PubMed Health⌕ Search

Biomedical subjects

T A Merritt

Publications and source records attributed to T A Merritt.

At least 37 records · Page 2Linked to original sources
PubMed1995

The influence of pH on surface properties of lung surfactants.

Protein-lipid interactions at air-liquid interfaces are dependent on electrostatic charges, cations, anions, distribution of protons, and surface potential, which are influenced by pH changes. All of these factors may affect lung surfactant function. To verify the pH dependence of surface activity of pulmonary surfactant, we studied the in vitro effects of pH and Ca2+ on the surface tension-lowering abilities of various surfactants in an oscillating bubble surfactometer. Surface tension measurements were made of mixtures at known pHs or after the replacement of the subphase fluid of surfactant films with buffered saline at various pH values. At the pH range 4.0-7.0, the average equilibrium surface tension (EST)/minimum surface tension (MST) for natural surfactants human amniotic fluid and natural lung surfactant from rabbit lung lavage was 24/2 mN/m. At the same pH range, Exosurf and phospholipids alone had an EST/MST of 44/25 and 44/12 mN/m, respectively. Survanta (SUR) containing SP-B and SP-C and a phospholipid surfactant (KL4) containing a leucine/lysine peptide had an EST/MST of 29/5 and 36/3, respectively. Alkalinization of the subphase (pH > 7.4) significantly decreased the surface tension-lowering ability of SUR (P < 0.01) and to a lesser extent that of KL4 surfactant (P < 0.05), but natural lung surfactants were not significantly affected over a pH range of 3-7.5. These data demonstrate that natural surfactants maintain their optimal surface activities over a broader pH range than do the commercial products because of a lack of SP-A. Careful monitoring of the pH for optimal surface activity is recommended when evaluating surfactant function and the effects of specific inhibitors on this function.

Acid-Base Equilibrium↗
PubMed1995

Levels of SP-A-anti-SP-A immune complexes in neonatal respiratory distress syndrome correlate with subsequent development of bronchopulmonary dysplasia.

As part of a double-blind, randomized, placebo-controlled study of human surfactant therapy for neonatal respiratory distress syndrome (NRDS), we measured circulating immune complexes between surfactant protein-A and anti-surfactant protein-A antibodies (SAS). Plasma from almost all infants contained detectable immune complexes. Immune complex levels in surfactant-treated infants were comparable with those of placebo-treated controls. Despite the relatively small sample size, maximum SAS immune complex values between 2 and 4 weeks after birth correlated significantly with subsequent development of BPD. Levels of these immune complexes correlated with eventual BPD independently of, and more strongly than, gestational age and birth weight. Thus, plasma SAS immune complex measurements may be useful in analyzing the course and outcome of NRDS, in particular the likelihood of subsequent development of BPD. This assay may also help to identify infants at risk for BPD and to target preventative therapy to them.

Antigen-Antibody Complex↗
PubMed1995

Combined effects of nitric oxide and hyperoxia on surfactant function and pulmonary inflammation.

NO and its derivative ONOO- are potent free radicals that can cause cell damage, especially in the presence of O2. To determine the potential pulmonary toxicities of nitric oxide (NO) and peroxynitrite (ONOO-) in vitro, Survanta (2.5 mg/ml) was exposed to ONOO- (0.3-8 mM) in the presence of two different buffering systems (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid and phosphate buffer) and minimum surface tension (MST) was determined with an oscillating bubble surfactometer. Significant increases in MST were seen only with exposure to 8 mM ONOO-, indicating that in vitro, high concentrations of ONOO- can inhibit natural surfactant function. The in vivo effects of NO and hyperoxia were then studied in four groups of newborn piglets ventilated for 48 h with 21% O2, 100% O2, 21% O2 and 100 ppm NO, or with 90% O2 and 100 ppm NO. Five animals served as an untreated control group. Bronchoalveolar lavage fluid (BAL) obtained at 48 h was subjected to centrifugation and the surfactant pellet was reconstituted to 5 mg phospholipid/ml. Significant increases in MST were seen in surfactant from piglets ventilated with NO and 90% O2, compared with either untreated controls or piglets ventilated with 21% O2 for 48 h (P < 0.05, analysis of variance). Significant increases in neutrophil chemotactic activity (NCA) of BAL were also found in the NO and O2 group (P < 0.05), with significant positive interaction between NO and O2 found (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Positive end-expiratory pressure during KL4 surfactant instillation enhances intrapulmonary distribution in a simian model of respiratory distress syndrome.

Intrapulmonary distribution of a peptide-phospholipid (KL4) surfactant administered through an adapter permitting maintenance of positive end-expiratory pressure was compared with distribution by instillation with disconnection from mechanical ventilation in 10 surfactant-deficient Macaca mullata preterm infants. Animals received KL4 surfactant (200 mg/kg) when the arterial to alveolar (oxygen ratio) (a/Ao2) was < or = 0.22 (approximately 50 min after birth) on mechanical ventilation. Six rhesus infants received bolus instillation of two half doses of KL4 surfactant through an endotracheal tube adapter over 10-15 s while maintaining positive end-expiratory pressure (0.4 kPa) accompanied by turning to the right and left lateral positions for 60 s. In four rhesus premature infants KL4 surfactant was injected as two half-dose boluses through the endotracheal tube with disconnection from mechanical ventilation while positioning the infant rhesus monkey in the right and left lateral positions for 30 s of mechanical ventilation between instillation. Acute effects on oxygen saturation were monitored, and physiologic measures of a/Ao2, mean airway pressure, and the ventilatory efficiency index were monitored over the 12-h study. Intrapulmonary distribution of KL4 surfactant was determined using dye-labeled microspheres or [3H]dipalmitoylphosphatidylcholine-labeled surfactant, measured by colorimetry or by scintillation counting. Lungs of each monkey were processed into 50 +/- 5 pieces to determine distribution of radiolabel or microspheres and for scanning electron microscopy. The drop in oxygen saturation was greater among monkey infants disconnected from the ventilator for surfactant instillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of different surfactants on pulmonary group B streptococcal infection in premature rabbits.

OBJECTIVES: To evaluate the effects of different surfactants on pulmonary infection with group B streptococci in premature rabbits and to examine the effects of different surfactants on pulmonary alveolar macrophage function of newborn rabbits. MODEL: Preterm and term rabbit pups. METHODS: Rabbit pups were infected with GBS aerosols followed by intratracheal administration of either calf lung surfactant extract, minced porcine lung surfactant (Curosurf), synthetic surfactant (Exosurf Neonatal), minced bovine lung surfactant (Survanta), human amniotic fluid-derived surfactant, rabbit surfactant, saline vehicle, or no treatment. Intrapulmonary clearance of GBS was determined by comparing bacterial counts in left lungs cultured immediately after aerosol infection with similarly infected lungs analyzed 4 hours after surfactant therapy. Phagocytosis of streptococci was ascertained by microscopic examination of the right lungs fixed in situ at 4 hours. For comparison, an in vitro method was used to measure growth of GBS in the different surfactants. RESULTS: Preterm animals had a sixfold increase in pulmonary bacterial growth compared with a slight decrease in intrapulmonary GBS in term animals when all were delivered by cesarean section (p < 0.05). In premature rabbits, GBS proliferation was lowest in animals treated with Exosurf Neonatal and highest in animals receiving Curosurf and human amniotic fluid-derived surfactant (p < 0.05). None of the surfactants promoted accelerated growth of GBS in comparison with control animals. Similar growth of GBS was seen in in vitro cultures. Intrapulmonary phagocytosis of GBS in premature pups was not altered by any of the surfactants. In term rabbit pups, the following measures of macrophage population kinetics remained normal at 1 and 24 hours after surfactant administration: viability, cell numbers based on lung lavage, and in vivo incorporation of thymidine. CONCLUSIONS: Surfactants used in clinical practice do not accelerate the in vivo growth of group B streptococci in the lungs of preterm rabbits. Some surfactants inhibit streptococcal proliferation. The effects of different surfactants are not explained by changes in macrophage function.

Animals↗
PubMed1994

Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency.

Congenital alveolar proteinosis (CAP) is an often fatal cause of respiratory failure in term newborn infants, which has been associated with a genetic deficiency of surfactant protein B (SP-B) as a result of a frameshift mutation (121ins2) in a family with three affected siblings. In the index cases the deficiency of SP-B was associated with qualitative and quantitative abnormalities of the surfactant proteins A and C. Immunostaining for lung surfactant proteins and a search for the 121ins2 mutation by restriction enzyme analysis of DNA extracted from paraffin-embedded lung tissue was performed for 7 additional affected infants from 6 families, bringing to 10 the total number of patients with CAP who have been studied. In six infants, the surfactant protein immunostaining pattern was similar to that of the index cases. Of these, three patients were homozygous for the 121ins2 mutation; one was a compound heterozygote with the 121ins2 in one allele and a different mutation in the other; and three patients lacked the mutation in both alleles. One infant had an abundance of SP-B, suggesting phenotypic heterogeneity in CAP. Lung ultrastructural abnormalities, such as a reduced number of lamellar bodies, absent tubular myelin, and basal secretion of surfactant lipids and proteins, suggest a significant derangement of surfactant metabolism. The phenotypic heterogeneity in infants with CAP raises the possibility that variable degrees of SP-B deficiency may be more common than previously suspected.

Female↗
PubMed1994

Exposure of the hydrophobic components of porcine lung surfactant to oxidant stress alters surface tension properties.

We have tested the hypothesis that oxidation of lung surfactant results in loss of surface tension lowering function. Porcine lung surfactant was exposed to conditions known to cause lipid peroxidation (0.2 mM FeCl2 + 0.1 mM H2O2 or 5 microM CuCl2). Lipid peroxidation was verified by detection of conjugated dienes, thiobarbituric acid reactive substances, fluorescent products, hydroxy alkenals, and loss of unsaturated fatty acids. Exposed samples had significantly diminished surface tension lowering ability in vitro as measured in a bubble surfactometer. Samples exposed to FeCl2 + H2O2 had significantly diminished surface tension lowering ability in vivo as indicated by their reduced ability to improve lung compliance of surfactant-deficient fetal rabbits. Oxidation of phospholipid mixtures with surface tension lowering activity and containing unsaturated acyl groups resulted in partial loss of activity as determined in vitro. These results suggest that the effect of oxidants on lung surfactant function is due, in part, to effects on the phospholipid components and that acute pulmonary inflammation accompanied by oxygen radical production may result in surfactant lipid peroxidation and loss of surface tension lowering function.

Animals↗
PubMed1994

Prenatal exposure to epidermal growth factor attenuates respiratory distress syndrome in rhesus infants.

Treatment of nonhuman primate fetuses with epidermal growth factor (EGF) results in histologic and biochemical maturation of their lungs. To determine whether these effects improve lung function postnatally, we studied premature rhesus infants delivered at 78% of gestation after in utero treatment with EGF (n = 5) or placebo (n = 5). Indices of lung function during the 4 d of postnatal care included fractional concentration of inspired oxygen, peak inspiratory pressure, ventilator rate, mean airway pressure, arterial to alveolar oxygen tension ratio, and ventilation index. Statistically significant differences were noted in the time courses of these variables between EGF- and placebo-treated infants. The direction of the differences indicated that the EGF-treated infants had less severe lung disease. Surfactant apoprotein A concentration and lecithin to sphingomyelin ratio were both significantly higher in the amniotic fluid of the EGF-treated group, indicating advanced biochemical maturation in this group of animals. Whereas birth weight was not affected by EGF exposure, adrenal and gut weights, standardized for body weight, were increased significantly. Histologic studies showed advanced cellular maturation with increased parenchymal airspace and decreased parenchymal tissue space in the EGF-treated group compared with the control group. We conclude that prenatal exposure to EGF stimulates biochemical and histologic maturation of the lung and markedly attenuates the clinical severity of respiratory disease in this model of simian respiratory distress syndrome.

Amniotic Fluid↗
PubMed1994

Surfactant therapy and high-frequency jet ventilation in the management of a piglet model of the meconium aspiration syndrome.

In vitro data have shown a concentration-dependent inhibition of surfactant by meconium, while anecdotal reports demonstrate improved oxygenation after surfactant replacement in babies with meconium aspiration syndrome, particularly in conjunction with high-frequency jet ventilation. We randomized 70 newborn piglets to either conventional or high-frequency jet ventilation, followed by insufflation of 3 mL/kg of a 33% meconium solution. Each group was further randomized to one of five surfactant therapies: 1) control, 2) 4 mL/kg Survanta, 3) 8 mL/kg Survanta, 4) 5 mL/kg Exosurf, or 5) 10 mL/kg Exosurf. We followed arterial blood gases and ventilator requirements over 6 h of ventilation. Aspirates of airway fluids were obtained for surface tension measurements, as well as total protein and phospholipid concentrations. Using a previously established scoring system, a pathologist blinded to treatment evaluated four sections of lung per animal for histologic changes of meconium aspiration syndrome. There were no differences noted between groups in any physiologic parameter measured (mean airway pressure, arterial partial pressure of oxygen/alveolar partial pressure of oxygen ratio, etc.) during the 6 h of ventilation. Airway fluid aspirate total protein concentrations increased significantly after meconium instillation (4- to 5-fold, p < 0.007) and remained elevated in spite of surfactant therapy. There was an initial decline in airway phospholipid concentrations after meconium instillation followed by a rise to levels equal to or greater than premeconium levels. Surface tension measurements increased in all groups after meconium insufflation (p < 0.012) and did not decline thereafter, despite standard and twice-standard surfactant doses of both types.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The fate of exogenous surfactant in neonates with respiratory distress syndrome.

Respiratory distress syndrome (RDS) in newborn neonates is characterised by deficient secretion of surfactant from type III alveolar cells. Administration of surfactant to airways acutely decreases the degree of respiratory failure and increases the survival rate in neonates with RDS. Clinically available surfactants are lipid extracts derived from animal lung lavage or from whole lung. Synthetic surfactants contain phospholipids or additional spreading agents. An optimal exogenous surfactant would be efficacious, nontoxic and nonimmunogenic, resistant to oxidants and proteolytic agents, widely available at reasonable cost and manufactured with little batch-to-batch variability. Surfactant has been instilled into the airways as a bolus infusion through the endotracheal tube. In addition, surfactant may be given by aerosolisation or continuous infusion into the airways. Suggested dosages range from 50 to 200 mg/kg. Exogenous surfactant is cleared from the epithelial lining fluid (ELF) mainly by alveolar epithelial cells, although alveolar macrophages and the central airways may also contribute to clearance of the drug. Only small quantities of surfactant actually enter the blood stream. A significant fraction of surfactant is taken up, processed, and secreted back into the alveolar space by type II alveolar cells. This process is termed recycling. Phosphatidylglycerol, given to small premature neonates as a component of exogenous human surfactant, has an apparent pulmonary half-life of 31 +/- 3 hours (n = 11). The apparent pulmonary half-life of the main surfactant component dipalmitoyl phosphatidylcholine is 45 hours (n = 3) and that of surfactant protein A is about 9 hours (n = 4). A relationship between the dose of exogenous surfactant and its concentration in the ELF has been demonstrated. Some neonates with RDS respond poorly to surfactant therapy. The reasons for this include insufficient levels of surfactant in the ELF, uneven distribution of exogenous surfactant, inability of exogenous surfactant to enter the metabolic pathways, inhibition of surface activity by plasma-derived proteins, or inactivation of surfactant as a result of proteases, phospholipases, or oxygen free radicals. In addition, surfactant therapy may be ineffective in neonates with respiratory failure caused by factors other than surfactant deficiency. The efficacy of exogenous surfactant can be improved by increasing the dosage of surfactant and by administration of surfactant very early in respiratory failure.

Animals↗
PubMed1993

Reduction of the surface-tension-lowering ability of surfactant after exposure to hypochlorous acid.

The reactive species hypochlorous acid (HOCl/OCl-) is a major product of the respiratory burst in activated neutrophils. We studied the effects of HOCl/OCl- on human surfactant and upon surfactants Survanta, KL4 and Exosurf, utilizing a pulsating surfactometer for measuring surface tension. HOCl/OCl- induced a marked dose-dependent decrease in the surface-tension-lowering activity of human surfactant. The surfactant containing surfactant proteins B and C (Survanta) was less sensitive; however, synthetic surfactants with or without peptides were not affected by HOCl/OCl- (KL4, Exosurf). Ascorbic acid and GSH protected human surfactant against inactivation by HOCl/OC1-. We suggest that HOCl/OCl- produced by activated phagocytes in the alveolar compartment of the lung could damage endogenous surfactant and affect the function of exogenously administered natural or other surfactants, especially if ascorbic acid and GSH levels in the lung lining fluids are subnormal, as is known to be the case in some inflammatory lung diseases.

Amniotic Fluid↗
PubMed1993

Atrial natriuretic factor and pulmonary status in premature infants with respiratory distress syndrome: preliminary investigation.

We studied the correlation of atrial natriuretic factor (ANF) with lung compliance in a series of 16 premature infants with respiratory distress syndrome (RDS). The infants were followed during the first week of life by sequential Doppler echocardiography, lung compliance, and ANF measurements. Plasma ANF concentration varied between 38 and 2220 pg/mL; mean concentrations of 393 and 123 pg/mL with the ductus open and with it closed, respectively (P < 0.01). The arteriolar/alveolar oxygen-tension ratio showed an inverse correlation with the logarithm (In) of the ANF concentration (r = -0.55, P = 0.0002). Both mean airway pressure and In ANF showed an inverse correlation with the arteriolar/alveolar oxygen tension ratio (R = -0.77, F = 20.5 and 13.8, respectively). Plasma ANF was inversely correlated to lung compliance (r = -0.64, P < 0.0001). In infants with RDS, plasma ANF concentrations increase with the severity of respiratory distress. Because ANF increases endothelial permeability, in this preliminary investigation lead to the hypothesis that it may contribute to respiratory distress by causing extravasation of fluid from the pulmonary circulation in these patients.

Atrial Natriuretic Factor↗
PubMed1993

Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: a randomized, placebo-controlled trial of human surfactant.

We compared the neurodevelopmental outcome of extremely premature, surfactant-deficient infants who received either prophylactic surfactant at birth, "rescue" surfactant after the clinical diagnosis of respiratory distress syndrome was established, or placebo. Infants studied were participants in a randomized, bicenter (San Diego, Calif., and Helsinki, Finland), controlled trial of human surfactant therapy. One hundred fifty infants (prophylaxis group, 63 infants; rescue group, 57; placebo group, 30) were prospectively enrolled at 38 weeks of gestational age. There were no neonatal intergroup differences in the incidence or severity of sonographic central nervous system abnormality or retinopathy. One hundred forty-five infants were alive at 1 year of adjusted age, at which time growth, neurosensory, and neurologic outcome were similar in all three treatment groups at both centers. Cerebral palsy occurred in 20% overall. Five infants (3.5%) were functionally blind. However, infants treated at birth had lower mean mental and motor scores on the Bayley Scales of Infant Development compared with those of infants rescued with surfactant after the onset of respiratory distress syndrome (Mental Development Index: 78 vs 96, p = 0.02; Psychomotor Development Index: 73 vs 87, p = 0.04). Chronic lung disease occurred more frequently in the prophylactically treated group and contributed to the subjects' neurologic and developmental morbidity. Because prophylactic surfactant treatment offered no neurodevelopmental advantage and may contribute to poorer outcome, we currently recommend early surfactant replacement only for those infants who have postnatal evidence of respiratory distress syndrome.

Brain↗
PubMed1993

Surfactant replacement therapy for pulmonary diseases.

Surfactant therapy has clearly been a meaningful addition to the therapeutic armamentarium in the management of premature infants with RDS. Pediatricians and others involved in the care of newborn infants should familiarize themselves with the various surfactant preparations, the indications for their use, the techniques of administration, and the possible side effects. All such care provides should also be skilled in endotracheal intubation and ventilation of neonates; recognition of the clinical and radiographic signs of RDS; and have the appropriate equipment to monitor cardiopulmonary status, oxygenation, and ventilation in these infants until transport to a tertiary care facility can be accomplished. In addition to the two current FDA-approved surfactants, several other surfactants are in various stages of evaluation. When administered to infants with established RDS, both natural and synthetic surfactants have clearly been shown to improve survival, decrease requirements for ventilatory support, and reduce the incidence of air leak complications. Although by no means conclusively demonstrated, certain infants, particularly those delivered at < 30 week gestation, may benefit from immediate treatment in the delivery room. It should be emphasized that, except under extenuating but controlled circumstances and except in the hands of an experienced physician, surfactant treatment should not be viewed as an integral part of neonatal resuscitation. Adequate treatment requires the administration of a minimum of two surfactant doses, although some infants may benefit from additional doses or treatment with an alternative preparation. Massive pulmonary hemorrhage, although rare, is observed with prophylactic and rescue treatment protocols and may result from hemorrhagic pulmonary edema due to a hemodynamically significant PDA. Currently there are no data to recommend the use of one surfactant preparation over another. The short- and long-term benefits may be similar with different products. Therefore, we must await results of trials with then necessary power (large number of subjects) and unbiased design to discern any clinically relevant differences. Results of studies directly comparing the relative efficacy of Survanta and Exosurf, conducted under the auspices of the National Institutes of Health, are expected in 1993. Multicenter trials comparing prophylactic and rescue administration of Exosurf versus CLSE and Survanta versus CLSE are currently underway. It is encouraging to note that follow-up studies up to 2 years of age do not reveal an increase in physical or neurodevelopmental handicaps, BPD, or other problems in preterm infants who received surfactant preparations either for prophylaxis or rescue therapy. Results of long-term follow-up studies, however, are not yet available.(ABSTRACT TRUNCATED AT 400 WORDS)

Bronchopulmonary Dysplasia↗
PubMed1993

Association between neonatal care practices and efficacy of exogenous human surfactant: results of a bicenter randomized trial.

The purpose of this study was to analyze the impact of neonatal care practices on the efficacy of exogenous human surfactant. Two hundred newborns (gestational age 24.0 to 29.9 weeks, lecithin-sphingomyelin ratio less than 2 or absent phosphatidylglycerol, and requirement of mechanical ventilation at birth) participated in a randomized bicenter trial of human surfactant substitution. In only one of the two sites (site 2) surfactant substitution decreased the severity of respiratory failure and increased neonatal survival without bronchopulmonary dysplasia. For analysis of three-way association, continuous variables describing patient characteristics and treatment were dichotomized at the median. The following variables were significantly associated with good outcome in site 1 and 2 and with surfactant substitution in site 2: low oxygen requirement during first three neonatal days, low mean airway pressure during second and third day, low PaCO2 during first two neonatal days, and no ligation of ductus arteriosus. Low fluid intake during the first three days and low colloid intake during the first two days of life were associated with good outcome in both sites. The ratio between mean airway pressure and the oxygen requirement was higher in site 2 than in site 1 during the first day of life. Fluid intake and ventilatory management may influence the efficacy of exogenous surfactant.

Humans↗