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R Spragg

Publications and source records attributed to R Spragg.

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Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies carries a high morbidity, mortality (10-90%) and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those whose wish to know the true incidence and outcome on this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Clinical Protocols

Making progress.

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Extracorporeal Membrane Oxygenation

Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity rate, mortality rate (10% to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Clinical Trials as Topic

The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.

The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality (10 to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged, and it may be different in Europe. Part of the reason for these uncertainties are the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The American-European Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Americas

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

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

Endobronchial surface active phospholipids in various pulmonary diseases.

In the present study we investigated the phospholipid composition of small-volume (up to 20 ml) in vivo bronchoalveolar lavage and that of quantitative ex vivo bronchoalveolar lavage. Furthermore, the accuracy of the small-volume lavage in predicting lung disease was evaluated. There was a positive linear correlation (r approximately equal to 0.87-0.91) between the amount of saturated phosphatidylcholine and the saturated phosphatidylcholine/sphingomyelin ratio in quantitative bronchoalveolar lavage. The phospholipid distributions in the small-volume lavage and the quantitative lavage were similar (r approximately equal to 0.78-0.94, n = 14). The overall accuracy of phosphatidylcholine/sphingomyelin ratio and phosphatidylglycerol/total phospholipid ratio in predicting the presence or absence of respiratory failure was 85-87% in newborns, children, and adults. In respiratory diseases without respiratory failure, the abnormalities in the phospholipids were frequent, although less distinct. According to animal experiments the surfactant system is inhibited at the onset of high permeability lung edema. Soon thereafter, the lavageable surfactant pool is decreased. Present findings support the view that surfactant defects are of importance in the pathogenesis of respiratory disease, and that surfactant-oriented therapy may be effective in the treatment and prevention of respiratory failure.

Animals

Nonspecificity of elevated angiotensin-converting enzyme activity in bronchoalveolar lavage fluid from high permeability lung edema states.

Elevated levels of angiotensin-converting enzyme activity (ACE) in bronchoalveolar lavage fluid (BAL) have been used as a specific marker for pulmonary endothelial cell injury associated with high permeability lung edema. Alternatively, however, BAL-ACE elevations might reflect a nonspecific leak of plasma proteins into bronchoalveolar spaces. To investigate the cause of BAL-ACE elevations in high permeability lung injury states, we measured ACE and protein concentrations in BAL from isolated perfused rabbit lungs injured with oleic acid or hyperoxia. Although BAL-ACE was elevated, we found no increase in the BAL-ACE:protein ratio over values from control preparations, despite the presence of marked nonhydrostatic lung edema. We conclude that, in the experimental setting of nonhydrostatic lung edema, BAL-ACE elevations are no more helpful in identifying acute lung injury than are elevated BAL-protein levels.

Animals

Pathogenesis of the adult respiratory distress syndrome. Evidence of oxidant activity in bronchoalveolar lavage fluid.

Evidence is presented indicating that oxidants are generated in lungs of patients with the adult respiratory distress syndrome (ARDS). The evidence was derived from observations that alpha-1-PI, recovered in bronchoalveolar lavage (BAL) fluid, had been inactivated by oxidation, presumably oxidation of the methionyl residue in the reaction site of the molecule. This was indicated by findings that activity of the alpha-1-PI could be restored by exposure to the reducing agent, dithiothreitol in the presence of methionyl sulfoxide peptide reductase. The amount of activity restored was proportional to the amount of inactive alpha-1-PI present at 52,000 D. Oxidation of the 52,000-D alpha-1-PI was also revealed by the finding that the inactive molecule was subject to proteolytic cleavage to 47,000 D when exposed to porcine pancreatic elastase, a characteristic of alpha-1-PI with oxidized methionyl residues in the reactive site. Inactivation of the alpha-1-PI in vivo also resulted from complexing to an active enzyme, shown previously to be neutrophil elastase, and from proteolytic cleavage in vivo, that produced a fragment of 47,000 mol wt. In contrast to that in BAL fluids, the alpha-1-PI in plasma of patients with respiratory distress syndrome was found to be greater than 90% active in 14 of 22 cases and 50-90% active in 8 cases. This suggested that for the most part, alpha-1-PI was inactivated after leaving the vessels and entering the lung. The circulating alpha-1-PI in patients with the respiratory distress syndrome was found to be equally susceptible to oxidative inactivation as alpha-1-PI from normal individuals. It seems improbable therefore that patients develop ARDS because of labile alpha-1-PI inhibitor.

Adult

Evidence of lung surfactant abnormality in respiratory failure. Study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol.

Autopsy findings suggest that lung surfactant is damaged in the adult respiratory distress syndrome. In the present study 225 bronchoalveolar lavage specimens (78 from 36 patients, 1-78 yr old with respiratory failure, 135 from another 128 patients with other respiratory disease, and 12 from healthy controls) were assayed for the lung profile [lecithin/sphingomyelin (L/S) ratio, saturated lecithin, phosphatidylinositol, and phosphatidylglycerol]. Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities. A lipid-protein complex was isolated and analyzed for surface activity, and plasma was measured for myoinositol. There were only small differences seen in the recovery of total phospholipid between respiratory failure patients and normal controls. However, in respiratory failure, phospholipids in bronchoalveolar lavage were qualitatively different from those recovered either from normal controls or from patients with other lung disease: the LO/S ratio, phosphatidylglycerol, and disaturated lecithin were low, whereas sphingomyelin and phosphatidylserine were prominent. These abnormalities were present early in respiratory failure and tended to normalize during recovery. Low L/S ratio (less than 2), and low phosphatidylglycerol (1% or less of glycerophospholipids) in bronchoalveolar lavage was always associated with respiratory failure. Abnormal lavage phospholipids were not due to plasma contamination. The phospholipase studies revealed little evidence of increased catabolism of phospholipids. In respiratory failure, the lipid-protein complexes from lung lavage were not surface active, whereas that from healthy controls had surface properties similar to lung surfactant. Phospholipids from patients with respiratory failure were similar to those from respiratory distress syndrome in the newborn. However, the latter condition is characterized by fast recovery of surfactant deficiency and by high plasma myoinositol that suppresses the synthesis of surfactant phosphatidylglycerol and increases phosphatidylinositol (Pediatr. Res. 1981. 15: 720). On the other hand, in adult respiratory distress syndrome, the abnormality in surfactant phospholipids may last for weeks and in most cases is associated with low phosphatidylinositol, low phosphatidylglycerol, and low plasma myoinositol.

Adult

The impact of concomitant viral pathogens on the course of Pneumocystis carinii pneumonia.

A large retrospective study was conducted to evaluate the impact of culturing cytomegalovirus from the respiratory secretions of AIDS patients with Pneumocystis carinii pneumonia. Pneumocystis carinii was found in 220 (67%) of 327 episodes and cytomegalovirus was found in 106 (48%) of the P. carinii-positive patients. Cytomegalovirus-positive and -negative patients were similar at baseline and had a similar number of hospital days, but had a lower incidence of early deterioration in oxygenation, fewer intensive-care days, were less frequently intubated, and had a higher 30-day survival. The better short-term outcome of cytomegalovirus positive patients observed in this study may relate to the immunosuppressive effects of cytomegalovirus.

Acquired Immunodeficiency Syndrome