Pulmonary Capillary Permeability Research Articles

Pulmonary Edema Associated With Hyperbaric Oxygen Therapy

We report three cases of pulmonary edema associated with hyperbaric oxygen therapy, including one fatality. All three patients had cardiac disease and reduced left ventricular (LV) ejection fractions (EFs). Two patients had diabetes, and one patient had severe aortic stenosis. Hyperbaric oxygen therapy may contribute to pulmonary edema by increasing LV afterload, increasing LV filling pressures, increasing oxidative myocardial stress, decreasing LV compliance by oxygen radical-mediated reduction in nitric oxide, altering cardiac output between the right and left hearts, inducing bradycardia with concomitant LV dysfunction, increasing pulmonary capillary permeability, or by causing pulmonary oxygen toxicity. We advise caution in the use of hyperbaric oxygen therapy in patients with heart failure or in patients with reduced cardiac EFs.

Methylene blue reduces lung fluid filtration during the early phase of endotoxemia in awake sheep.

To determine whether methylene blue (MB), an inhibitor of soluble guanylate cyclase and nitric oxide synthase, alters lung hemodynamics and fluid filtration after endotoxin in sheep. Prospective, randomized, controlled experimental study with repeated measurements. University animal laboratory. Eight yearling, awake sheep. Sheep were instrumented for a chronic study with vascular and lung lymph catheters. In two experiments, separated by 1 wk of recovery, the animals received intravenously either an injection of MB 10 mg/kg or a corresponding volume of 0.9% sodium chloride as pretreatment. Thirty minutes later, sheep received a bolus injection of Escherichia coli endotoxin 1 microg/kg, followed by either an infusion of MB 2.5 mg/kg/hr or a corresponding volume of 0.9% sodium chloride for 5 hrs. MB decreased the early phase endotoxin-induced rises in pulmonary capillary pressure and pulmonary vascular resistance. MB also reduced the increments in lung lymph flow (QL) and protein clearance (CL) as well as the rightward shift of the permeability-surface area product (PS). In addition, MB diminished the decrease in cardiac output, stabilized mean arterial pressure, and precluded the rise in plasma and lung lymph cyclic guanosine 3'-5' monophosphate. However, during the late phase, MB-treated sheep presented with a faster rise in QL with no difference in CL and PS from the endotoxemic controls. During the early phase of endotoxemia in sheep, MB attenuates lung injury by decreasing the enhanced lung fluid filtration as a result of reduced pulmonary capillary pressure and permeability. However, MB does not counteract the late phase increase in lung fluid filtration.

Effect of prone position on pulmonary vascular permeability in acute respiratory distress syndrome

In early acute respiratory distress syndrome (ARDS), alteration in the pulmonary capillary permeability is associated with outcome [1]. Alteration in the relation of extravascular lung water to intrathoracic blood volume (EVLW/ITBV) derived from thermal-dye dilution curves indicates changes in the pulmonary vascular permeability. Prone positioning improves gas exchange in most patients with ARDS, however whether this improvement is related to effects on pulmonary vascular permeability has not been evaluated. This prospective pilot study was designed to investigate whether prone positioning would alter EVLW/ITBV as a measure of pulmonary vascular permeability. Patients with ARDS on inverse ratio pressure-controlled ventilation with PEEP > 10 cmH2O for at least 24 hours were recruited. Patients were turned prone for 18 hours. Except for FiO2, ventilatory settings remained unchanged during the study period. Values of EVLW and ITBV were obtained using a single transpulmonary arterial thermodilution technique with a 5F-fibreoptic thermistor femoral artery catheter. Measurements of EVLW and ITBV were taken at pre-prone, 1, 2, 6, 12 and 18 hours after proning and 1 hour after supine. EVLW/ITBV while prone was normalised to pre-prone values as a baseline to illustrate differences during prone and supine. Data were expressed as mean (SEM). Repeated measures ANOVA was used for statistical analysis. Twelve episodes of proning in 11 patients were studied. Although mean PaO2/FiO2 improved within 1 hour, it continued to improve during the period studied and only reached significance 12 hours after proning (17.9 ± 2.9 v 35.1 ± 4.2, P < 0.05). Mean EVLW/ITBV did not change significantly. At least 12 hours may be needed for maximal benefit with prone positioning. Changes in pulmonary vascular permeability in ARDS do not appear to be an important mechanism to account for the improvement in gas exchange seen following prone positioning. Table 1 Changes in EVLW/ITBV after prone positioning in ARDS

Radioisotope albumin flux measurement of microvascular lung permeability: an independent parameter in acute respiratory failure?

To evaluate the extent to which single measurements of microvascular lung permeability may be relevant as an additional parameter in a heterogenous clinical patient collective with Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). In 36 patients with pneumonia (13), non pneumogenic sepsis (9) or trauma (14) meeting the consensus conference criteria of ALI or ARDS double-isotope protein flux measurements (51Cr erythrocytes as intravascular tracer, Tc-99m human albumin as diffusible tracer) of microvascular lung permeability were performed using the Normalized Slope Index (NSI). The examination was to determine whether there is a relationship between the clinical diagnosis of ALI/ARDS, impaired permeability and clinical parameters, that is the underlying disease, oxygenation, duration of mechanical ventilation and mean pulmonary-artery pressure (PAP). At the time of study, 25 patients presented with increased permeability (NSI > 1 x 10(-3) min-1) indicating on exudative stage of disease, and 11 patients with normal permeability. The permeability impairment correlated with the underlying disease (p > 0.05). With respect to survival, there was a negative correlation to PAP (p < 0.01). Apart from that no correlations between the individual parameters were found. Especially no correlation was found between permeability impairment and oxygenation, duration of disease or PAP. In ALI and ARDS, pulmonary capillary permeability is a diagnostic parameter which is independent from clinical variables. Permeability measurement makes a stage classification (exudative versus non exudative phase) of ALI/ARDS possible based on a measurable pathophysiological correlate.

Part 8: Advanced Challenges in Resuscitation

Part 8: Advanced Challenges in Resuscitation

Effect of hypothermic pulmonary artery flushing on capillary filtration coefficient.

We previously demonstrated that surfactant dilution and inhibition occur immediately after pulmonary artery flushing with hypothermic modified Euro-Collins solution. Consequently, we speculated that increased capillary permeability contributed to these surfactant changes. To test this hypothesis, we evaluated the effects of hypothermic pulmonary artery flushing on the pulmonary capillary filtration coefficient (Kfc), and additionally performed a biochemical analysis of surfactant. We used a murine isolated, perfused lung model to measure the pulmonary capillary filtration coefficient and hemodynamic parameters, to determine the wet to dry weight ratio, and to evaluate surfactant by biochemical analysis of lung lavage fluid. We defined three study groups. In group I (controls), we harvested lungs without hypothermic pulmonary artery flushing, and measured Kfc immediately. In group II (in situ flush), we harvested lungs after hypothermic pulmonary artery flushing with modified Euro-Collins solution, and then measured Kfc. Experiments in groups I and II were designed to evaluate persistent changes in Kfc after pulmonary artery flushing. In group III (ex vivo flush), we flushed lungs ex vivo to evaluate transient changes in Kfc during hypothermic pulmonary artery flushing. Groups I and II did not differ significantly in capillary filtration coefficient and hemodynamics. Group II showed significant alterations on biochemical surfactant analysis and a significant increase in wet-to-dry weight ratio, when compared with group I. In group III, we observed a significant transient increase in capillary filtration coefficient during pulmonary artery flushing. Hypothermic pulmonary artery flushing transiently increases the capillary filtration coefficient, leads to an increase in the wet to dry weight ratio, and induces biochemical surfactant changes. These findings could be explained by the effects of hypothermic modified Euro-Collins solution on pulmonary capillary permeability.

Purified fumonisin B(1) decreases cardiovascular function but does not alter pulmonary capillary permeability in swine.

Fumonisins are mycotoxins produced by Fusarium verticillioides, which induce acute pulmonary edema in swine. We previously reported that ingestion of fumonisin-containing culture material decreases cardiovascular function in swine (1996,a,b; Fundam. Appl. Toxicol. 31, 169-172; 33, 140-148; 1999, Am. J Vet. Res. 60, 1291-1300). The main purpose of this study was to confirm that fumonisin B(1) was responsible for the observed cardiovascular changes. Treated pigs (n = 6) were given daily intravenous injections of purified fumonisin B(1) at 1 mg/kg for 4 days, while controls (n = 6) were injected with equal volumes of saline. On day 5, pigs were anesthetized with butorphanol-chloralose and instrumented for hemodynamic studies. Terminally, bronchoalveolar lavage was performed on each pig to determine the relative permeability index of the pulmonary endothelium. Fumonisin B(1)-treated pigs had marked decreases in the maximal rate of change of left ventricular pressure (dP/dt(max)), mean aortic pressure, cardiac output, and arterial pO(2), accompanied by increases in mean pulmonary artery pressure, oxygen extraction ratio, and blood hemoglobin concentration. Plasma and left ventricular sphingosine and sphinganine concentrations were markedly increased in treated pigs at day 5; however, there was no difference in the relative permeability index between groups. Serum cholesterol concentrations and activities of hepatic-derived enzymes were increased, and hepatocyte apoptosis and mitoses were present in the livers of fumonisin-treated pigs. In the lungs of treated pigs, there was proteinaceous edema and membranous accumulations in capillary endothelial cells. These results indicate that cardiovascular function is altered by fumonisin B(1), and that fumonisin-induced pulmonary edema is caused by left-sided heart failure and not by altered endothelial permeability. Because of the potential for contamination of human foodstuffs by fumonisins, the cardiovascular toxicity of these compounds must be taken into consideration.

Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema.

We hypothesized that the angiogenic mediator, vascular endothelial growth factor (VEGF), known to be expressed in the lung and to be capable of inducing local edema in skin, might evoke the development of lung edema if expressed in excess amounts. To test this hypothesis, we developed an in vivo model of VEGF overexpression in the lung on the basis of delivery to the respiratory epithelium of the VEGF165 complementary DNA by an E1(-) adenovirus vector (AdVEGF165). Administration of AdVEGF165 by the intratracheal route (10(9) plaque-forming units [pfu]) to C57Bl/6 mice showed increased expression of VEGF messenger RNA in lung tissue by Northern analysis. Overexpression of VEGF protein in the lung at Days 1 to 10 was confirmed by enzyme-linked immunosorbent assay. Intratracheal administration of AdVEGF165 resulted in a dose-dependent increase in lung wet/dry weight ratios over time, lung histology showed widespread intra- alveolar edema, and pulmonary capillary permeability was significantly increased as quantified by the Evans blue dye assay and [(131)I]albumin permeability. To confirm the specificity of these observations, mice were pretreated with intranasal administration of an adenovirus vector expressing a truncated soluble form of the VEGF receptor flt-1 (Adsflt). Adsflt (10(9) pfu) pretreatment completely abrogated the increased lung wet/dry weight ratio caused by AdVEGF165 administration, whereas an identical adenovirus vector with an irrelevant transgene had no effect upon subsequent AdVEGF165-induced pulmonary edema. Together, these data suggest that overexpression of VEGF in the lung may be one mechanism of increased pulmonary vascular permeability in the early stages of acute lung injury.

Hepatic cryoablation-induced acute lung injury: pulmonary hemodynamic and permeability effects in a sheep model.

Hepatic cryoablation of 30% to 35% or more of liver parenchyma in a sheep model results in eicosanoid and nuclear factor-kappaB (NF-kappaB)-mediated changes in pulmonary hemodynamics and lung permeability. Laboratory. At initial thoracotomy, catheters were placed in the main pulmonary artery, left atrium, right carotid artery, and efferent duct of the caudal mediastinal lymph node for subsequent monitoring in adult sheep. After a 1- to 2-week period of recovery, animals underwent laparotomy and left-lobe cryoablation (approximately 35% by volume) with subsequent awake monitoring and on postoperative days 1 to 3. Cryoablation-induced lung permeability and hemodynamic changes were compared with baseline values in sheep that underwent instrumentation. Similarly handled sheep underwent resection of a similar volume of hepatic parenchyma or had pulmonary artery pressure increases induced by mechanical left atrial obstruction. Activation of NF-kappaB was assessed with electrophoretic mobility shift assay, and serum thromboxane levels were measured with mass spectroscopy. Cryoablation resulted in acutely increased mean pulmonary (20 to 35 cm water) and systemic pressures, which returned to baseline at 24 hours with no change in cardiac output. Serum thromboxane levels increased 30 minutes after cryoablation (9-fold) and returned to baseline at 24 hours. Activation of NF-kappaB was present in liver and lung tissue by 30 minutes after cryoablation. Lung lymph-plasma protein clearance markedly exceeded the expected increase from pulmonary pressures alone, and increased lymph-plasma protein ratio persisted after pulmonary artery pressures normalized. Similar changes were not associated with 35% hepatic resection. This study demonstrates that 35% hepatic cryoablation results in an acute but transient increase in pulmonary artery pressure that may be mediated by increased thromboxane levels. Increases in pulmonary capillary permeability are not accounted for by pressure changes alone, and may be a result of NF-kappaB-mediated inflammatory mechanisms. These data show that cryosurgery causes pathophysiological changes similar to those observed with endotoxin and other systemic inflammatory stimuli.

Pulmonary edema in fatal heroin overdose: immunohistological investigations with IgE, collagen IV and laminin — no increase of defects of alveolar-capillary membranes

Pulmonary edema complicating heroin overdosage is a well recognized entity and regarded as the major mechanism contributing to death in heroin addicts. It’s pathogenesis is unknown, several mechanisms are discussed: hypoxia-induced increase of pulmonary capillary permeability, depressed myocardial contractility, centrally induced respiratory depression, primary toxic effects on the alveolar capillaries and acute anaphylactic shock. The present study included opiate-related deaths ( n=23) and a control group of sudden cardiovascular deaths ( n=12) to verify the hypothesis, that defects of the alveolar capillary membranes and/or an acute anaphylactic reaction leads to pulmonary congestion, edema and hemorrhages. Lung specimens were obtained from these 35 autopsies of persons autopsied in the Institute of Forensic Medicine, University of Bonn, in 1997 and 1998. All specimens were examined with hematoxylin–eosin, prussian blue and investigated with immunohistological methods using primary antibodies against collagen IV, laminin and IgE. Defects of the basal laminae of the alveoli were found, demonstrated by laminin and collagen IV, and the number of IgE-positive cells was counted in both groups. There was an increased but not significant number of IgE-positive cells in the heroin-group and defects of the epithelial and endothelial basal laminae were found in both groups without significant differences.

Evidence of a central role for p38 map kinase induction of tumor necrosis factor α in pancreatitis-associated pulmonary injury

Background: Tumor necrosis factor alpha (TNFα) has been implicated as an important mediator in acute pancreatitis-associated adult respiratory distress syndrome, but the precise pathogenesis remains unclear. The purpose of this work was to clarify the role of TNFα that is produced within the lung parenchyma in the inducement of pancreatitis-related pulmonary injury and to examine 1 of the potential pathways leading to the production of pulmonary TNFα. Methods: Bile salt pancreatitis was induced in rats (n = 40) that were randomized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or vehicle. A separate group (n = 16) underwent sham operation. Pulmonary capillary permeability was determined with fluorescein isothiocyanate–labeled albumin and Evans blue dye, and lung histologic analysis was performed. TNFα protein was measured in bronchoalveolar lavage fluid, and p38 MAP kinase was activity determined by Western blot analysis. Results: The induction of pancreatitis resulted in increased pulmonary capillary leakage and worsened histologic condition (P < .01 vs sham). Effective inhibition of p38 MAP kinase-induced TNFα production completely prevented pancreatitis-associated pulmonary injury (P < .01 vs vehicle). Conclusions: p38 MAP kinase–induced TNFα production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model. (Surgery 1999:126:216-22.)

Evidence of a central role for p38 map kinase induction of tumor necrosis factor [alpha ] in pancreatitis-associated pulmonary injury

Background: Tumor necrosis factor alpha (TNFα) has been implicated as an important mediator in acute pancreatitis-associated adult respiratory distress syndrome, but the precise pathogenesis remains unclear. The purpose of this work was to clarify the role of TNFα that is produced within the lung parenchyma in the inducement of pancreatitis-related pulmonary injury and to examine 1 of the potential pathways leading to the production of pulmonary TNFα. Methods: Bile salt pancreatitis was induced in rats (n = 40) that were randomized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or vehicle. A separate group (n = 16) underwent sham operation. Pulmonary capillary permeability was determined with fluorescein isothiocyanate–labeled albumin and Evans blue dye, and lung histologic analysis was performed. TNFα protein was measured in bronchoalveolar lavage fluid, and p38 MAP kinase was activity determined by Western blot analysis. Results: The induction of pancreatitis resulted in increased pulmonary capillary leakage and worsened histologic condition (P < .01 vs sham). Effective inhibition of p38 MAP kinase-induced TNFα production completely prevented pancreatitis-associated pulmonary injury (P < .01 vs vehicle). Conclusions: p38 MAP kinase–induced TNFα production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model. (Surgery 1999:126:216-22.)

Pulmonary capillary sieving of hetastarch is not altered by LPS-induced sepsis.

Gram-negative lipopolysaccharide (LPS) has been demonstrated to increase pulmonary capillary permeability as judged by the increased flow of protein-rich lymph from the lungs of sheep infused with LPS. This finding suggests that LPS-injured pulmonary capillaries might be less restrictive than uninjured capillaries to the filtration of large hetastarch molecules. Hetastarch has a broad molecular mass spectrum (35-1,500 kilodaltons (kDa)), and one way to test the restrictiveness of pulmonary capillaries is to measure the size of the largest hetastarch molecules that cross the microvascular barrier and enter the lymph. To evaluate the effects of LPS, we compared hetastarch molecular distributions in the lung lymph of normal and LPS-injured sheep. Adult sheep (38.2 +/- 0.8 kg) were surgically prepared for the collection of lung lymph, with study initiation after a 5- to 7-day recovery period. Hetastarch (6%) was infused (10 mL/kg) 24 hours before study to allow for stabilization of the hetastarch molecular distribution. On the day of study, LPS (Escherichia coli lipopolysaccharide, 2 microg/kg; n = 6) was infused, and plasma and lymph samples were collected for 12 hours. An additional group of animals not infused with LPS (n = 6) served as controls. Hetastarch molecular distributions in plasma and lymph were measured by using high performance size exclusion chromatography. In control sheep, the largest hetastarch molecules in lymph averaged 861 +/- 18 kDa (mean +/- SEM) (plasma, 1,065 +/- 18 kDa). In LPS-treated sheep, the largest hetastarch molecules in lymph averaged 845 +/- 19 kDa (not significant vs. normal) (plasma, 1,025 +/- 14 kDa). Hetastarch concentrations in plasma and lung lymph of normal sheep, respectively, were 0.61 +/- 0.05% and 0.34 +/- 0.07%. In LPS-treated sheep, hetastarch concentrations in plasma and lymph were 0.56 +/- 0.08 (not significant vs. normal) and 0.29 +/- 0.07, respectively (p < or = 0.05). Lymph concentrations were lower after LPS because of increased lymph flows (19.9 +/- 5.4 mL/30 min, compared with 3.6 +/- 0.8 mL/30 min in normal sheep). Our results suggest that LPS does not alter the diameter of the largest pores perforating the walls of pulmonary capillaries. Rather, the number of these pores in the capillary wall appears to be increased. This increase would explain why lymph flows rise after LPS with little change in the lymph protein concentration. Our results are also consistent with a filtration model in which capillaries are assumed to be perforated by small pores (protein reflection coefficient = 1) as well as large pores (protein reflection coefficient = 0).

Post-pneumonectomy pulmonary edema: is anesthesia to blame?

Post-pneumonectomy pulmonary edema is a major cause of early mortality following lung resection surgery. It is not clear whether this complication is caused by excessive perioperative intravenous fluid as was previously thought. The recent demonstration of increased pulmonary capillary permeability of the lung following a pneumonectomy suggests measures to try and decrease the incidence of this highly lethal syndrome. These measures include the judicious use of intravenous crystalloids, avoidance of lung hyperinflation and efforts to minimize the pulmonary artery pressure.

Coagulatory response after femoral instrumentation after severe trauma in sheep.

Pulmonary complications after intramedullary femoral nailing have been attributed to bone marrow fat embolization and a variety of cascade effects. We investigated whether the coagulatory response after intramedullary femoral nailing in merino sheep is altered after severe trauma. Adult merino sheep were submitted to hemorrhagic shock (2 hours, 50 mm Hg) and unilateral lung contusion. After recovery (day 3 of the study), reamed femoral intramedullary nailing (RFN), unreamed femoral intramedullary nailing (UFN), or plate osteosynthesis of the femur (P) was performed. Pulmonary artery pressure, central venous levels of factor V, protein C, antithrombin III, and fibrinogen, were determined. At 1 and 3 days before and after femur instrumentation, pulmonary capillary permeability was assessed on the basis of the comparative albumin content in bronchoalveolar lavage fluid. Group RFN, n=8; group UFN, n=7; group P, n=6. A significant (p < 0.05) postoperative increase in the relative albumin content in terms of the BAL/plasma albumin ratio was measured in group RFN (day 3 preoperatively: 0.38+/-0.05 day 3 postoperatively: 0.53+/-0.06, p < 0.05 (RFN vs. P), which contrasted with group UFN (day 3 preoperatively: 0.44+/-0.09, day 3 postoperatively: 0.46+/-0.09, no significant difference). This evidence of increased pulmonary permeability occurred in association with evidence of increased activation of coagulation factors (data presented as percentage of day 3 preoperative baseline values). The data for fibrinogen (15 min postoperatively) is as follows: group RFN, 74+/-9% (p < 0.05 vs. P); group UFN, 83+/-8% (not significant); group P, 98+/-6%. The data for antithrombin III (15 min. postoperatively) is as follows: group RFN, 72+/-6% (p < 0.05 vs. P); group UFN, 79+/-8% (not significant); group P, 92+/-8% (not significant). After severe trauma, an increase of pulmonary permeability after reamed femoral nailing was associated with increased consumption of coagulation factors. After unreamed nailing, a similar trend was apparent, but this was not found to be statistically significant. These data provide support for the theory that after severe trauma, unreamed femoral nailing reduces but does not abolish pulmonary sequelae when compared with reamed femoral nailing.

Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat.

Tumor necrosis factor (TNF) is released during hepatic ischemia/reperfusion (I/R) and plays an important role in the ensuing neutrophil-mediated lung and liver injury. Since TNF is not a direct neutrophil chemotaxin, we hypothesized that TNF may up-regulate neutrophil adhesion molecules, specifically intercellular adhesion molecule-1 (ICAM-1), following hepatic I/R, and that this molecule then plays an important role in tissue neutrophil influx. Rats underwent 90 min of lobar hepatic ischemia with reperfusion. Pulmonary and hepatic ICAM-1 expression were assessed by reverse transcription-polymerase chain reaction, Western blot analysis, and immunohistochemical staining. Increases in hepatic ICAM-1 were demonstrated within 1 h of reperfusion, while increases in pulmonary ICAM-1 were not seen until 6 h of reperfusion. Next, rats were treated with anti-TNF antibody or control antibody without TNF neutralizing properties prior to hepatic I/R. Pretreatment with anti-TNF antibody significantly decreased pulmonary and hepatic ICAM-1 expression after hepatic I/R. We next investigated the effects of pretreatment with anti-ICAM-1 antibodies on the lung and liver injury that follows hepatic I/R. Lung injury was assessed by changes in pulmonary capillary permeability as estimated by extravasation of Evans Blue dye and pulmonary neutrophil influx as measured by lung myeloperoxidase levels. Liver injury was assessed by hepatic neutrophil morphometrics and plasma liver enzymes (alanine aminotransferase). Pretreatment with anti-ICAM-1 antibodies significantly decreased pulmonary capillary permeability, pulmonary myeloperoxidase, hepatic neutrophil influx, and plasma alanine aminotransferase, as compared to animals pretreated with control antibody. These data suggest that TNF is a proximal trigger for pulmonary and hepatic ICAM-1 up-regulation following hepatic ischemia with reperfusion, and that ICAM-1 is important for pulmonary and hepatic neutrophil influx, with the resultant tissue injury, following hepatic I/R.

Post-exposure treatment with isoproterenol attenuates pulmonary edema in phosgene-exposed rabbits.

This study investigated the post-treatment effect of isoproterenol (ISO) on pulmonary parameters in rabbits whole-body-exposed to a lethal dose of the toxic gas phosgene. Phosgene is widely used in industry as a chemical intermediate for the production of plastics, drugs and polyurethane products. The results of this study are from five study groups: 10-min perfused baseline; uninjured controls exposed to air; phosgene-exposed; phosgene-exposed isoproterenol-treated intravascularly and intratracheally (ISO i.v.+i.t.); and phosgene-exposed isoproterenol-treated intratracheally (ISO i.t.). Treatment with ISO was administered as either a continuous intravascular infusion (24 microg min(-1)) from the beginning to end of perfusion (i.v.) and a 24-microg intratracheal bolus (i.t.) or just an i.t. bolus immediately prior to the start of perfusion. Rabbits of 2.5-3 kg were exposed to a cumulative dose of phosgene to attain a concentration x time exposure-effect of 1500 ppm x min. Lungs were isolated in situ and perfused 50-60 min after the start of exposure with Krebs-Henseleit buffer at 40 ml min(-1). Pulmonary artery pressure (Ppa), tracheal pressure (Pt) and lung weight gain (lwg) were continuously measured. Leukotrienes (LT) C4/D4/E4 were measured in the perfusate every 20 min during perfusion. At the immediate conclusion of the experiment, lung tissue was frozen in liquid N2 and analyzed for glutathione (GSH) and cyclic 3',5'-adenosine monophosphate (cAMP). Post-treatment with ISO by either i.v.+i.t. or i.t. routes 50+ min after phosgene exposure significantly lowered Ppa, Pt and lwg. Phosgene-exposed rabbits post-treated with ISO i.t. had significantly higher levels of reduced GSH (3 +/- 0.4 nmol mg(-1) protein), GSH/GSSG ratios (3.3 +/- 0.6 nmol mg(-1) protein) and percentage of total as reduced GSH (75 +/- 2.5%) compared with phosgene-exposed rabbits: 1.9 +/- 0.3, 2 +/- 0.3 and 58 +/- 6.3%, respectively. The ISO (i.v.+i.t.) post-treatment route significantly increased reduced GSH (6.2 +/- 1.7 nmol mg(-1) protein), GSH/GSSG ratio (5.9 +/- 0.8 nmol mg(-1) protein) and percentage of total as reduced GSH (85 +/- 1.7%) when compared to the phosgene-only group. The ISO i.t. and ISO i.v.+i.t. treatments significantly reduced perfusate LTC4/D4/E4 150 min after the start of exposure by 90% and 48%, respectively. These data suggest that protective mechanisms for ISO involve reduced vascular pressure, decreased LTC4/D4/E4-mediated pulmonary capillary permeability and a favorable lung tissue redox state compared with untreated phosgene-exposed rabbits.

Significance of hemodynamic changes in four cardiac chambers of guinea pigs infected with Pichinde virus

Strain 13 guinea pigs infected with Pichinde virus have been commonly used as an animal model for studying pathophysiological mechanisms and treatment of human Lassa fever. During Pichinde virus infection of these animals, severe cardiac dysfunction and pulmonary edema develop, despite dehydration. The main purpose of this study was to develop techniques for measuring hemodynamic changes of four cardiac chambers and selected cardiovascular functions of control and Pichinde virus-infected strain 13 guinea pigs. Experiments were conducted on postinoculation days 7 and 11 in anesthetized, open-chest and mechanically ventilated guinea pigs. In virus-infected guinea pigs, arterial blood pressure, cardiac output, heart rate and left ventricular contractility decreased, while the total peripheral resistance and left atrial mean pressure increased significantly ( P<0.05–0.001). Despite a highly significant elevation (5–6-fold) of left atrial pressure was developed on day 7 and 11 postinoculation of Pichinde virus, the maximal mean value reached approximately 10 mmHg. Although the actual pulmonary capillary pressure was not measured, the magnitude of increased left atrial pressure was insufficient to account for the increased capillary pressure that would exceed plasma oncotic pressure (25 mmHg). These results suggest that the Pichinde virus-induced pulmonary edema is probably not a result of increased capillary hydrostatic pressure in the lung. An increased pulmonary capillary permeability, induced either by Pichinde virus directly or through the action of released mediators, may play a major role in the development of pulmonary edema.

Bilioptysis: A sign of pulmonary capillary permeability injury

B ilothorax, the presence of bi le or bil iary pigment in the thoracic cavity, is extremely rare.1 Bilothorax has been reported in infectious empyemas and most commonly as a result of hepatic trauma, 2 percutaneous bil iary drainage, bil iary obstruction, 3 and bi l iopleural fistula. 4 We describe the first case, to our knowledge, of cardiogenic pulmonary edema stained with bi l irubin as a result of massive hemolysis in the se t t ing of sys temic in f lammatory response synd rome (SIRS) and sickle cel l crisis.

Neurogenic disorders of heart and lung function in acute cerebral lesions

Incidence and clinical significance of cardiopulmonary complications of acute cerebral lesions are still unclear. Neurogenic pulmonary edema (NPE) is characterized as an acute, protein-rich lung edema occurring shortly after cerebral lesions associated with an acute rise of intracranial pressure. NPE is infrequently diagnosed, usually in association with head trauma. Pathophysiological mechanisms include a rise of the pulmonary vascular hydrostatic pressure either due to sympathetic innervation with pulmonary vasoconstriction or increased left-atrial pressure following systemic arterial hypertension or an increase in pulmonary capillary permeability. In contrast to NPE, cardiac complications are frequently observed, most consistently in patients with subarachnoid hemorrhage. Typical ECG changes are repolarization abnormalities, similar to those observed in coronary heart disease, and cardiac arrhythmias. The CK-MB may be slightly elevated; echocardiographic findings show a depressed left-ventricular function. Pathological examination reveals myofibrillar necrosis. Cardiac complications are explained with overactivity of the sympathetic innervation and high levels of circulating catecholamines. For adequate treatment, close cardiac monitoring is required in all patients with acute cerebral lesions.