The BPD problem.
Explore the source record for details and available documents.
Bronchopulmonary Dysplasia↗
Biomedical subjects
T A Merritt
Publications and source records attributed to T A Merritt.
A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birth weight infants.
In a randomized, controlled study, human surfactant derived from amniotic fluid was administered within 12 hours of birth to infants with severe respiratory distress syndrome who were born at 24 to 32 weeks of gestation weighing less than or equal to 1500 gm. A second dose of surfactant was given to patients in the treatment group if they met ventilator requirements indicating relapse or lack of response to the initial dose. No significant improvement was observed in mortality rate (9/28 vs 15/31) or incidence of bronchopulmonary dysplasia (5/28 vs 3/31) when surfactant-treated infants were compared with control subjects, although there was a significant reduction in initial respirator and inspired oxygen requirements and the arterial/alveolar oxygen ratio improved. In addition, there was a significant reduction in pulmonary air leak in treated infants (10/28 vs 20/31; p less than 0.05). Retreatment was associated with an attenuated ventilatory response and with a higher mortality rate (7/14) than that of infants who did not require a second dose (2/14; p = 0.05), indicating a more severe form of disease. Multiple discriminant analysis, including eight independent variables, revealed that increasing birth weight, earlier age at surfactant treatment, and female gender were significantly associated with survival. These data suggest that early surfactant treatment may reduce mortality rates in very low birth weight infants with severe respiratory distress syndrome, as well as reduce ventilator requirements and the incidence of pulmonary air leaks.
Age Factors↗
Effect of volume and dose on the pulmonary distribution of exogenous surfactant administered to normal rabbits or to rabbits with oleic acid lung injury.
Administration of exogenous lung surfactant to infants with or at risk for respiratory distress syndrome has been demonstrated to improve gas exchange and survival; administration of surfactant to patients with the adult respiratory distress syndrome is currently undergoing clinical evaluation. Although it is currently assumed the optimal effect will occur when administered surfactant is distributed homogeneously throughout the lung, little is known of the influence of variables inherent in the administration procedure on subsequent distribution. To address this question, we studied the effect of the volume size in which the surfactant is suspended for instillation, and demonstrated a marked relationship in the normal rabbit lung between this volume and the subsequent homogeneity of surfactant distribution. In the rabbit lung that was acutely injured by oleic acid, this relationship was not evident. Concentration of administered surfactant was not demonstrated to be of major influence on its distribution after administration. Our results focus attention on the importance of parameters of the administration procedure, and also demonstrate the usefulness of the techniques used for determination of surfactant distribution.
Animals↗
Impact of surfactant treatment on cost of neonatal intensive care: a cost-benefit analysis.
Explore the source record for details and available documents.
Canada↗
Closure of the ductus arteriosus and mechanics of breathing in preterm infants after surfactant replacement therapy.
Treatment of premature infants with exogenous surfactant is thought to increase the incidence of the patent ductus arteriosus (PDA) due to improved mechanics of breathing and the resultant reduced pulmonary vascular resistance. As part of a prospective, blinded, controlled study of human amniotic fluid-derived surfactant, we assessed the time of closure of the PDA, defined by Doppler echocardiographic studies, performed at 6-h intervals, and the mechanics of breathing at 6, 18, and 30 h of age in 61 infants (gestational age, 25-29 wk, and birth wt, 450-1580 g). All infants had respiratory distress syndrome as confirmed by immature surfactant phospholipid profiles determined on either amniotic fluid and/or tracheal aspirate analysis, and chest radiograph, and all had a PDA at 6 h of age. Surfactant treatment was associated with more frequent clinically determined need for treatment of the PDA, but did not prolong the patency of the ductus in infants with spontaneous closure or in those requiring treatment with indomethacin. Infants with spontaneous closure of the PDA had significantly higher dynamic lung compliances and lower oxygen requirements and were treated with lower mean airway pressures than those requiring PDA treatment, although their arterial blood gas status was the same. The dynamic lung compliance of infants with right to left ductal shunting was significantly lower than those with left to right shunting at 6 and 18 h but was not different thereafter. This study suggests that the maturity of the ductus arteriosus, reflected by its tendency to close spontaneously, parallels the maturity of the lungs, reflected by their mechanical stability, and that ductal closing is not significantly altered by surfactant therapy.
Clinical Trials as Topic↗
Exogenous surfactant treatments for neonatal respiratory distress syndrome and their potential role in the adult respiratory distress syndrome.
Exogenous surfactant therapy has been recognised as an approach to alleviating the surfactant-deficine state for 3 decades. Natural and lipid-extracted surfactants derived from amniotic fluid, lung lavage, or lung homogenates are being used in worldwide clinical trials in premature infants. These studies are demonstrating a generally favourable influence on lung function by improving oxygenation and reducing the risk for pneumothorax and pulmonary interstitial emphysema. In some studies, reduction in death and the occurrence of bronchopulmonary dysplasia have been found. Numerous questions are unresolved and pharmacokinetic data are limited in preterm infants. Artificial surfactants are similarly under evaluation but current data demonstrate less overall effect. Adult respiratory distress syndrome has also been treated with exogenous surfactants. Although complex in terms of multiple initiating factors and in terms of high permeability of surfactant inhibitors, further studies are under way to determine the ideal methods of administration to enhance distribution and to monitor surfactant function in vivo.
Humans↗
Human surfactant in the treatment of respiratory distress syndrome. A spectrum of clinical responses.
Surfactant substitution is an incompletely studied, promising approach to treat respiratory distress syndrome (RDS). In this report we describe a spectrum of clinical responses following administration of human surfactant from amniotic fluid to 64 newborn infants. There was apparently no harm when surfactant was given to three infants with "mature" surfactant profile. Altogether 40% of the 42 "immature" small preterm infants (gestational age 26-29 weeks) required only a single dose, and 50% of them required two or three doses for successful treatment. In infants with persistent foetal circulation (6 cases) or hydrops (2 cases), there was only a transient or a small improvement of respiratory function. Most notably, the very small preterm infants (24-26 weeks, 15 cases) may require substantial increase in blood volume to prevent cardiac failure during the first neonatal day. We propose that the clinical response to exogenous surfactant can be improved by modifying the current management of very small preterm infants.
Amniotic Fluid↗
The use of exogenous surfactant to treat patients with acute high-permeability lung edema.
Explore the source record for details and available documents.
Bronchi↗
Antigenicity of low molecular weight surfactant species.
The authors tested the antigenicity of human lung surfactant isolated from amniotic fluid. Mice and rabbits were immunized. Rabbit polyclonal antisera to these surfactant preparations were absorbed with normal human plasma proteins. Polyclonal antisera reacted with both high molecular weight (35 kd) surfactant apoprotein and to lower molecular weight species, both 18 kd and 9 kd. Mice were used to generate monoclonal antibodies to surfactant. Enzyme-linked immunosorbant assay was used to identify five monoclonal antibodies that reacted with surfactant. By Western blot analysis, all of these recognized a low molecular weight surfactant species (9 kd) that could be either SP-B or SP-C. One reacted with a 37 kd protein in the surfactant preparation, consistent with SP-A. One monoclonal antibody also recognized a higher molecular weight species (44 kd) of unknown origin. The ability of antisera and monoclonal antibodies to inhibit the functional activity of surfactant was assayed using a pulsating bubble surfactometer. Rabbit polyclonal antisera inhibited initial surface adsorption to equilibrium surface tension and increased the minimum surface tension after 1 and 5 minutes of initiation of pulsations. This inhibitory activity of the antisera was noted in divalent F(ab')2 fragments. Monovalent F(ab) fragments and control normal rabbit sera did not inhibit surfactant function in this assay. Of the anti-surfactant monoclonal antibodies that reacted with surfactant by ELISA and Western blot, three inhibited its capacity to lower surface tension on the pulsating bubble apparatus. The other two monoclonal antibodies showed no functional inhibitory activity. It is concluded that both the 35 kd SP-A and the 9 kd proteins of human surfactant are highly immunogenic and partially crossreactive. Resulting antibodies could alter the ability of surfactant to perform its physiologic function, ie, to lower surface tension.
Animals↗
The adult respiratory distress syndrome: first trials with surfactant replacement.
Following diverse insults, patients may develop a high permeability lung oedema which results in tachypnoea, cyanosis, hypoxaemia, and pan-lobar infiltrates on the chest radiograph. Although a variety of interventional therapies have been evaluated, none has been found effective, and current treatments are entirely supportive. Recently, cellular and biochemical analyses of bronchoalveolar lavage fluid have disclosed abnormalities which suggest that acute inflammatory events and surfactant abnormalities are present in the lungs of patients with adult respiratory distress syndrome (ARDS). The similarities to abnormalities seen in neonates with respiratory distress syndrome are striking. Treatment of those infants with surfactant replacement has been of both short-term and long-term benefit. Therefore, it is rational to investigate the benefits which surfactant administration may have for patients with ARDS. We present an overview of ARDS, and our initial experience with surfactant replacement in three patients.
Adult↗
Surfactant replacement: immunological considerations.
We sought to analyse the potential immunogenicity of human alveolar surfactant as it is currently used in the treatment of neonatal respiratory distress syndrome (RDS). An enzyme linked immunosorbant assay capable of detecting specific immune complexes between surfactant and antibodies directed to surfactant was developed. Premature infants with RDS were divided into groups: one group received surfactant replacement and one received conventional therapy. Plasma samples obtained from these infants at birth and thereafter were examined for specific circulating immune complexes between surfactant and anti-surfactant antibodies. All babies were also examined for clinical and serological evidence of immune complex-mediated tissue damage. We found that almost all infants with RDS, regardless of their therapy, showed evidence of circulating surfactant-anti-surfactant immune complexes. Plasma samples from infants without RDS showed no such complexes. Immune complexes appeared early in postnatal life, usually within the first week, and diminished thereafter. We detected no evidence of altered plasma complement levels or end organ damage attributable to these immune complexes. Thus, circulating immune complexes between surfactant and antibodies to surfactant are common in neonatal respiratory distress syndrome, though they do not appear to cause injury. Since not only human but heterologous surfactants are now used in treating RDS, we feel that cautious evaluation of potential immune reactions to the administered materials should be undertaken.
Antigen-Antibody Complex↗
Neurodevelopmental and respiratory outcome in early childhood after human surfactant treatment.
We assessed postnatal growth, neurodevelopmental outcome, and occurrence of respiratory illnesses in 46 infants of very low birth weight who were enrolled in a randomized, controlled, bicenter clinical trial of human surfactant treatment for respiratory distress syndrome. No long-term adverse effects of human surfactant treatment were detected between control and human surfactant-treated infants with respect to growth, neurologic, or developmental outcome. Infants with chronic lung disease, regardless of treatment group, had poorer growth and were more likely to have neurodevelopmental abnormalities at 12 to 24 months of age.
Brain Diseases↗
Surfactant replacement. A new era with many challenges for neonatal medicine.
Explore the source record for details and available documents.
Clinical Trials as Topic↗
Use of human surfactant low molecular weight apoproteins in the reconstitution of surfactant biologic activity.
Two low molecular weight (LMW) apoproteins were isolated from human pulmonary surfactant. SDS polyacrylamide gel analysis showed one protein (SP 18) to have an apparent molecular weight of 18,000 when unreduced and 9,000 D after reduction. The second protein (SP 9) migrated at approximately 9,000 D in the presence or absence of reducing agents. Both proteins contain a high number of hydrophobic amino acids. The NH2-terminal sequence of SP 18 was determined to be: NH2-phe-pro-ile-pro-leu-pro-tyr-. A cDNA clone isolated from a human adult lung cDNA library contained a long open reading frame encoding at an internal position the human SP 18 amino-terminal sequence. Mixtures of phospholipids (PL) and SP 9 and SP 18 were assessed for their capacity to reduce surface tensions on a pulsating bubble surfactometer. The addition of 1% apoprotein resulted in a reduction of surface tension after 15 s from 42.9 dyn/cm for PL alone to 16.7 and 6.3 dyn/cm for preparations containing SP 9 and SP 18, respectively. In vivo assessment of reconstituted surfactant activity was performed in fetal rabbits. Reconstituted surfactant consisting of PL + 0.5% SP 18 instilled intratracheally at delivery resulted in a marked increase in lung compliance, while the incorporation of 0.5% SP 9 yielded a moderate increase. These data show the ability to produce biologically active surfactant by the addition of isolated LMW apoproteins to defined PL.
Amino Acid Sequence↗
Immunologic consequences of exogenous surfactant administration.
In conclusion, we have shown that human surfactant is immunogenic and that circulating surfactant-antisurfactant immune complexes are detectable in the plasma from infants and in adults with RDS. We found these immune complexes regardless of whether exogenous surfactant was used in the individual treatment regimen. These immune complexes do not yet seem to cause disease in the short term. Long-term effects, if any, are unknown. Indications for surfactant replacement therapy in neonatal RDS are clear. Trials of exogenous surfactant are just beginning in adult RDS, and potential immunogenicity will be of even greater concern in these patients. In all such situations, potential for side effects must be balanced against therapeutic efficacy and the gravity of the disease. Our data indicate that surfactants, particularly heterologous surfactants, are potent immunogens. One cannot assume that using homologous or heterologous surfactants in patients with RDS will always be immunologically innocuous. Nonetheless, based on present data, moderately long-term follow-up (2 to 4 years), we are encouraged by our observation that no selective adverse effects attributable to human surfactant have been recognized, yet mortality from RDS in infants less than 30 weeks has been nearly cut in half.
Adult↗
Severe intracranial hemorrhage and hydrocephalus in low-birthweight infants treated with CSF shunts.
The high-risk low-birth-weight newborn not uncommonly develops intracranial hemorrhage and intraventricular hemorrhage (ICH/IVH) from the immature state of the germinal matrix. Posthemorrhagic hydrocephalus may develop. Infants with small hemorrhages (grades I, II of Papile), with or without hydrocephalus have been shown to develop normally in 80%-90% of cases. There is limited information in the literature about the management and outcome of infants with more severe hemorrhages (grades III, IV of Papile), due to the dismal outlook as to their outcome in most centers. The current status and concerns as to the management of these infants is reviewed, and the aspects of neurosurgical and neonatal follow-up and outcome are described. A significant number of these infants have severe handicaps, which are primarily motor. However, a group of infants is noted who have normal intellectual performance despite varying degrees of motor handicaps: 18% have normal intellectual and motor development. In the current series predictors of poorest outcome are the presence of grade IV hemorrhage and/or seizures. The vast majority of the grades III and IV hemorrhages develop hydrocephalus that is a complex management issue for the neurosurgeon.
Acute Disease↗
Natural surfactant substitution in respiratory distress syndrome.
Natural surfactants consist of unique proteins and lipids. Their effectiveness in improving subnormal lung function in surfactant deficiency should be established prior to any clinical trials. Rigorous tests are required to document batch to batch variability in surface activity and to exclude toxic contaminants. Up to this date randomized clinical trials in small preterm infants have demonstrated a striking improvement in lung function, and a decrease in incidence of acute complications (pneumothorax, interstitial emphysema). Administration of human surfactant at birth or in severe RDS decreased deaths and incidence of bronchopulmonary dysplasia. Although homologous surfactant may not be more advantageous than the heterologous one in terms of its acute beneficial effects on lung function, the safety and efficacy of animal surfactant in improving the outcome remains to be established. Human surfactant may serve as a model for unlimited natural surfactant produced by gene technology. The pharmacodynamics aspects of surfactant substitution, the indications of exogenous surfactant, and the management of the patients undergoing surfactant substitution remain to be studied. Exogenous surfactant offers a potential to treat or prevent severe respiratory failure in infants, children and adults.
Animals↗
Infant follow-up programs: their impact on infants and families.
Explore the source record for details and available documents.
Child Development↗