On exogenous surfactant therapy.
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Biological Products↗
Biomedical subjects
T A Merritt
Publications and source records attributed to T A Merritt.
Congenital pulmonary alveolar proteinosis: failure of treatment with extracorporeal life support.
Pulmonary alveolar proteinosis, a rare disease in neonates, is characterized by the accumulation of insoluble amorphous material within the alveoli. We describe two pairs of siblings with pulmonary alveolar proteinosis in two otherwise unaffected families. All four patients were term neonates in whom severe pulmonary failure developed within hours after birth; three had mature lung profiles. Radiographic lung markings were characterized by an early granular pattern followed by lung opacification. All patients were treated with extracorporeal life support for periods of 212 to 381 hours, but none survived. Life spans ranged from 16 to 190 days. We speculate that pulmonary alveolar proteinosis in neonates results from a genetic defect in surfactant processing that may not be amenable to conventional or unconventional therapies, including extracorporeal life support.
Extracorporeal Membrane Oxygenation↗
Acceleration of alveolar type II cell differentiation in fetal rhesus monkey lung by administration of EGF.
To examine the effect of epidermal growth factor (EGF) on lung parenchymal maturation in fetal rhesus monkey, recombinant human EGF was administered intraperitoneally (IP) at 66 mg/kg body wt over a 7-day period into the fetal peritoneal cavity alone or IP and into the amniotic fluid (AF) simultaneously. The saline carrier was injected IP and AF into control (CO) fetuses. The body weights of the IP + AF group were significantly larger than CO. Overall lung growth, measured as wet lung weight or fixed volume of the right cranial lobe, was unchanged. Fixed lung volume per gram body weight was significantly lower for both IP + AF and IP compared with CO. Morphogenesis of lung parenchyma, measured as percent parenchymal airspace or airspace size, was unchanged. Alveolar type II cell ultrastructure was significantly altered by EGF treatment; volume fraction of cytoplasmic glycogen was 50% less and lamellar bodies threefold greater for IP + AF and IP groups compared with CO. Total phospholipid content of AF was not altered, but relative percentages of different phospholipids were changed by EGF treatments; phosphatidylinositol was significantly reduced, and phosphatidylglycerol was significantly elevated. The lecithin-to-sphingomyelin ratio was unchanged. Surfactant apoprotein A concentration in AF was significantly elevated and was detected by immunoperoxidase in more cuboidal alveolar cells in EGF-treated animals when compared with CO. We conclude that exogenous EGF administered in the last trimester of pregnancy accelerates structural and functional cytodifferentiation of the alveolar type II cell in fetal primates. These maturational changes occur in the absence of significant alterations in overall lung growth or morphogenesis of the gas exchange area.
Amniotic Fluid↗
Bicarbonate concentration in rhesus monkey and guinea pig fetal lung liquid.
Fetal lung liquid secretion is essential for the normal growth of the lung in utero. Previous studies of fetal lung liquid secretion, mostly performed in lambs, have demonstrated that it has high Cl and very low HCO3- concentrations relative to plasma values. Because it is unknown whether primates have a similar electrolyte profile in their lung liquid, we sampled the lung liquid from rhesus monkeys (Macaca mulatta) at 127 to 128 days gestation (0.8 gestation). Although we found that lung liquid Cl concentration was higher than plasma values (p < 0.05), the HCO3- concentration was the same as in the plasma. This indicates that nonhuman primates, relative to lambs, have different cellular mechanisms for regulating fetal lung liquid HCO3- concentrations.
Animals↗
Distribution of surfactant, lung compliance, and aeration of preterm rabbit lungs after surfactant therapy and conventional and high-frequency oscillatory ventilation.
Previous studies in preterm lambs have shown that exogenous surfactant is more uniformly distributed if given at birth before ventilation or if followed by high-frequency ventilation (HFV) after establishing conventional ventilation (CV). We hypothesized that the pre-term rabbit pup would respond similarly and that improved respiratory system compliance (Crs) would accompany improved surfactant distribution. We randomized pups (27 d gestation) into three groups: control, surfactant at birth, and surfactant after 15 min of CV (rescue). We administered dipalmitoylphosphatidyl-[3H]choline-labeled natural surfactant by tracheostomy to each of the treated groups. The two treatment groups were treated for 15 min with either HFV or CV and subsequently with CV. We measured Crs at 15, 25, 35, and 45 min after surfactant. Lungs from pups treated with CV or HFV (n = 89) for 15 min, with and without 30 min of subsequent CV, were cut into 32 pieces that were counted for distribution of label or were sectioned for quantitative morphometry (n = 36). Pups receiving surfactant after 15 min of CV had higher Crs 15 min after surfactant than either pups treated with surfactant at birth or controls (p less than 0.001). The Crs of pups 15 min after rescue surfactant followed by HFV was lower than that of pups treated with CV (p less than 0.05) but was higher than that of either control or pups treated at birth groups (p less than 0.05). Crs at 35 and 45 min after surfactant were the same in all treatment groups. Application of HFV appeared to delay the delivery of surfactant to the distal airspaces.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Improving the prediction of surfactant deficiency in very low-birthweight infants with respiratory distress.
With the availability of exogenous surfactant therapy, distinguishing between surfactant deficiency and other causes of respiratory distress soon after birth is critical. Of 149 very low-birthweight (VLBW) infants of 24 to 30 weeks' gestation, 107 (72%) had both clinical and radiographic features of respiratory distress syndrome (RDS). Analysis of amniotic fluid obtained within 24 hours before birth or of the initial tracheal aspirate after birth for phosphatidylglycerol (PG) showed that absence of PG had a positive predictive value (PPV) of 80% for predicting RDS, while an immature lecithin/sphingomyelin (L/S) ratio had a PPV of 86% with a 68% specificity. When PG was absent and the L/S ratio was immature, the PPV for RDS increased to 89% (97% specificity). Phospholipid analysis was superior to gestational age alone in predicting RDS (P less than or equal to .02). Receiver operating characteristic (ROC) analysis detected different thresholds for immature L/S ratios for amniotic fluid (2.0) and initial tracheal aspirate (3.0) for predicting RDS. A tracheal aspirate L/S ratio less than or equal to 3.0 predicted RDS with 91% accuracy, while an amniotic fluid L/S ratio less than or equal to 2.0 predicted RDS with 90% accuracy. ROC curve thresholds for either tracheal aspirate or amniotic fluid permit selection of VLBW infants most likely to benefit from surfactant treatment. These analyses improve the accuracy of diagnosing surfactant-deficiency-associated RDS using only clinical and radiographic diagnoses, and may permit a more focused approach for rescue surfactant therapy in infants presenting with clinical symptoms of respiratory distress.(ABSTRACT TRUNCATED AT 250 WORDS)
Amniotic Fluid↗
Surfactant-replacement therapy.
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Drug Administration Schedule↗
Radiolabeling of the hydrophobic components of lung surfactant with 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine.
Studies of the metabolism and distribution of lung surfactant are aided by use of radiolabeled surfactant or surfactant components. These studies have often made use of [3H]- or [14C]phosphatidylcholine. Analysis of the lung content of surfactant containing these beta-emitting labels usually requires tissue digestion, use of scintillation fluids, and significant correction for quenching of photon production. Because use of a gamma-emitting isotope would obviate these requirements, we have investigated the use of 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine ([125I]TID), a lipophilic photoactivatable compound, to radiolabel pulmonary surfactant. Our results indicate that, during photoactivation, products of [125I]TID are produced that result in radiolabeling of both the lipid and protein components of extracted porcine surfactant. Separation of radiolabeled surfactant from hydrophobic nonlabelling photolysis products was accomplished by gel chromatography. Exposure of surfactant (34 mumol/ml) to [125I]TID under labeling conditions resulted in incorporation of 45.3 +/- 5.1% of the radiolabel. Incorporation of radiolabel in the various phospholipids of lung surfactant was approximately equivalent. Lipophilic surfactant apoproteins were also radiolabeled. Finally, both in vitro and in vivo testing of radiolabeled surfactant (0.1 microCi/mg) revealed full retention of surface tension lowering ability.
Animals↗
Controlled study of the effects of indomethacin on cerebral blood flow velocities in newborn infants.
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Blood Flow Velocity↗
Randomized, placebo-controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity.
A randomized, placebo-controlled trial of human surfactant given intratracheally at birth (prophylactic) versus rescue administration after the onset of severe respiratory distress syndrome (RDS) was conducted among preterm infants born at 24 to 29 weeks of gestation. Singleton fetuses were randomly assigned to receive (1) placebo (air), (2) prophylactic surfactant treatment, or (3) rescue surfactant treatment; infants of multiple births received either (1) prophylactic or (2) rescue treatment. Of 282 potentially eligible fetuses, 246 infants received treatments at birth and 200 infants had RDS. Outcomes are presented both as an intention-to-treat analysis (including infants who met exclusion criteria at or after birth) and as a full treatment protocol analysis for those infants with RDS and likely to benefit from surfactant. Preterm infants (mean 1.0 kg birth weight, 27 to 28 weeks of gestational age) randomly assigned to receive prophylactic treatment received surfactant soon after birth; those assigned to receive rescue surfactant had instillation at a mean age of 220 minutes if the lecithin-sphingomyelin ratio was less than or equal to 2.0 and no phosphatidylglycerol was detected in either amniotic fluid or initial airway aspirate, oxygen requirements were a fraction of inspired oxygen of greater than 0.5, and mean airway pressure was greater than or equal to 7 cm H2O from 2 to 12 hours after birth. Up to four treatment doses (or air) were permitted within 48 hours; approximately 60% of surfactant-treated infants required two or more doses. Surfactant-treated infants had significantly less pulmonary interstitial emphysema than placebo-treated infants (p = 0.02), but there were no other significant differences in mortality rates or morbidity. Indexes of oxygenation and ventilation were improved in surfactant recipients during the first 24 hours. An intention-to-treat analysis found no significant differences between infants given placebo and surfactant-treated infants or between prophylactic- and rescue-treated infants; an improved total mortality rate (p = 0.002) was found among surfactant-treated infants in Helsinki but not in San Diego. Among infants with RDS, the total mortality rate was significantly improved (p = 0.004) with surfactant treatment but not the proportion alive and without bronchopulmonary dysplasia at 28 days (p = 0.052), or the proportion alive and without bronchopulmonary dysplasia at 38 weeks of postconceptional age (p = 0.18) to adjust for differences in prematurity. Deaths caused by RDS or bronchopulmonary dysplasia were significantly reduced among surfactant recipients (p = 0.0001). Neither among singletons nor among multiple-birth infants was there a selective advantage to prophylactic versus rescue treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Bronchopulmonary Dysplasia↗
Neonatal surfactant deficiency and surfactant replacement therapy.
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Age Factors↗
Immunogenicity of surfactant. I. Human alveolar surfactant.
The immunogenicity of lung surfactant derived from amniotic fluid has been well established. We have set out to examine the antigenic similarity of human surfactant to non-human alveolar surfactants currently being used therapeutically in clinical trials with neonatal respiratory distress syndrome. To this end, we raised a series of eight monoclonal antibodies in rats directed to human surfactant (H1 to H8). All antibodies bound human surfactant as measured by ELISA. Four of these monoclonal antibodies bound surfactant components by Western blot analysis: all bound a 9-10-kD species. In addition, one antibody (H2) bound a protein of 16 kD, one (H8) a 6-kD protein, and one (H6) a 30-kD protein. When mixed with surfactant, three antibodies, H4, H7 and H8, profoundly altered surfactant activity in vitro in the pulsating bubble surfactometer. Three other antibodies, H1, H2, and H5 moderately inhibited surfactant's surface activity. We also examined the cross-reactivity of these monoclonal antibodies with bovine (CLSE) and porcine (Curosurf) surfactants. By Western blot analysis, only H6 bound these heterologous surfactants. Other antibodies did so by ELISA. However, functional assays indicated that antibodies H7, H8 and H4 all greatly inhibited CLSE surface activity in vitro. Five antibodies (H1-H4 and H8) inhibited Curosurf function. Thus, human surfactant species, especially low molecular weight species, are highly antigenic. Antibodies to alveolar surfactants may inhibit surfactant function in vitro. As indicated by Western blot and cross-inhibition data, human lower molecular weight surfactants share epitopes with proteins from therapeutically important porcine and bovine surfactants. The potential importance of these findings to treatment of neonatal respiratory distress syndrome with heterologous surfactants is discussed.
Amniotic Fluid↗
Immunogenicity of surfactant. II. Porcine and bovine surfactants.
Protein-containing surfactants of human and animal origin are being used increasingly to treat neonatal and adult respiratory distress syndromes. This trend led us to examine the antigenicity of two important preparations of animal surfactant, cow lung surfactant extract (CLSE) and a porcine surfactant preparation, Curosurf. We describe here 15 monoclonal antibodies against Curosurf and four against CLSE. Antibodies were studied by Western blot analysis to determine their ability to recognize protein components of their respective surfactant preparations. They were also tested for their ability to inactivate surfactant in vitro, assayed using the pulsating bubble surfactometer. Several antibodies directed against CLSE or Curosurf functionally inactivate the surfactant to which they were raised. We determined the degree of immunologic cross-reactivity between antibodies directed to CLSE and Curosurf against the other surfactant and also against human surfactant, both by Western blot and by examining functional inactivation in vitro. Antibodies to these animal surfactants that are commonly used therapeutically may inactivate the specific animal surfactant to which they were raised, as well as human and other surfactants. Generally, when antibodies inactivate surfactant from more than one animal species, they inactivate heterologous surfactants comparably to the extent to which they inactivate the surfactant to which they are directed. Immune complexes between anti-surfactant antibodies and surfactant have been described in the course of neonatal respiratory distress syndrome. The potential pathophysiological importance of anti-surfactant antibodies may therefore lie in their ability to inactivate administered surfactant, other similar surfactants and endogenous surfactant. In so doing, these antibodies may potentiate surfactant deficiency or pulmonary injury initiated by other stimuli.
Animals↗
Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Correlation with surface activity, severity of respiratory distress syndrome, and outcome in small premature infants.
Although surfactant deficiency at birth is the major cause of respiratory distress syndrome (RDS), there is insufficient data on surfactant and surfactant inhibitors after birth. In the present study, a total of 345 airway specimens (AS) from 61 neonates of gestational age of 24 to 29 wk (54 with RDS) were analyzed for concentrations of phosphatidylcholine (PC), saturated PC (SPC), surfactant protein A (SP-A), nonsedimentable protein, and free amino acids in epithelial lining fluid (ELF). The relationship between surfactant indices, surface activity, and severity of RDS was studied. Treatment with human surfactant containing SP-A increased [PC]ELF and [SPC]ELF to levels found in infants without RDS. In placebo-treated infants similar concentrations were first reached between Days 4 and 7. Surfactant treatment increased the low SP-A/SPC ratio, although this ratio remained lower than that in exogenous surfactant. In RDS, the concentrations of free amino acids in ELF were 6 to 31 times higher than in infants without RDS. The nonsedimentable proteins of AS and cationic amino acids increased the minimum surface tension of SP-A-deficient surfactant from AS. Addition of SP-A improved the surface activity. According to multiple regression analysis, In [PC]ELF (p less than 0.0001), SPC/PC ratio (p less than 0.0001), In SP-A/SPC ratio (p less than 0.0002), and [protein]ELF (p less than 0.01) correlated with alveolar-arterial oxygen pressure gradient. Of the infants weighing less than 1,000 g, those who were going to die or develop bronchopulmonary dysplasia had a strikingly lower SP-A/SPC ratio during the first week (less than 25 ng/nmol) than those surviving without BPD.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
The use of synthetic peptides in the formation of biophysically and biologically active pulmonary surfactants.
Synthetic pulmonary surfactants consisting of mixtures of phospholipids with synthetic peptides based on the amino acid sequence of human surfactant apoprotein SP-B were prepared. These surfactants were analyzed for their ability to lower surface tension on a pulsating bubble surfactometer and for their capacity to improve lung compliance and increase alveolar expansion in a fetal rabbit model of surfactant deficiency. The data demonstrate that several peptides, ranging from 17 to 45 residues in length, matching the carboxy-terminal sequence of the SP-B protein, when appropriately recombined with the phospholipid dipalmitoylphosphatidylcholine and phosphatidylglycerol (3:1), are capable of producing a synthetic surfactant with biophysical and biologic activity approaching that of human surfactant derived from amniotic fluid.
1,2-Dipalmitoylphosphatidylcholine↗
Synthetic vs human surfactants in the treatment of respiratory distress syndrome: radiographic findings.
Exosurf, a synthetic surfactant, was instilled endotracheally in 49 neonates as treatment for respiratory distress syndrome. The radiologic courses of these neonates were compared with the courses of 18 neonates previously treated with human surfactant and of 18 untreated neonates. The radiologic severity of respiratory distress syndrome decreased significantly in neonates treated with Exosurf compared with that in untreated neonates. Radiologic improvement in those treated with Exosurf was slightly delayed when compared with the improvement of age-matched neonates treated with human surfactant. Otherwise no significant difference was noted between Exosurf and human surfactant in radiologic severity of respiratory distress syndrome or in the prevalence of pulmonary interstitial emphysema, pneumothorax, and bronchopulmonary dysplasia. These findings support the thesis that artificial surfactant is an acceptable substitute for surfactants of biological origin, with possible benefits of safety and ease of use.
Bronchopulmonary Dysplasia↗
Factors affecting surfactant responsiveness.
There is a wide variability in the therapeutic responsiveness to exogenous surfactant, a drug that has become generally available for the treatment of lung immaturity and respiratory distress syndrome. Recent studies have demonstrated evidence that therapies decreasing lung edema improve the effectiveness of surfactant substitution. In addition, exogenous surfactant may acutely decrease pulmonary perfusion since the airway pressures are effectively transmitted to airspaces, compressing alveolar capillaries, especially in hypovolemia. Therapies aimed at decreasing lung edema, improving cardiac output, and stepwise weaning from oxygen and ventilatory pressures are cornerstones in the successful management of patients undergoing surfactant therapy.
Ductus Arteriosus, Patent↗
In vivo and in vitro inactivation of bovine surfactant by an anti-surfactant monoclonal antibody.
In this study the importance of a low-weight surfactant protein (11 kDa) is demonstrated by selectively blocking this protein with a monoclonal antibody. In adult rats respiratory failure was induced by repeated bronchoalveolar lavage to remove all pulmonary surfactant. It was shown that surfactant mixed with the antibody was not capable of restoring lung function when compared with surfactant alone or surfactant mixed with control serum. Using the pulsating bubble surfactometer, it could be demonstrated that surfactant mixed with this antibody had a significant higher minimum surface tension when compared with surfactant alone, or surfactant mixed with an unrelated mouse immunoglobulin G (IgG). The inhibition of surfactant function by the monoclonal antibody suggests the importance of the 11 kDa protein for normal surfactant function.
Animals↗