactant biology in patients or an absence of therapeutic effect in this population. Crucially, the mechanism of lung injury in neonates is different from that in ARDS: surfactant inhibition by plasma constituents is a typical feature of ARDS, whereas the primary pathology in neonates is the deficiency of surfactant material due to reduced synthesis. Absence of phenotypic characterisation of patients, the lack of an ideal natural surfactant material with adequate surfactant proteins, coupled with uncertainty about optimal timing, dosing and delivery method are some of the limitations of published surfactant replacement clinical trials. Recent advances in stable isotope labelling of surfactant phospholipids coupled with analytical methods using electrospray ionisation mass spectrometry enable highly specific molecular assessment of phospholipid subclasses and synthetic rates that can be utilised for phenotypic characterisation and individualisation of exogenous surfactant replacement therapy. Exploring the clinical benefit of such an approach should be a priority for future ARDS research.

Respiratory Failure in Premature Babies Born from Multiple Pregnancy

Objective: to reveal the factors that are responsible for the development of respiratory distress syndrome (RDS) and the specific features of its course in preterm twin neonates. Subjects and methods. Twenty-three patients who had had twin pregnancy, including 9 (39.1%) and 14 (60%) with monochorial and bichorial biamniotic twin pregnancies, respectively, were examined. Their mean age was 28.5±5.4 years. Obstetric and gynecologic histories, conditions at conception, the course of pregnancy, the type of pla-centation, and fetal presentation were considered. The placentas were morphologically examined. In all the patients, pregnancy ended in birth of 46 premature neonates, of them there were 19 (41.3%) boys and 27 (58.7%) girls. The gestational age of the neonates averaged 31.7±2.3 weeks. The evaluation of the efficiency of performed therapy used clinical assessment of the status of the premature neonates; measurement of partial oxygen tension (pO2) and calculation of alveolar-arterial oxygen gradient (A-a DO2), respiratory index (RI), and oxygenation index (OI); death rates were analyzed. Results. The main cause of respiratory failure (RF) was RDS in premature twins. Neonatal blood aspiration-caused pneumonia occurred in one case. The course of RDS was variable. Most neonatal infants needed exogenous surfactant replacement therapy and mechanical ventilation (MV). No signs of RF were present in 7 (15.2%) premature neonates. Conclusion. Premature twins are a high RDS risk group. The unfavorable factors that contribute to the development of the disease are multiple pregnancy, a past maternal obstetric history, in-vitro fertilization-induced pregnancy, severe gestosis in the second half of pregnancy, and preterm delivery. The type of placentation affects the fetal status after birth. Fatal outcome occurred in infants from the monochorial bioamniotic twins. In multiple pregnancies, there are pathological changes in the placenta, its membranes, and umbilical cord, which induces fetal circulatory disorders and creates unfavorable conditions for untrauterine development of the fetal lung. In premature twins, MV considerably varies in duration: from short-term to long-term, which is suggestive of the severe course of RDS in a number of cases despite the administration of a surfactant. Hgh neonata! RSD death rates recorded in the twins. Key words: premature neonates, respiratory distress syndrome, surfactant, mechanical ventilation, multiple pregnancy, type of placentation.

Lucinactant (Surfaxin™) for Prevention and Treatment of Respiratory Distress Syndrome in Newborns

Respiratory distress syndrome, resulting from the deficiency of endogenous surfactant, remains a leading cause of mortality and morbidity in preterm infants. Exogenous surfactant replacement therapy is one of the most widely researched areas in neonatal medicine and is now accepted as the standard of care for preventing and treating respiratory distress syndrome in these newborns. Exogenous surfactant replacement therapy has evolved in the past three decades, but controversies still exist as to the choice of preparation (i.e., is one better than the others?), dosing and volume of individual preparations, and cost. At present, animal-derived surfactants that contain proteins appear to be the choice of most clinicians; however, they may have the limitation of being derived from animal sources. This has prompted the development of newer synthetic surfactants such as lucinactant (Surfaxin™, Discovery Laboratories, PA, USA), which contains the protein B mimic synthetic peptide, sinapultide. Although it is not yet commercially available or approved for clinical use by regulatory authorities, recent Phase III clinical trials with lucinactant demonstrated promising results with similar efficacy to animal-derived surfactants whilst avoiding the disadvantage associated with animal products. The availability of such a surfactant in large amounts at a relatively lower production cost should also prompt further investigations regarding expanded use of surfactants in conditions other than neonatal respiratory distress syndrome, such as meconium aspiration syndromes and pneumonia, and as a vehicle for administering drugs directly to the lungs. There are also some developments towards making aerosolized forms of surfactant, which could be administered noninvasively, thus obviating the need for endotracheal intubation and its associated complications. The purpose of this article is to provide an appraisal of the recent advances in surfactant replacement therapy and its future developments.

Role of Lung Surfactant in Respiratory Disease: Current Knowledge in Large Animal Medicine

Lung surfactant is produced by type II alveolar cells as a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension and is crucial for the prevention of alveolar collapse. In addition, surfactant contributes to smaller airway patency and improves mucociliary clearance. Surfactant-specific proteins are part of the innate immune defense mechanisms of the lung. Lung surfactant alterations have been described in a number of respiratory diseases. Surfactant deficiency (quantitative deficit of surfactant) in premature animals causes neonatal respiratory distress syndrome. Surfactant dysfunction (qualitative changes in surfactant) has been implicated in the pathophysiology of acute respiratory distress syndrome and asthma. Analysis of surfactant from amniotic fluid allows assessment of fetal lung maturity (FLM) in the human fetus and exogenous surfactant replacement therapy is part of the standard care in premature human infants. In contrast to human medicine, use and success of FLM testing or surfactant replacement therapy remain limited in veterinary medicine. Lung surfactant has been studied in large animal models of human disease. However, only a few reports exist on lung surfactant alterations in naturally occurring respiratory disease in large animals. This article gives a general review on the role of lung surfactant in respiratory disease followed by an overview of our current knowledge on surfactant in large animal veterinary medicine.

Treatment of severe meconium aspiration syndrome with porcine surfactant: A multicentre, randomized, controlled trial

A randomized, controlled clinical trial was performed in 19 Chinese neonatal intensive care units to evaluate the safety and efficacy of exogenous surfactant replacement therapy for severe meconium aspiration syndrome (MAS) in term and near-term neonates. Sixty-one term infants with severe MAS were randomly assigned to either a surfactant or a control group within 36 h after birth. The infants in the surfactant group (n=31) received an initial dose of porcine lung-derived surfactant (Curosurf) at 200 mg/kg, and repeated doses of 200, 100 and 100 mg/kg were given at 6-12 h intervals to a maximum of four doses if oxygenation index (OI) deteriorated by >2 from baseline. The primary outcomes were a reduction of OI to less than 10 and an increase of the pre-treatment a/A PO(2) ratio of 100% over baseline 24 h after surfactant treatment. The secondary outcomes were duration of mechanical ventilation, incidence of complications and survival to discharge from hospital. The general demographic characteristics of the study subjects were similar. There was a trend for surfactant-treated infants to have an improvement in arterial oxygenation compared to the control group. In comparison with the control group at 24 h, the surfactant group had a lower mean OI (8.1 vs 10.9), more infants with a 100% increase of a/A PO(2) (83% vs 48%, p<0.01) over baseline, and a larger area under the curve for PaO(2)/FiO(2) over baseline (3762+/-1877 vs 2715+/-1644 mmHg(.)h, p<0.05). Repeated measures of these parameters were also in favour of the surfactant group during 24 h to 3 and 7 d compared to the baseline (p<0.05). No differences were found in mean duration of mechanical ventilation, incidence of major complications and number of survivors between the two groups. Surfactant replacement therapy improved oxygenation in the study subjects, suggesting that surfactant may have a role in the treatment of severe MAS in term and near-term infants.

Liquid Ventilation: Current Status

1. Thomas H. Shaffer, PhD* 2. Marla R. Wolfson, PhD† 3. Jay S. Greenspan, MD‡ 1. 2. *Professor of Physiology and Pediatrics; Director, Respiratory Physiology Section, Temple University School of Medicine, Philadelphia, PA. 3. 4. †Associate Professor of Physiology and Pediatrics, Temple University School of Medicine, Philadelphia, PA. 5. ‡Professor of Pediatrics; Director, Section of Neonatology, Thomas Jefferson University, Philadelphia, PA. After reading this article, the reader should be able to: 1. List the potential medical applications of liquid-assisted ventilation (LAV). 2. Describe the properties of perfluorochemical liquids that are important for their use in liquid ventilation. 3. Describe the potential benefits of LAV in respiratory distress syndrome, congenital diaphragmatic hernia, acute respiratory distress syndrome, and aspiration syndromes. 4. Delineate specific nonrespiratory applications of LAV. With the advent of modern technology and the evolution of intensive care units, the ability to treat respiratory problems has improved remarkably. This accomplishment is particularly remarkable with respect to the 40,000 preterm infants born each year of whom thousands have severe respiratory problems. Fortunately, the number of smaller and more immature infants who are treated, survive respiratory distress, and recover uneventfully is increasing. However, the overall success of treating neonatal respiratory distress remains limited by the inherent problems of surfactant deficiency and structural immaturity of the lung. Consequently, infants delivered preterm who have respiratory insufficiency experience diminished lung distensibility that results in progressive atelectasis and respiratory failure requiring mechanical ventilation. Currently, many of these infants improve over time when their ventilation is supported mechanically and surfactant is introduced into their lungs. However, as many as 37% of these severely impaired infants are left with bronchopulmonary dysplasia related to damage of pulmonary tissues and structures from conventional mechanical ventilation (CMV). Of equal importance, acute respiratory distress syndrome (ARDS) due to trauma, aspiration, or infection strikes more than 100,000 adults in the United States annually. Despite aggressive therapeutic procedures, 60% to 70% of these patients die, and as in infants, many suffer complications associated with CMV. Although structural damage in adults or immaturity in infants cannot be altered acutely, current advances, such as exogenous surfactant replacement therapy to reduce alveolar interfacial surface tension and subsequent inflation pressures, have allowed clinical improvement …

The appearance of "early" chest radiographs and the response to surfactant replacement therapy.

We have assessed whether the appearance of the chest radiograph performed within the first 2 h of birth was predictive of the response to exogenous surfactant replacement therapy (SRT), as indicated by changes in sensitive indices of disease severity, that is lung volume (functional residual capacity (FRC)) and oxygenation (a/A ratio). 18 premature infants who received two doses of a synthetic surfactant (Exosurf) were studied. The appearances of chest radiographs taken prior to the first and immediately after the second dose of SRT were scored for lung volume, degree of inflation, presence of opacification, interstitial shadows and air bronchograms. At similar times, FRC was measured and the a/A ratio calculated. Although following SRT, the chest radiograph score decreased (p < 0.01) and the FRC (p < 0.01) and a/A ratio (ns) improved, there was no significant relationship between the change in chest radiograph score and either the change in FRC or a/A ratio. In addition, only the post-SRT chest radiograph appearance correlated significantly with the respective FRC, a/A ratio and outcome (death or oxygen dependency beyond 28 days). Although the appearance of an early chest radiograph is frequently used as an indicator of the need for SRT, these results demonstrate that, unlike the post-SRT radiograph, it is a poor predictor of the response to SRT and outcome.

Pharmacologie Interactions of Exogenous Lung Surfactant and Recombinant Human Cu/Zn Superoxide Dismutase

The effect of exogenous surfactant on the pharmacokinetics of intratracheally administered recombinant human superoxide dismutase (rhSOD) was studied. Five groups of rats received the following intratracheally: 1 mL/kg of saline; 5 or 25 mg/kg of rhSOD; or 4 mL/kg of exogenous surfactant followed in 30 min by 5 or 25 mg/kg of rhSOD. Animals were killed at 24, 48, and 72 h, and serum, bronchoalveolar lavage, and lung tissue were analyzed for rhSOD. rhSOD was not detected in the lungs of saline-treated animals or in serum from any animals. At 24 h, lung-tissue rhSOD was higher in rats treated with surfactant and rhSOD versus rhSOD alone (5 mg/kg: 6.8 +/- 2.5 versus 0 microgram/whole lung, p < 0.05; 25 mg/kg: 29.9 +/- 9.6 versus 0.1 +/- 0.1 microgram/whole lung, p < 0.05). Bronchoalveolar lavage fluid levels correlated well with lung tissue concentrations. By 48 h, lung tissue rhSOD concentrations were insignificant in all groups. rhSOD was still present in lavage fluid from rats treated with surfactant and rhSOD. No rhSOD was detected at 72 h. In separate in vitro experiments, physical and biological drug-drug interaction studies were performed. When radiolabeled rhSOD was combined with exogenous surfactant and centrifuged at 10,000 x g for 30 min, 81.3 +/- 2.5% of rhSOD was found in the supernatant versus 18.7 +/- 2.5% in the surfactant pellet. Serial washing of the surfactant pellet removed virtually all remaining rhSOD. This finding suggests that the rhSOD and surfactant were only weakly associated. Combining rhSOD and exogenous surfactant did not alter the activity of either agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of antenatal dexamethasone administration on respiratory distress syndrome in surfactant-treated infants

Neonatal lung disease is primarily responsible for the perinatal morbidity and mortality associated with preterm birth. Recently exogenous surfactant replacement therapy has been used to prevent or treat respiratory distress syndrome. As part of a multicenter, preventive trial between February 1986 and December 1988 using calf-lung surfactant extract, we treated 147 infants with single dose calf-lung surfactant extract. We analyzed this experience to evaluate the possibility that antenatal steroids may be additive (with calf-lung surfactant extract) in reducing both the incidence and severity of respiratory distress syndrome. Although a reduction in the incidence of respiratory distress syndrome was observed among the 33 neonates exposed to antenatal dexamethasone when compared with the 114 infants given calf-lung surfactant extract alone, the difference was not significant (37.7% vs. 24.2% p = 0.15). However, comparison of neonatal subsets previously shown to benefit most from steroid use revealed an additive effect between calf-lung surfactant extract and dexamethasone in reducing both the incidence and severity of respiratory distress syndrome. Of the 99 singleton pregnancies, only 2 of 16 infants treated with calf-lung surfactant extract and dexamethasone developed respiratory distress syndrome, compared with the 33 of 83 calf-lung surfactant extract cases (p < 0.05). A similar reduction was observed in infants between 28 and 32 weeks' gestation (calf-lung surfactant extract, 21 of 79 vs. calf-lung surfactant extract and dexamethasone, 0 of 24; p < 0.05). A reduction in disease severity was observed in male offspring (moderate or severe respiratory distress syndrome only; 22 of 63 vs. 2 of 22; p < 0.05). Potential confounding variables (e.g., gestational age at birth, birth weight, exposure to tocolytics before delivery, fetal pH at birth) were similar in all comparisons. We conclude that an additive effect between dexamethasone and calf-lung surfactant extract is observed in selected cases. It may therefore be appropriate to maximize antenatal steroid use in centers where exogenous surfactant is available.

Biophysical activity of synthetic phospholipids combined with purified lung surfactant 6000 Dalton apoprotein

This research studies the biophysical surface activity of synthetic phospholipids combined in vitro with purified lung surfactant apoprotein, having an M r of 6000. Hydrophobic surfactant-associated protein (SAP-6) was delipidated and purified from both bovine and canine lung lavage, and was combined in vitro with a synthetic phospholipid mixture (SM) of similar composition to natural lung surfactant phospholipids. SM phospholipids were also combined and studied biophysically with another purified surfactant-associated protein, SAP-35. The biophysical activity of synthetic phospholipid-apoprotein combinants was assessed by measurements of adsorption facility and dynamic surface tension lowering ability at 37°C. The SM-SAP-6 combinants had adsorption facility equivalent to natural lung surfactant, and to the surfactant extract preparations CLSE and surfactant-TA used in exogenous surfactant replacement therapy for the neonatal Respiratory Distress Syndrome (RDS). The synthetic phospholipid-SAP-6 combinants also lowered surface tension to < 1 dyne/cm under dynamic compression in an oscillating bubble apparatus at concentrations as low as 0.5 mg phospholipid/ml. A striking finding was that this excellent dynamic surface activity was preserved as SAP-6 composition was reduced to values as low as 5 μ/5 mg SM phospholipid (0.1% SAP-6 protein), an order of magnitude less than the 1% protein content of CLSE and surfactant-TA. Mixtures of SM phospholipids plus SAP-35, the major surfactant glycoprotein, had significantly lower biophysical activity, which did not approach that of a functional lung surfactant. These results suggest that synthetic exogenous surfactants of potential utility for replacement therapy in RDS can be formulated by combining synthetic phospholipids in vitro with specifically purified, hydrophobic surfactant-associated protein, SAP-6.

Phospholipid binding and biophysical activity of pulmonary surfactant-associated protein (SAP)-35 and its non-collagenous COOH-terminal domains.

Surfactant-associated protein of Mr = 35,000, SAP-35, is the major glycoprotein present in mammalian pulmonary surfactants. In this study, canine SAP-35 and several of its COOH-terminal peptides were purified and characterized by amino acid composition and NH2-terminal sequencing analysis. These proteins were then studied in terms of their specific lipid-binding characteristics and surface activity when combined with a synthetic phospholipid mixture, SM, chosen as an approximation of lung surfactant phospholipids. Purified, delipidated SAP-35 bound SM strongly. In contrast, SAP-21 (a non-collagenous fragment generated by collagenase digestion) bound phospholipid weakly; SAP-18 (an acidic COOH-terminal fragment comprising residues Gly-118 to Phe-231) did not bind phospholipid, demonstrating the importance of hydrophobic amino acid residues Gly-81 to Val-117 and the NH2-terminal collagenous domain in interaction of the SAP-35 with phospholipids. In surface activity experiments, purified SAP-35 enhanced the adsorption of SM phospholipids in terms of both rate and overall surface tension lowering. However, the adsorption facility of the SM-SAP-35 mixture did not approach that of either whole surfactant or the surfactant extract preparations, calf lung surfactant extract or surfactant-TA, used in exogenous surfactant replacement therapy for the neonatal respiratory distress syndrome. In addition, the dynamic surface activity of the SM-SAP-35 mixture was well below that of natural surfactant or surfactant extracts. This was also true of mixtures of SM phospholipids combined with the SAP-18 and SAP-21 fragments of SAP-35.

THE EFFECTS OF SURFACE TENSION ON LUNG FUNCTION DURING EARLY DEVELOPMENT

Pressure-volume and lung compliance/kg determinations were made in a total of 45 preterm lambs during gas ventilation (GR I: n = 31; 122-140 days gestation; 3.3-3.9 kg birthweight and liquid fluorocarbon (RIMAR 101) ventilation (GR II: n = 14; 106-138 days gestation; 1.1-3.4 kg birthweight. After effective ventilation (PaO2 > 60mmHg; PaCO2 = 30-45mmHg) and acid-base status (pH = 7.25 - 7.45) were achieved, pulmonary function was evaluated. Regression analysis showed significantly different relationships between lung compliance and developmental age for GR I (r = 0.95) and GR II (r = 0.99). Compliance for GR II lambs was consistently greater than for GR I lambs, this difference did not become significant until after 125 days gestation. These results indicate that minimizing interfacial surface tension has little effect on lung compliance in animals at earlier gestational ages, therefore suggesting that morphologic and tissue properties predominate surface properties in limiting lung distensibility. By defining the stage of development in which pulmonary function is most effectively improved by reduced surface tension, these findings suggest age-related criteria regarding the benefit of exogenous surfactant replacement therapy. (Supported by NIH Grant HL/HD 30525).

1862 AGE-RELATED EFFECTS OF SURFACE TENSION ON LUNG FUNCTION DURING EARLY DEVELOPMENT

To study the effect of surface tension (ST) on lung mechanics during early development, in vivo pressure-volume and lung compliance/kg (CI) determinations were made in preterm lambs. GR I (n=31; 122-140 days gestation; 2.25-3.90 kg BW) were gas ventilated and GR II (n=14; 106-138 days gestation; 1.10-3.40 kg BW) were liquid ventilated with oxygenated fluorocarbon (RIMAR 101). After effective ventilation (PaO2>60 mmHg; PaCO2=30-45 mmHg) and acid-base status (pH=7.25-7.45) were achieved, pulmonary function was evaluated (30-60 mins postnatally). Regression analysis showed significantly different relationships between CL and age for GR I (r=0.95; p<.001) and GR II (r=0.99; p<.001). Whereas CL for GR II consistently exceeded that for GR I, this difference did not become significant until after 125 days gestational age (GA). These data indicate that minimizing interfacial ST has little effect on CL in animals <125 days GA, thereby suggesting that morphologic and tissue properties predominate surface properties in limiting lung distensibility at this early age. By defining the stage of development in which pulmonary function is most effectively improved by reduced ST, these findings suggest age-related criteria regarding the benefit of exogenous surfactant replacement therapy. (Supported by NIH Grant HL/HD 30525).

Natural and artificial lung surfactant replacement therapy in premature lambs.

The effect of tracheal instillation of surface-active mixtures in premature lambs was studied as an animal model of exogenous surfactant replacement therapy for the respiratory distress syndrome (RDS). Specific mixtures studied were 7:3 (molar ratio) dipalmitoyl phosphatidylcholine (DPPC):egg phosphatidylglycerol (PG) and extracted mixed lipids (with 1% protein) from cow lung lavage (CLL). Preventilatory tracheal instillation of greater than 15 mg/kg of CLL in 10 ml 0.15 M NaCl to premature lambs gave improved alveolar-arterial O2 gradient and blood gases and increased lung compliance, compared with control lambs over a 15-h period. Lambs receiving 7:3 DPPC:PG dispersions were not improved over controls with regard to pressure-volume characteristics and were worse than controls in arterial oxygenation. In terms of in vitro surface properties, both extracted natural CLL and 7:3 DPPC:egg PG were able to lower aqueous surface tension to 1 dyn/cm under dynamic compression. However, the dynamic respreading of CLL films on successive surface cycles was superior to that of 7:3 DPPC:PG. Moreover, after dispersal in 0.15 M NaCl by vortexing (5 mg/80 ml), CLL adsorbed to surface pressure (tau values of 45 dyn/cm within 10 min. 7:3 DPPC:PG adsorbed to significantly lower tau values after subphase dispersal by a variety of methods.