Ultrastructural changes in skeletal muscle mitochondria in gram-negative sepsis.

Energy metabolism during sepsis is incompletely understood, but alterations in mitochondrial structure and function appear important. We measured time-dependent changes in mitochondrial structure during sepsis using serial skeletal muscle biopsies in anesthetized baboons injected with 10(10) CFU/kg of live Escherichia coli (LD(100)). Skeletal muscle biopsies were taken before bacterial challenge (0 h controls) and at 12 h, 24 h, and death. By qualitative electron microscopy, the organelles became enlarged with distorted cristae and developed electron lucent areas within the matrix. With advanced injury the inner membrane became fragmented. Quantitative morphometric analysis showed a 50% increase in mean cristal membrane surface density by 24 h (p < .05) accompanied by a 100% increase in intermembrane space (p < .01). Matrix volume density decreased progressively (p < .01). These changes in mitochondrial ultrastructure occur within 12 h after the onset of the bacterial insult. This damage, including destruction or reorganization of both membrane and matrix proteins, is severe enough to compromise oxidative metabolism in muscle in Gram-negative sepsis.

Synthetic surfactant scavenges oxidants and protects against hyperoxic lung injury.

Injury and mortality after exposure to 100% oxygen can be diminished by surfactants that may operate by mechanisms other than those responsible for surface tension effects. We tested the hypotheses that 1) synthetic surfactant and its components function as antioxidants in vitro and 2) decrements in hyperoxic injury after treatment with a surfactant and its components are associated with decreases in oxidative stress to the lung. A synthetic surfactant (Exosurf) and its non-surface-active components tyloxapol and cetyl alcohol were incubated in an iron-containing hydroxyl radical-generating system to determine their abilities to prevent oxidation of deoxyribose. Doses of tyloxapol, cetyl alcohol, and artificial surfactant diminished the absorbance of thiobarbituric acid-reactive products of deoxyribose. Similarly, tyloxapol, cetyl alcohol, and the surfactant decreased hydroxylated products of salicylate in the same system. Rats were instilled intratracheally with saline, tyloxapol, tyloxapol plus cetyl alcohol, or artificial surfactant and immediately exposed to air or 100% oxygen. After 61 h of oxygen exposure, pleural fluid volume and wet-to-dry lung weight ratios were decreased in animals treated with surfactant and/or its components. There were also decrements in thiobarbituric acid-reactive products of lung tissue. In separate experiments, mean survival of saline-treated rats exposed to 100% oxygen was 67.3 +/- 8.1 h and > 96 h for rats given the surfactant or its components. We conclude that tyloxapol, cetyl alcohol, and Exosurf can function as antioxidants in vitro and their in vivo instillation is associated with reduction in measures of hyperoxic injury, oxidized tissue products, and mortality.

Artificial surfactant attenuates hyperoxic lung injury in primates. II. Morphometric analysis.

Diffuse lung injury from hyperoxia is accompanied by low compliance and hypoxemia with disruption of endothelial and alveolar epithelial cell layers. Because both function and content of surfactant in diffuse lung injury decrease in animals and in humans, changes in the extent of injury during continuous hyperoxia were evaluated after treatments with a protein-free surfactant in primates. Ten baboons were ventilated with 100% O2 for 96 h and five were intermittently given an aerosol of an artificial surfactant (Exosurf). Physiological and biochemical measurements of the effects of the surfactant treatment are presented in a companion paper (Y.-C. T. Huang, A. C. Sane, S. G. Simonson, T. A. Fawcett, R. E. Moon, P. J. Fracica, M. G. Menache, C. A. Piantadosi, and S. L. Young. J. Appl. Physiol. 78: 1823-1829, 1995.) After O2 exposures, lungs were fixed and processed for electron microscopy. The cellular responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. Morphometry was used to quantitate changes in lungs of animals treated with the artificial surfactant during O2 exposure and to compare them with the untreated animals. The surfactant decreased neutrophil accumulation, increased fibroblast proliferation, and decreased changes in the volume of type I epithelial cells. Surfactant-treated animals also demonstrated better preservation of endothelial cell integrity. These responses indicate ameliorating effects of the surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction. Significant interstitial inflammation and fibroblast proliferation remained, however, in surfactant-treated lungs exposed to continuous hyperoxia.

Natural surfactant and hyperoxic lung injury in primates. II. Morphometric analyses.

Diffuse lung injury is accompanied by low compliance and hypoxemia with histological evidence of endothelial and alveolar epithelial cell disruption. The histological effects of treatment of an acute diffuse lung injury with a natural surfactant product were evaluated in a primate model because surfactant function and content have been shown to be abnormal in diffuse lung injury in both animals and humans. Ten baboons were ventilated with 100% O2 for 96 h, and 5 were given an aerosol of natural porcine surfactant. Physiological and biochemical measurements of the effects of hyperoxia and surfactant treatment are presented in a companion paper. After O2 exposure, lungs were fixed and processed for quantitative electron microscopy. The responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. The hyperoxic animals treated with surfactant were compared with the untreated animals; the treatments altered neutrophil distribution, fibroblast proliferation, and changes in the volumes of type I epithelial cells and endothelial cells. Surfactant-treated animals also had decreased lamellar body volume density in type II epithelial cells and preservation of endothelial cell integrity. These changes suggest complex effects of natural surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction as well as significant interstitial inflammation and fibroblast proliferation. We conclude that natural surfactant treatment of hyperoxic lung injury in primates resulted in partial protection of epithelial and endothelial cells but also increased the accumulation of fibroblasts in the lung.

Natural surfactant and hyperoxic lung injury in primates. I. Physiology and biochemistry.

Surfactant dysfunction contributes to the pathophysiology of adult respiratory distress syndrome (ARDS), and we hypothesized that surfactant treatment would improve experimental ARDS produced by continuous exposure to hyperoxia. Twelve healthy male baboons (10-15 kg) were anesthetized, paralyzed, and mechanically ventilated with 2.5 cmH2O positive end-expiratory pressure (PEEP) for 96 h. Baboons were divided into three groups: 1) the O2 group (n = 5) received 100% O2, 2) the surfactant group (n = 5) received 100% O2 and aerosolized porcine surfactant, and 3) a control group (n = 2) was ventilated at fractional concentration of inspired O2 of 0.21 for 96 h to control for effects of anesthesia and mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion (VA/Q) distribution was measured daily by multiple inert gas elimination technique. PEEP was increased once or twice daily to 10 cmH2O for 30 min to study its effects on measurements of VA/Q. At the end of experiments, lungs were obtained for biochemical analysis. Prolonged hyperoxia resulted in progressive worsening in VA/Q, hemodynamic deterioration, severe lung edema, and altered surfactant metabolism. Surfactant administration increased disaturated phosphatidylcholine in lavage fluid but did not improve lung edema or gas exchange. In the surfactant group, however, the addition of 10 cmH2O PEEP resulted in a greater degree of shunt reduction than did 2.5 cmH2O PEEP (47 vs. 31% in the O2 group, P < 0.05). We conclude that aerosolized porcine surfactant did not prevent pulmonary O2 injury in baboons, but it potentiated the shunt-reducing effect of PEEP.

Responses of baboons to prolonged hyperoxia: physiology and qualitative pathology.

Cardiopulmonary responses to prolonged hyperoxia and their relationships to the development of lung pathology have not been fully characterized in primates. In this study, circulatory hemodynamics and pulmonary function, vascular permeability, and leukocyte sequestration were measured in male baboons after 100% O2 exposure and related to ultrastructural changes of lung injury by electron microscopy. Three groups of animals were exposed to 100% O2 in an exposure cage for 40, 66, and 80 h, respectively. A fourth group of animals was exposed in a cage for 80 h and then anesthetized and ventilated with 100% O2 for additional time. These animals were exposed for a total duration of 110 h or until death from the injury. Physiological responses to hyperoxia were characterized by decreases in total lung capacity and inspiratory capacity at 80 and 110 h. A significant increase in pulmonary leukocyte accumulation was noted by 80 h. Extravascular lung water and permeability surface-area product increased at 80 and 110 h. Cardiac output and stroke volume also decreased, and systemic vascular resistance increased after 80 and 110 h of hyperoxia. Histopathological changes were present in the lungs of all but the 40-h exposure group. Animals exposed for 66 h showed endothelial injury and neutrophil accumulation. By 80 h, animals showed endothelial cell destruction, interstitial edema, and type I cell injury. At 110 h, animals showed substantial destruction of endothelial and type I epithelial cells, exposure of alveolar basement membrane, congestion of capillaries, and substantial interstitial edema. The data indicate that histological changes by electron microscopy precede physiological responses to hyperoxic pulmonary injury in baboons by as much as 14 h and that the physiological responses to early hyperoxic injury are relatively insensitive to the pathological injury.

Artificial surfactant attenuates hyperoxic lung injury in primates. I. Physiology and biochemistry.

Prolonged exposure to O2 causes diffuse alveolar damage and surfactant dysfunction that contribute to the pathophysiology of hyperoxic lung injury. We hypothesized that exogenous surfactant would improve lung function during O2 exposure in primates. Sixteen healthy male baboons (10-15 kg) were anesthetized and mechanically ventilated for 96 h. The animals received either 100% O2 (n = 6) or 100% O2 plus aerosolized artificial surfactant (Exosurf; n = 5). A third group of animals (n = 5) was ventilated with an inspired fraction of O2 of 0.21 to control for the effects of sedation and mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion distribution (VA/Q) was measured daily using a multiple inert-gas elimination technique. Positive end-expiratory pressure was kept at 2.5 cmH2O and was intermittently raised to 10 cmH2O for 30 min to obtain additional measurements of VA/Q. After the experiments, lungs were obtained for biochemical and histological assessment of injury. O2 exposures altered hemodynamics, progressively worsened VA/Q, altered lung phospholipid composition, and produced severe lung edema. Artificial surfactant therapy significantly increased disaturated phosphatidylcholine in lavage fluid and improved intrapulmonary shunt, arterial PO2, and lung edema. Surfactant also enhanced the shunt-reducing effect of positive end-expiratory pressure. We conclude that an aerosolized protein-free surfactant decreased the progression of pulmonary O2 toxicity in baboons.

Brown recluse spider envenomation: a prospective trial of hyperbaric oxygen therapy.

OBJECTIVES: Loxosceles reclusa (brown recluse) spider bites can produce severe skin lesions that may necessitate extensive surgical repair. This study delineated the effects of hyperbaric oxygen (HBO) therapy on these lesions by performing a prospective controlled animal study. METHODS: After approval by the Institutional Animal Care and Use Committee, 41 New Zealand white rabbits received 64 intradermal injections of 73 microL of raw venom extract mixed with physiologic buffered saline (Dulbecco's solution). Control injections were made with buffer. The animals were divided into 5 groups: 1) venom and no HBO; 2) venom and 1 immediate HBO treatment (100% O2); 3) venom and immediate HBO with 10 treatments (100% O2); 4) venom and then delayed (48 hr) HBO therapy with 10 treatments (100% O2); and 5) venom and immediate hyperbaric treatment with normal inspired PO2 for 10 treatments (8.4% O2). Three animals in group 2 also received a control sodium citrate buffer injection. HBO treatments were at 2.5 atm absolute (ATA) for 90 minutes twice daily. Daily measurements were made of the lesion diameter, and skin blood flow using a laser Doppler probe. RESULTS: There was no significant effect of HBO on blood flow at the wound center or 1-2 cm from the wound center. Standard HBO significantly decreased wound diameter at 10 days (p < 0.0001; ANOVA), whereas hyperbaric treatment with normoxic gas had no effect. Histologic preparations from 2 animals in each group revealed that there were more polymorphonuclear leukocytes in the dermis of all the HBO-treated animals when compared with the venom-alone and sodium-citrate controls. CONCLUSION: HBO treatment within 48 hours of a simulated bite from L. reclusa reduces skin necrosis and results in a significantly smaller wound in this model. The mechanism appears unrelated to augmented local blood flow between treatments.

Changes in the lung after prolonged positive pressure ventilation in normal baboons.

PURPOSE: The effects of prolonged positive pressure ventilation on lung ultrastructure are not well defined in primates. This study was designed to measure cardiopulmonary and morphological responses to 4 days of positive pressure ventilation in normal baboons. MATERIALS AND METHODS: Six adult male baboons were mechanically ventilated on air for 96 hours with 2.5 cm positive end-expiratory ventilation and a tidal volume of 12 to 15 mL/kg. Physiological measurements were obtained every 12 hours and serial measurements of ventilation-perfusion (VA/Q) were performed using the multiple inert gas elimination technique. Quantitative morphotometry, lung dry-to-wet ratio, and surfactant analysis were performed at the end of the experiment. RESULTS: Cardiovascular variables, except for a small increase in mean pulmonary artery pressure at 84 and 96 hours, were not significantly affected by positive pressure ventilation. Arterial Po2 decreased, and shunt fraction increased from 0.7% of cardiac output to 5.4% (P < .01). Dispersion of perfusion increased threefold (P < .01), and dispersion of ventilation doubled (P < .01) indicating increased VA/Q mismatch mismatch. Respiratory system compliance decreased by 30% (P < .01). There was no lung edema or change in surfactant composition. Lung morphometry showed increases in polymorphonuclear cells and type II cell volume. Vacuolated endothelial cells and bare basement membrane were observed consistently. CONCLUSION: Four days of positive pressure ventilation decreases lung compliance and worsens gas exchange by increasing shunt and VA/Q mismatch in healthy baboons. These effects are accompanied by only minor ultrastructural changes and mild inflammatory responses in the lung.

Tumor necrosis factor-alpha-induced lung injury and its modulation by synthetic polynucleotide: a physiologic-morphometric analysis.

PolyI:C, a potent interferon (IFN) inducer, protects the isolated perfused lung (IPL) against platelet-activating factor (PAF)-induced injury. Because the release of PAF is stimulated by tumor necrosis factor (TNF), this study was designed to measure the effects of polyI:C on TNF-induced lung inflammation and injury. TNF (2.5 micrograms/kg) was administered to rabbits intravenously as continuous infusion over 2 h. PolyI:C was given intraperitoneally 16 h before TNF infusion. The rabbits were then anesthetized and sacrificed, and the lungs were ventilated with 20% O2 + 5% CO2 and perfused with buffer for 60 min. Lung weight gain was recorded continuously. After perfusion, lungs were inflation fixed for light and electron microscopy with morphometric analysis. Four groups of rabbit lungs were studied: (1) control; (2) polyI:C; (3) TNF, and (4) polyI:C + TNF. Lungs in the TNF group showed increased weight gain (15.4 +/- 2.4 g/h vs. 7.1 +/- 0.5 g/h in controls, p = .02) and increased volume of inflammatory cells (261% of control). These were mostly mononuclear cells (96%), primarily located in the interstitial and alveolar compartments (80%). In the polyI:C + TNF group, the weight gain of the IPL tended to be smaller (8.3 +/- 1.8 g/h, p = .08). Total inflammatory cell volume in the IPL remained elevated (330% of control), but mononuclear cells accounted for only 60% of the cell population. Most of these cells were found in the intravascular compartment (65%) implicating mononuclear cells in the early pathogenesis of TNF-induced pulmonary capillary injury in rabbits. PolyI:C, which attenuates TNF-induced injury, also modulates effects of TNF on mononuclear cell and granulocyte infiltration in the lung.

Patterns of progression and markers of lung injury in rodents and subhuman primates exposed to hyperoxia.

Exposure to high concentrations of oxygen causes injury throughout the respiratory tract. Good markers for the earliest stages of injury are not available although the course of tissue and cell responses to injury has been well characterized in a variety of animal models including rats and subhuman primates. Exposure to subacute levels of hyperoxia (40%-60% O2) causes lung injury that is difficult to detect even after exposures of up to 7 days in duration unless animals are subsequently stressed with a second form of lung injury. Rats preexposed to 40% and 60% O2 die sooner when exposed to 100% O2 than do control animals, suggesting an increased susceptibility to a second injury. Rats exposed to 60% O2 are more susceptible to development of pulmonary edema during high tidal volume mechanical ventilation, suggesting an increased susceptibility to mechanical stress. Exposures to 60% O2 may set up chronic progressive inflammatory reactions in the lung interstitium manifested by an increase in interstitial cells and matrix occurring weeks after the hyperoxic exposure. Both rats and baboons show similar responses to acute lethal exposures to hyperoxia, although the time course is more prolonged in the baboon. Both species demonstrate increased numbers of neutrophils in the lung microvasculature as one of the earliest structural evidences of lung injury. Both species demonstrate an increase in interstitial cells, quantitative evidence of injury to alveolar epithelial cells, and a significant fall in the number of capillary endothelial cells during the late phases of hyperoxic lung injury. These changes are associated with significant decreases in the total lung capacity and residual volume, increases in pulmonary artery pressure and pulmonary vascular resistance, and tachycardia. Baboons develop a 30% reduction in cardiac output after 80 h of 100% oxygen exposure because of a diminished ejection fraction. The primary difference in the progression of lung injury between species is in the time course rather than in the basic pattern of morphologic and physiologic responses.

Progressive alveolar septal injury in primates exposed to 60% oxygen for 14 days.

Moderate exposures to hyperoxia are becoming increasingly common in clinical medicine as advancing technology allows O2 to be more effectively delivered to nonintubated patients. The sensitivity of the lung to injury by a subchronic exposure to 60% O2 was investigated, using baboons and serial lobar biopsies. Because results obtained from different regions of the lung were compared, the alveolar architecture of different lung lobes of three controls was studied, with the use of electron microscopic morphometric analyses, to assess possible lobar differences in volume, surface, and numerical densities of cells and tissues. In animals exposed to 60% O2, the same techniques were used to assess specific tissue changes in the epithelial, interstitial, and endothelial compartments of the alveolar septa. All six lobes of the normal baboon lung were found to be identical with respect to alveolar architecture. Thus, for gases of low reactivity and given in high concentrations, such as O2, cross-comparisons between different lobes are appropriate. Exposure to 60% O2 was found to cause proliferation of alveolar type II epithelium, suggesting a low-grade, chronic epithelial injury. Animals allowed to recover for 8 wk in room air showed progressive changes in the alveolar interstitium, involving increases in both cells and matrix. Because sequential lobar resections were done, animals were exposed both to 60% O2 and to the effects of general anesthesia and thoracotomies. The exposure to 60% O2 for 2 wk in this experimental setting leads to an alveolar septal injury that includes a progressive interstitial fibrotic response.

Warehouse workers' headache. Carbon monoxide poisoning from propane-fueled forklifts.

We reviewed over 220 cases of acute carbon monoxide (CO) poisoning and now report on 17 patients whose poisoning occurred from the indoor use of propane-fueled forklifts. All patients in this series presented with neurologic symptoms or persistent headache and were given hyperbaric oxygen to resolve their symptomatology. We investigated the concentration of CO in the exhaust emissions of 12 propane-fueled forklifts used in various workplaces in our location. The average CO concentration in the exhaust during engine idling was 36,000 parts per million (3.6%). This value decreased slightly to 30,000 ppm (3.0%) at working engine speed. Measurements of exhaust flow indicate CO production rates of approximately 60 liters per minute at working engine speed. These quantities of CO constitute a significant occupational exposure risk to workers using propane-fueled forklifts in unventilated indoor environments.

Altered mitochondrial redox responses in gram negative septic shock in primates.

Gram negative sepsis causes changes in oxygen supply-demand relationships. We have used a primate model of hyperdynamic gram negative sepsis produced by intravenous infusion of Escherichia coli (E. coli) to evaluate sepsis-induced alterations in mitochondrial oxidation-reduction (redox) state in muscle in vivo. The redox state of cytochrome a,a3, the terminal member of the intramitochondrial respiratory chain, was assessed in the intact forearm by near-infrared (NIR) spectroscopy. The muscle NIR data were compared to routine measures of oxygen delivery (DO2) and oxygen consumption (VO2). After E. coli infusion and fluid resuscitation, DO2 and VO2 showed minimal changes through 24 hr of sepsis. In contrast, changes in cytochrome a,a3 redox state evaluated by NIR occurred within a few hours and were progressive. Mitochondrial functional responses were correlated with structural changes observed on serial muscle biopsies. Gross morphological changes in muscle mitochondria were present in some animals as early as 12 hr, and, in most animals, by 24 hr. The morphologic changes were consistent with decreases in oxidative capacity as suggested by NIR spectroscopy. The NIR data also suggest that two mechanisms are operating to explain abnormalities in oxygen metabolism and mitochondrial function in lethal sepsis. These mechanisms include an early defect in oxygen provision to mitochondria that is followed by a progressive loss in functional cytochrome a,a3 in the muscle.

Chronic osteomyelitis of the tibia: treatment with hyperbaric oxygen and autogenous microsurgical muscle transplantation.

To establish the success rate of combined therapy for tibial osteomyelitis, we reviewed all cases of this infection treated with surgery, antibiotics, and hyperbaric oxygen (HBO) between 1974 and 1991 at Duke University Medical Center. The median delay from diagnosis of osteomyelitis to initiation of HBO was 12.5 months (range, 1 month to 684 months). Of 34 patients in whom follow-up data were complete, 27 (79%) were male and 7 (21%) female, with a mean age of 37.9 years (range, 20 years to 77 years). Patients received an average of 8.3 surgical procedures (range, 2 to 19) and 35 HBO treatments (range, 6 to 99). Twenty patients (59%) received free vascularized muscle flaps as part of therapy. Actuarial analysis was used to examine the effect of free vascularized flap procedures. Of 26 patients with 24 months of follow-up after treatment, 21 (81%) remained drainage free. At 60 months and 84 months after treatment, 12 of 15 (80%) and 5 of 8 (63%), respectively, were drainage free. After more than 84 months, patients who had received muscle flaps were more likely to be drainage free than patients who had received only debridement, and this difference approached statistical significance.

VA/Q abnormalities during gram negative sepsis.

Hypoxemia in bacterial sepsis develops by mechanisms which are incompletely understood. In this study, we measured pulmonary gas exchange in eight baboons to determine the causes of hypoxemia after infusion of live Escherichia coli (1 x 10(10) CFU/kg) followed by resuscitation with intravenous fluid. VA/Q distributions were measured periodically using the multiple inert gas elimination technique until death or for a maximum of 42 h. After E. coli infusion, dispersion of perfusion (logSDq) increased rapidly and a transient rise in dead space was observed at 6 h coinciding with systemic hypotension and acidosis. The intrapulmonary shunt developed later and reached 27 +/- 6% at 24 h. PaO2 began to decrease at 12 h and correlated with increases in intrapulmonary shunt and logSDq. There was no evidence of diffusion limitation. Lung edema was mild despite aggressive fluid resuscitation. Morphometric analysis of postmortem lungs revealed dramatic intravascular accumulation of granulocytes. There were increases in arithmetic mean thicknesses of epithelium and interstitium. These data indicate that gram negative sepsis with fluid resuscitation causes progressive hypoxemia, primarily due to the development of intrapulmonary shunt and very low VA/Q regions in the lung. The VA/Q abnormalities occur early and likely reflect ongoing cellular responses in pulmonary vasculature and smaller airways in sepsis.

Eicosanoids and the hemodynamic course of live Escherichia coli-induced sepsis in baboons.

Time-related changes in eicosanoid release and hemodynamic parameters were characterized in baboons during the early development of sepsis induced by intravenous (i.v.) infusion of live Escherichia coli (4 x 10(10) organisms/kg) in baboons. Plasma levels of thromboxane B2 (TxB2), a stable metabolite of thromboxane A2 (TxA2), rose rapidly in arterial, venous, and pulmonary arterial blood after infusion of live E. coli, attaining maximal increases at 30 min and returning to control values by 60 min. In contrast, plasma concentrations of 6-keto-PGF1 alpha rose slowly after infusion, reaching peak concentrations at 120 min, then slowly returned to control values between 4 and 5 hr after infusion of live E. coli. Hemodynamic values remained stable during the first 2 hr after infusion, although early changes in cellular energy metabolism and incipient hemodynamic failure were inferred from pyrexia, tachycardia, and metabolic acidosis. At 3 hr, signs of further hemodynamic compromise developed, including increased venous PCO2, reduced pulmonary capillary wedge pressure, and reduced stroke volume, followed by gradual increases in systemic and pulmonary vascular resistance. These factors coincided with progressive reductions in cardiac output and deteriorating circulatory efficiency. The time course of events following infusion of live E. coli indicates that alterations in cellular energy provision occurred early (within 1 hr), whereas central hemodynamic parameters decayed much more slowly. Additionally, TxA2 and PGI2 appear related to the early events in the development of sepsis as their release preceded cardiocirculatory failure.